Recent publications on Residual Risk

This recent report from the National Health and Nutrition Examination Survey (NHANES) shows that previous improvements in the management of blood pressure and non–high-density lipoprotein cholesterol (non-HDL-C) control has stagnated. Risk factor control over the period 1999 to 2018 was evaluated in 55,021 adults (mean age 47 years, 48.0% men), including 5717 with atherosclerotic cardiovascular disease (ASCVD). Risk factor control was defined as hemoglobin A1c <7%, blood pressure <140/90mmHg, and non–HDL-C <100mg/dL.
 
While ASCVD prevalence was stable over this period (between 7.3% and 8.9%), among these patients the prevalence of diabetes almost doubled (from 21.4% to 38.0%). Additionally, the rate of improvement in risk factor control stalled; notably the prevalence of non-HDL-C control more than doubled between 1999 and 2006 (from 7.1% to 15.7%) but subsequently levelled off, with 22.5% in 2007-2010, 27.3% in 2011-2014, and 30.9% in 2015-2018 achieving non-HDL-C <100 mg/dL. Similar trends were observed for blood pressure and glycaemic control. This decline in risk factor control was exacerbated by increases in obesity and heavy alcohol consumption. Moreover, the study identified disparities in risk factor control between men and women, different ethnicities, and different socioeconomic groups. In particular, women with ASCVD were less likely to receive statin therapy and less likely to have all risk factors controlled. Taken together, the findings from this latest NHANES survey highlight the need for tailored interventions to improve cardiovascular health across all demographic groups.

Impaired cholesterol efflux is associated with higher cardiovascular event rates in patients with stable coronary artery disease and recent myocardial infarction (MI). These findings provide a rationale for investigating whether enhancing cholesterol efflux with CSL-112, a novel intravenous formulation of apolipoprotein (apo)A-I purified from human plasma, can reduce the rate of recurrent major adverse cardiovascular events. This was the aim of the AEGIS-11 trial, a phase 3, multicentre, double-blind, randomized, placebo-controlled, event-driven, parallel group trial. In total, 18,219 high-risk acute MI patients were randomized to treatment with 4 weekly infusions of CSL-112 (6 g) or placebo. The primary endpoint was first occurrence of cardiovascular death, MI or stroke at 90 days, with key secondary endpoints assessed at 180 and 365 days.
 
Treatment with CSL-112 was not associated with a significant reduction in the primary endpoint at 90 days (4.9% in the CSL 112 group versus 5.2% in the placebo group, Hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.81-1.05, p=0.24), with similar findings at 180 and 365 days (HR 0.91, 95% CI: 0.81-1.01 and HR 0.93, 95%CI: 0.85-1.02, respectively). There were suggestions for an effect of CSL-112 on MI in type 1 MI and type 4b MI (MI due to stent thrombosis). Exploratory analyses reported at the 2024 Scientific Sessions of the American College of Cardiology suggest that patients with baseline low-density lipoprotein cholesterol (LDL-C) levels ≥100 mg/dL had a lower rate of the primary endpoint with CSL-112 at 90 days compared with those in the placebo group (HR 0.69, 95%CI 0.53-0.90, p=0.007). There was, however, no benefit of CSL-112 infusion in the subgroup of patients with baseline LDL-C <100 mg/dL. While there is a plausible biological rationale for apoA-I infusion benefitting hyperlipidemic patients, this requires prospective validation.

Cardiometabolic diseases, which include type 2 diabetes, ischemic heart disease, and stroke, are the primary causes of premature mortality worldwide. Cardiometabolic multimorbidity exacerbates mortality risk and has a substantial adverse impact on patient quality of life. Higher levels of triglyceride (TG)-rich lipoproteins have been implicated as a risk factor for this multimorbidity. Consequently, this study utilised Mendelian randomization to investigate the associations between remnant cholesterol, TG and the risks of cardiometabolic multimorbidity in over 300,000 adults in the UK Biobank, free of cardiometabolic disease at baseline. The study used 13 biologically relevant single nucleotide polymorphisms as the genetic instruments to derive a weighted genetics risk score.
 
During a median follow-up of 12.5 years, there were 39,084 new-onset first cardiometabolic disease cases, and 3,794 subsequently progressed to cardiometabolic multimorbidity. Elevated remnant cholesterol and elevated TG were each significantly associated with higher risks of cardiometabolic multimorbidity, in particular the risk of progression from ischemic heart disease to ischemic heart disease-type 2 diabetes multimorbidity. This was supported by Mendelian randomization analyses, which provided genetic evidence that higher levels of remnant cholesterol and TG were causally related to higher risks of cardiometabolic multimorbidity. Notably, the risk of ischemic heart disease-type 2 diabetes multimorbidity causally increased by 26% and 24% for each 1.0 mmol/L increment in TG and 0.29 mmol/L increment in remnant cholesterol, respectively.
 
These findings therefore support a role for TG-rich lipoproteins as therapeutic targets for the prevention and treatment of cardiometabolic disease.

Obicetrapib, the latest cholesteryl ester transfer protein (CETP) inhibitor in development, has shown favourable efficacy either as monotherapy or in combination with ezetimibe plus statin treatment, in clinical trials predominantly conducted in Northern European/Caucasian participants. This latest trial addressed the gap in evidence in patients in the Asian-Pacific region.
 
This double-blind, randomized, placebo-controlled phase 2 trial evaluated obicetrapib 2.5, 5, and 10 mg administered daily for 8 weeks in Japanese dyslipidemic patients on stable statin therapy (atorvastatin 10 or 20 mg daily or rosuvastatin 5 or 10 mg daily). Lipid inclusion criteria included low-density lipoprotein cholesterol (LDL-C) ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL, and triglycerides (TG) ＜400 mg/dL. Randomization was stratified according to screening LDL-C level (either ≥ 100 or ＜100 mg/dL).
 
In total, the study randomized 102 patients (mean age 64.8 years, 72% male); two-thirds of patients had LDL-C levels ≥ 100 mg/dL. All doses of obicetrapib significantly lowered median LDL-C, apolipoprotein (apo) B, and non-HDL-C levels, and raised HDL-C levels. At 8 weeks, 10 mg obicetrapib was associated with median reductions of 45.8% in LDL-C, 29.7% in apoB, and 37.0% in non-HDL-C, together with 159% increase in HDL-C (all p<0.0001 versus placebo). The incidence of treatment-emergent adverse events was similar in the placebo and obicetrapib dose groups, and all events were of mild or moderate intensity. Overall, the results with obicetrapib in Japanese patients observed in this trial were similar to those reported in trials conducted in predominantly Caucasian populations, implying that race or ethnicity does not modify the lipid-modifying efficacy of obicetrapib.

Evidence supports elevated lipoprotein(a) [Lp(a)] as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, as well as a contributor to residual cardiovascular risk. Therefore, novel treatments that are effective in lowering elevated Lp(a) levels are a focus of clinical development. In this phase II trial, the siRNA zerlasiran produced sustained reductions in Lp(a) levels in healthy subjects and patients with established ASCVD and was well tolerated.
 
The trial incorporated 32 healthy subjects (single doses of zerlasiran 300 mg, 600 mg or placebo) and 36 patients with ASCVD (2 doses of placebo, zerlasiran 200 mg given every 4 weeks or 300 mg or 450 mg given every 8 weeks). All subjects had elevated Lp(a) at baseline (≥150 nmol/L); median baseline Lp(a) in the multiple dosing cohort was 288 (interquartile range [IQR] 199-352) nmol/L. In the single dose cohort, median changes in Lp(a) at 365 days were an increase of 14% for the placebo group, versus reduction of 30% with 300 mg zerlasiran and 29% for the 600 mg dose group. In the multiple dose cohort, the maximal median percent change after 2 doses was an increase of 7% in the placebo group, versus reductions of 97% for 200 mg zerlasiran given every 4 weeks, and 98% and 99% for 300 mg or 450 mg zerlasiran given every 8 weeks, respectively. Reduction in Lp(a) concentration was sustained 201 days after dosing, with reductions of 60% reported with the 4-weekly regimen, and 90% and 89%, respectively with the 300 mg and 450 mg 8-weekly regimens. Treatment with zerlasiran was well tolerated. These findings support further development of this novel therapeutic.

Diabetic dyslipidaemia, typically characterised by the combination of elevated triglycerides (TG) and low plasma levels of high-density lipoprotein cholesterol (HDL-C), is a key driver of cardiovascular risk even if low-density lipoprotein cholesterol (LDL-C) is well controlled. This report from the National Health and Nutrition Examination Survey (NHANES) highlights the heterogeneous profile of dyslipidaemia in diabetes patients.
 
The study analysed data from NHANES 2011-2016 in adults (>18 years) with and without diabetes. Low HDL-C was defined as <40 mg/dL in males and <50 mg/dL in females, and elevated TG were defined as >150 mg/dL. Overall, the study population comprised 7574 individuals, 3679 men and 3895 women, of whom 2048 (27%) were diagnosed with diabetes. The combination of elevated TG and low HDL-C was present in 19.3% of the diabetes group (versus 8.8% in those without diabetes). However, there was heterogeneity among the dyslipidaemia of the diabetes group; 14.1% only had elevated TG, 16.8% only had low HDL-C, and almost half had neither lipid abnormality. When the prevalence of diabetic dyslipidaemia (elevated TG and low HDL-C) was investigated by age group, there was a trend for decreasing prevalence in those aged over 30 years, although the highest prevalence (26.9%) was in individuals with diabetes aged 30-40 years. In contrast, in the group without diabetes, the proportions with elevated TG, low HDL-C, and both lipid abnormalities were similar across the different age groups.
 
The take home message from this report is that the combination of elevated TG and low HDL-C is common among individuals with diabetes, affecting about one in five of this patient group. Evidence that the prevalence of this dyslipidaemia was highest in younger individuals (30-40 years), underlines the need for a renewed focus on the management of dyslipidaemia in young people with diabetes.

Findings from the BiomarCaRE project show that residual inflammatory risk influences the association of lipoprotein(a) [Lp(a)] with risk for recurrent coronary heart disease (CHD) events.
 
Data were analysed from 71,678 patients (6,017 with established CHD at baseline) included in 8 European prospective population-based cohort studies with a median follow-up of up to 13.8 years. The aim was to investigate whether high-sensitive C-reactive protein (hsCRP) modulated the association between Lp(a) and CHD in the general population. Among individuals without CHD at baseline, Lp(a) was positively associated with risk for CHD events and this association was not influenced by hsCRP level; the odds ratio (95% confidence interval) for the highest versus lowest Lp(a) quintile was 1.45 (1.23-1.72) for individuals with hsCRP <2 mg/L and 1.48 (1.23-1.78) for those with hsCRP levels ≥ 2 mg/L. In contrast, among individuals with pre-existing CHD, the association between Lp(a) and CHD risk was only evident if hsCRP levels were ≥ 2 mg/L (odds ratio 1.34, 95% CI 1.03-1.76), with no clear association among individuals with lower hsCRP levels.
 
In conclusion, the findings from this report indicate that residual inflammatory risk modulates Lp(a)-related risk for recurrent CHD events, implying that this may be a factor to consider when selecting patients for novel Lp(a)-targeted therapies.

Results from the MESA (Multi-Ethnic Study of Atherosclerosis) study show that elevated remnant cholesterol was associated with an increased risk of aortic valve calcium (AVC) progression irrespective of traditional cardiovascular risk factors. This association was also evident in individuals with optimal levels of low-density lipoprotein cholesterol (LDL-C).
 
Progression of AVC is integral to the complex development of aortic valve disease, the third leading cardiovascular disease in the Western world. To date, there is an unmet clinical need for treatments that prevent or delay the progression of AVC, underlying the need to identify risk factors that may offer future therapeutic potential. Given evidence that elevated remnant cholesterol is associated with coronary artery disease (1), this analysis from MESA aimed to investigate the relationship between remnant cholesterol and AVC progression, based on data from 5597 individuals (mean age 61.8 years, 47.5% men) without atherosclerotic cardiovascular disease at baseline. Remnant cholesterol was calculated as total cholesterol minus high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).
 
Over a follow-up of 2.4±0.9 years, AVC progression was evident in 568 (10.1%) individuals. When categorised by remnant cholesterol quartiles, the percentage of AVC progression increased with increasing quartiles. Using Cox regression analyses adjusted for traditional cardiovascular risk factors, individuals with elevated remnant cholesterol were at increased risk for AVC progression (hazard ratio [95% confidence interval] comparing the second, third, and fourth quartiles versus first quartile for remnant cholesterol 1.195 [0.925–1.545], 1.322 [1.028–1.701] and 1.546 [1.188–2.012], respectively). Moreover, the study showed that individuals with high remnant cholesterol levels, but low LDL-C were at increased risk for AVC progression compared with those with both low remnant cholesterol and low LDL-C (hazard ratio 1.528 [95% CI 1.201–1.943]). In conclusion, the study identifies elevated remnant cholesterol as a residual risk factor for AVC progression, independent of traditional cardiovascular risk factors. Based on these findings, further investigation of the role of targeted remnant cholesterol reduction in primary prevention is merited.

This recent review highlights the high long-term residual cardiovascular risk that persists in secondary prevention patients treated with statins, and underlines the need for prompt, effective therapy to manage this. Among published studies, more than 40% of patients experience recurrent cardiovascular events over 10 years, and nearly one in five with cerebrovascular disease experience recurrent stroke over this time. This was despite well managed low-density lipoprotein cholesterol levels. This review highlights the urgent need for prompt action with additional therapies, targeting both lipids and non-lipid risk factors to reduce this high residual risk. This conclusion is very much aligned with the mission of the Residual Risk Reduction Initiative (R3i).

Stroke is the primary cause of disability and vascular death worldwide, conferring a high economic burden. Moreover, results from the Global Burden of Disease 2019 study highlight an increasing burden of ischaemic stroke in Asia for the future.
 
Age-standardised incidence rates for ischaemic stroke showed a gradual upward trend over the period 1990-2019, with the burden of disease more concentrated on older age groups, particularly those over 65 years. Notably, East Asia had the highest burden of ischaemic stroke compared to other regions in Asia. As more than half of the world population lives in Asia, this study has important health and socio-economic implications. Without targeted implementation of population-wide primary preventive strategies, the burden of ischaemic stroke is likely to escalate in the future.

Results from this study from Taiwan showed that prediabetes was associated with an increased risk of major adverse limb events (MALE) and major adverse cardiovascular events (MACE), notably peripheral artery disease (PAD), compared with individuals with normal glycaemia.
 
This was a longitudinal retrospective cohort analysis of electronic health records from 36,950 patients aged at least 45 years who were treated at a tertiary medical facility in Taiwan between 2014 and 2019. Patients with diabetes, or a previous history of PAD, critical limb ischaemia, amputation, acute myocardial infarction, or stroke were excluded. Prediabetes and normal glucose regulation was defined in accordance with the 2023 American Diabetes Association guidelines (prediabetes: fasting plasma glucose 100–125 mg/dL (5.6–6.9 mmol/L), 2-hour plasma glucose 140 −199 mg/dL (7.8–11.0 mmol/L) during a 75 g oral glucose tolerance test, or an HbA1c level within 5.7–6.4% (39–47 mmol/mol). In total, the study included 36,950 individuals, 19,196 with normal glucose regulation and 17,754 with prediabetes. Patients with prediabetes were older (65.2±10.7 years vs. 62.9±10.2 years, p<0.001), more likely to be men (48.9% vs. 40.7%, p<0.001), had higher body mass index and more comorbidities (hypertension, hyperlipidaemia, heart failure, atrial fibrillation, coronary artery disease, and chronic obstructive pulmonary disease) than those with normal glucose regulation.
 
Over a median duration of follow-up of 46.4 months, there were 1324 MALE and 1276 MACE. The incidence rate (per 1,000 person-years) of both events was higher in the cohort with prediabetes than normal glucose regulation (MALE: 10.8 versus was 9.53, MACE: 11.99 versus 7.56). Kaplan-Meier analysis confirmed a significant increase in MALE (p=0.024) and MACE (p<0.001) among individuals with prediabetes versus those with normal glucose regulation. The onset of complications was also evident at an earlier prediabetes trajectory. Taken together, these findings underline the need for intensive lifestyle modification to improve prognosis in patients with prediabetes.

In this report from the Côte d’Or MI observatory (RICO) registry, elevated triglycerides were common and associated with a risk of recurrent events in acute myocardial infarction (AMI), beyond traditional prognostic factors.
 
This large regional registry analysed data from 10,667 patients hospitalised with an AMI, who were categorised by baseline triglycerides (≤ 200 mg/dL or >200 mg/dL). Overall, 17.7% (n=1886) had elevated triglycerides; these patients were on average 10 years younger, had a higher prevalence of obesity and diabetes, and were more likely to smoke than those with lower triglyceride levels.
 
At 1-year follow-up, the incidence of combined ischaemic events (percutaneous coronary intervention, coronary artery bypass graft) including recurrent ischaemic events (unstable angina, recurrent MI) and stroke was higher in the group with high triglycerides (11.2% vs 9.1% in the group with low triglycerides, p≤0.004). Multivariant analysis showed that a high triglyceride level was one of the strongest predictors of combined ischaemic events (odds ratio 1.356, 95% confidence interval 1.095-1.679), p=0.005), comparable with the risk associated with diabetes.
 
In conclusion, results from this real-life large registry show the high prevalence (almost one in five) of elevated triglycerides among patients with an AMI, which was associated with an increased residual risk of recurrent ischaemic events.

A high level of serum remnant cholesterol was associated with increased risk of premature mortality and reduced life expectancy, according to this report from the UK Biobank. These findings support incorporating remnant cholesterol in risk stratification to improve cardiovascular disease prevention.
 
This study evaluated data from 428,804 subjects from the UK Biobank, with a median follow-up of 12.1 years (interquartile range 11.0 to 13.0 years). Subjects were categorised into three groups based on remnant cholesterol using a population percentile approach as low (mean 0.34 mmol/L), moderate (0.53 mmol/L), and high (1.02 mmol/L). Multivariable Cox proportional hazards models were used to investigate the relationship between remnant cholesterol and the risk of premature mortality (i.e. death before age 75 years), and life table methods were used to estimate life expectancy.
 
Over the follow-up period, there were 23,693 all-cause premature deaths (4.83 events per 1,000 person-years). Compared with low remnant cholesterol group, individuals with moderate remnant cholesterol levels had a 9% increased risk of all-cause premature mortality (hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.05 - 1.14), and those with high levels had an 11% higher risk (HR 1.11, 95% CI 1.07 - 1.16). At the age of 50 years, high remnant cholesterol was associated with an average 2.2 lower years of life expectancy for females, and an average 0.1 lower years of life expectancy for males when compared with the low remnant cholesterol group. These findings strengthen the case for considering remnant cholesterol, in addition to traditional risk factors, in risk stratification in cardiovascular disease prevention.

Remnant cholesterol may help to predict liver stiffness in individuals with nonalcoholic fatty liver disease (NAFLD), according to this analysis from the US National Health and Nutrition Examination Survey (NHANES).
 
Accumulating evidence supports remnant cholesterol as a likely causal risk factor for atherosclerotic disease, and potentially with increased severity of NAFLD, with higher serum levels of remnant cholesterol associated with more severe hepatic steatosis. Measurement of liver stiffness offers a non-invasive approach to estimate liver fibrosis severity associated with NAFLD, and thus to investigate the role of remnant cholesterol in the progression of NAFLD. This cross-sectional study evaluated data from 2,800 NAFLD patients enrolled in NHANES, using logistic regression to evaluate the relationship between serum remnant cholesterol levels and liver stiffness. The study showed a positive, independent association between remnant cholesterol levels and the extent of liver stiffness, with odds ratios of 1.02 for liver steatosis (p = 0.014) and 1.02 for liver fibrosis (p = 0.014). Optimal remnant cholesterol thresholds predictive of liver steatosis were 17.25 mg/dL for men and 15.25 mg/dL for women. These findings therefore provide further support for the role of remnant cholesterol in metabolic disorders, notably NAFLD, and may help to drive innovative approaches for diagnosing and treating NAFLD.

Lipoprotein(a) [Lp(a)], a risk factor for cardiovascular outcomes, is measured either using immunoassays reporting mass or molar concentration, or with a reference measurement system using mass spectrometry. However, it is not known whether the association between Lp(a) concentration and cardiovascular events in high-risk patients, such as those with acute coronary syndrome (ACS), differs with these different ascertainment methods. This analysis investigated this question using data from the ODYSSEY OUTCOMES trial in ACS patients.
 
Researchers compared the risk of major adverse cardiovascular events (MACE) in the placebo group and the reduction in risk of MACE with alirocumab according to baseline Lp(a) concentration measured by different immunoassays (Siemens n-latex nephelometric immunoassay (mass, mg/dL) or Roche tina-quant® turbidimetric immunoassay (molar, nmol/L)), and a non-commercial mass spectrometry-based test (nmol/L).
 
The association of Lp(a) concentration with risk of MACE in the placebo group was almost identical with each test and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol. Furthermore, the predicted alirocumab treatment effect was also nearly identical for each of the three tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles. The authors concluded that these three methods for assessment of Lp(a) were similarly prognostic for MACE in the placebo group, and predictive of reduction in MACE risk with alirocumab in ACS patients.

In a study from China, remnant cholesterol levels were associated with the severity of chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients, even if lipids were well controlled.
 
In total, 3,383 T2DM patients were included in this cross-sectional study. CKD severity was defined as none (2,587 patients, 76.5%), moderate (520 patients, 15.4%), severe (189 patients, or 5.6%), and very severe (87 patients or 2.5%), based on the urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Multivariate logistic regression and multivariate ordinal logistic regression analysis were used to investigate the association between remnant cholesterol and CKD.
 
After adjusting for confounding factors, CKD severity increased for each one-unit increase in log-transformed remnant cholesterol level (odds ratio 1.76, 95% confidence interval 1.52-2.05). The association between remnant cholesterol and CKD severity was present even in patients with lipid levels in the normal range.

In a post hoc analysis, changes in eicosapentaenoic acid (EPA) levels and the ratio of EPA to arachidonic acid (AA) were identified as the most likely mediators of the 25% reduction in first major adverse cardiovascular events (MACE) reported with icosapent ethyl in the REDUCE-IT study.
 
This analysis evaluated 20 biomarkers as possible mediators of the reduction in MACE observed in REDUCE-IT. Compared with placebo, univariate analysis showed that EPA changes and the EPA:AA ratio mediated 57.0% and 64.8%, respectively, of the reduction in risk of MACE with icosapent ethyl. Moreover, in multivariate analyses, increasing EPA levels and decreases in AA and triglycerides together mediated 77.1-78.9% of the effect of active treatment on MACE risk. The findings, although post hoc, provide further insight into the beneficial effects observed with icosapent ethyl in REDUCE-IT.

Another potential target for reducing triglycerides and atherogenic lipoproteins- apolipoprotein C3 (apoC3)- was the focus of preclinical studies with the anti-APOC3 GalNAc-siRNA agent, RBD5044. In rhesus monkeys with spontaneous hypertriglyceridaemia, apoC3 was reduced by 61.2%, with more than halving of plasma triglycerides. A second study with RBD5044 in humanized APOC3 transgenic mice showed a maximum inhibition of apoC3 of 90% and about 90% reduction in plasma triglycerides, with reduction of 41.6% for APOC3 and 49.4% for plasma triglycerides persisting 9 weeks after last dosing with RBD5044 3 mg/kg. These preclinical findings provide a basis for phase 1 clinical development.

Phase I data were reported for ARO-ANG3, a novel RNA interference (RNAi) therapy that targets angiopoietin-like protein 3 (ANGPTL3). This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat doses of this agent in healthy volunteers and in patients with hepatic steatosis.
 
In healthy subjects, single ascending dosing (SAD, n=40) and multiple ascending dosing (MAD, n=12) showed that ARO-ANG3 (100 mg, 200 mg or 300 mg) was generally well tolerated, with similar frequencies of treatment-emergent adverse events (TEAEs) in active and placebo groups. Dose-related reductions in ANGPTL3 of up to 75% over 12 weeks in the SAD cohort, and up to 93% across 16 weeks in the MAD study were reported. Exploratory analyses showed reductions in plasma triglycerides of up to 50% and 70%, respectively, together with reductions of up to 20% in low-density lipoprotein cholesterol and up to 40% in apolipoprotein B.
 
In subjects with hepatic steatosis on multiple doses of ARO-ANG3 200 mg or placebo, 22 TEAEs were reported for 5/6 patients on ARO-ANG3 versus 3/3 on placebo. All were of mild to moderate intensity and did not necessitate treatment discontinuation. Overall, ARO-ANG3 200 mg reduced ANGPTL3 by a mean of 85.3% (versus 10.7% with placebo) and triglycerides by a median 44.1% (versus 47.1% with placebo).
 
These early-phase data support ANGPTL3 as a potential therapeutic target for reducing residual cardiovascular risk in patients with dyslipidaemia and provide a basis for further clinical development with ARO-ANG3.

In the ORION-8 open-label extension trial, twice-yearly dosing with inclisiran adjunctive to statin therapy provided consistent low-density lipoprotein cholesterol (LDL-C) reduction beyond 6 years in patients with atherosclerotic cardiovascular disease (ASCVD), increased risk of ASCVD or heterozygous familial hypercholesterolaemia (HeFH).
 
ORION-8 is a 3-year open-label extension of the placebo-controlled 18-month Phase III trials ORION-9, ORION-10, and ORION-11 and the four-year Phase II ORION-3 trial, with a total exposure of more than 8,500 patient-years. The study evaluated the long-term safety, efficacy and tolerability of inclisiran in 3,274 patients; 2,446 patients completed the trial to Day 1080 (3 years). The primary endpoint of the study was the proportion of patients achieving pre-specified risk-based LDL-C targets at the end of the study, either Day 1080 or 90 days after the last injection.
 
Overall, nearly 80% (78.4%, 95% confidence interval [CI] 76.8% to 80.0%) of patients reached their pre-specified LDL-C targets, with LDL-C levels reduced on average by approximately 50% (49.4%, 95% CI 48.3% to 50.4%). These data provide further evidence of the durability of LDL-C lowering with inclisiran.
 
ORION-8 is part of VictORION, a large worldwide clinical trial program which is enrolling over 60,000 patients, across more than 50 countries and more than 30 clinical trials.

In survivors of spontaneous intracerebral haemorrhage (ICH), statin use was associated with a lower risk of any stroke, including ischaemic stroke, and did not increase the risk of recurrent ICH. Using data from the Danish Stroke Registry, researchers identified patients admitted to hospital in Denmark with a first-ever ICH over the period January 2003 to-December 2021, aged ≥50-years who survived more than 30-days. Over follow-up to August 2022, 1,959 patients had any stroke (1,073 with ischaemic stroke, and 984 with recurrent ICH). When matched to appropriate controls, statin use was associated with a lower risk of any stroke (cases 38.6% versus controls 41.1%; adjusted odds ratio 0.88; 95% confidence interval [CI] 0.78-0.99) and ischaemic stroke (cases 39.8% versus controls 41.8%, adjusted odds ratio 0.79; 95% CI 0.67-0.92), but was not associated with recurrent ICH risk (cases 39.1% versus controls 40.8%, adjusted odds ratio 1.05; 95%CI, 0.88-1.24). These data provide reassurance on the use of statins in ICH survivors to prevent recurrent stroke.

Four new European Society of Cardiology Guidelines were presented, covering acute coronary syndromes, endocarditis, cardiovascular disease in diabetes, and cardiomyopathies. In the guideline on cardiovascular disease in diabetes, recommendations focused on reducing cardiovascular risk in patients with diabetes mellitus. With evidence that 25-40% of patients with cardiovascular disease have undetected diabetes, these guidelines recommend systematic screening for diabetes in all patients with cardiovascular disease.
The guideline introduces a novel score, SCORE2-Diabetes, to estimate the 10-year risk of fatal and non-fatal myocardial infarction and stroke in patients with type 2 diabetes. This score integrates information on conventional cardiovascular risk factors (age, smoking, blood pressure, cholesterol) with diabetes-specific information (age at diagnosis, blood glucose, kidney function) to classify patients as low, moderate, high or very high risk.
In addition to lifestyle recommendations, the guideline now recommends SGLT2 inhibitors and/or GLP-1 receptor agonists to reduce cardiovascular risk in all patients with diabetes and cardiovascular disease, independent of glucose control and concomitant glucose-lowering medication and, in addition to standard of care, antiplatelet, antihypertensive and lipid-lowering therapies.

In the most comprehensive analysis since 2006, cardiovascular disease (CVD) cost the European Union (EU) an estimated €282 billion in 2021, which represents more than the entire EU budget. Importantly, health and long-term care accounted for over half of these costs (€155 billion). The analysis was a collaboration between the European Society of Cardiology and the University of Oxford, UK.
In a breakdown of costs, healthcare accounted for €130 billion (46%), social care €25 billion (9%), and informal care €79 billion (28%). Hospital care was the main contributor to health and social care costs, accounting for €79 billion or 51% of CVD-related care costs.
This updated analysis not only underlines the growing economic burden associated with CVD in the EU, but also disparities between EU countries in healthcare expenditure.

Valve replacement surgery is the first‐line therapy for patients with valvular heart disease. Bioprosthetic heart valves are increasingly becoming the treatment of choice, given that they are less thrombogenic and have more favourable haemodynamic properties compared with mechanical heart valves. Structural valve degeneration is, however, a complication of bioprosthetic valves, with the underlying mechanisms not fully understood.
 
There is extensive evidence to support an observational and genetic causal association between elevated remnant cholesterol, the cholesterol contained in triglyceride-rich lipoproteins, and atherosclerotic cardiovascular disease outcomes, including aortic stenosis. The current study investigated the impact of elevated remnant cholesterol levels on prosthetic valve degeneration, given that this process may share similar lipid-mediated pathways with aortic stenosis.
 
In total, 203 patients with a median of 7.0 years (interquartile range: 5.1-9.2) after surgical aortic valve replacement were included in the study. Patients in the top tertile for remnant cholesterol levels (>23.7 mg/dL), showed increased progression rates for bioprosthetic aortic valve degeneration compared with those in the lower tertiles (p=0.008). In addition, elevated remnant cholesterol >23.7 mg/dL was independently associated with increased mortality or re-intervention (hazard ratio 1.98; 95% confidence interval 1.31-2.99; p = 0.001). These findings suggest a role for remnant cholesterol in the underlying processes involved in bioprosthetic valve degeneration.

While both pemafibrate and sodium glucose cotransporter-2 (SGLT2) inhibition can decrease serum transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD), type 2 diabetes and dyslipidaemia, the effect of combined treatment is uncertain. Results from this pilot study showed that treatment with pemafibrate for one year improved markers of hepatic inflammation, function, and fibrosis in NAFLD patients in whom long-term SGLT2 inhibitor therapy had previously proved inadequate in normalizing transaminase levels.
 
This was a two-centre retrospective observational study in nine NAFLD patients treated with pemafibrate who were refractory to previous SGLT2 inhibitor therapy, i.e., with sustained alanine transaminase (ALT) elevation > 30 U/L for more than 12 months before pemafibrate. Two patients were subsequently excluded due to loss to follow-up. The seven patients were all male with a median age of 49 years, and the median interval between starting an SGLT2 inhibitor and pemafibrate was 845 days. Over one year, pemafibrate significantly improved aspartate transaminase (AST), ALT, γ-glutamyl transpeptidase (γ-GTP), triglycerides, total bilirubin, and serum albumin without any significant change in weight. In three patients, ALT normalized over the course of the study (≤30 IU/L). Pemafibrate also significantly improved markers of hepatic function and fibrosis.
 
Taken together, these results suggest that the combination of pemafibrate and an SGLT2 inhibitor may be useful for patients with NAFLD, type 2 diabetes and dyslipidaemia. This approach merits further study in a phase 2 trial.

The SUSTAIN 6 and PIONEER 6 trials showed cardiovascular benefit with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist in type 2 diabetes patients across the continuum of baseline cardiovascular risk. Cardiovascular and all-cause mortality were also significantly reduced by oral semaglutide in PIONEER 6. Because GLP-1 receptor agonists have been shown to have a modest effect on plasma triglycerides (TGs), this post hoc analysis of these studies investigated whether semaglutide reduced the risk of major adverse cardiovascular events (MACE) in type 2 diabetes patients across baseline TG levels, as well as the change in plasma TGs over time on treatment.
 
In total, 6417 patients from both trials with baseline TG measurements were included in the analysis; 3191 (49.7%) had TG levels ≤ 151 (low), 1459 (22.7%) had TG levels > 151-≤ 205 mg/dL (medium) and 1767 (27.5%) had TG levels > 205 mg/dL (high). Median (range) baseline TG levels were 108.6 (10.7-151.3), 175.3 (152.2-204.7) and 272.3 (205.6-3378) mg/dL for the low, medium and high baseline TG subgroups, respectively.
 
The incidence of MACE increased with increasing baseline TGs. Treatment with semaglutide reduced the risk of MACE versus placebo across all TG groups, with significant reduction only in the group with low plasma TGs at baseline. In both trials, semaglutide reduced plasma TGs from baseline to week 104 (by 14.8 mg/dL versus 5.4 mg/dL with placebo, p = 0.024 in SUSTAIN-6, and by 16.4 mg/dL versus 6.5 mg/dL with placebo, p=0.005 in PIONEER-6). Thus, the authors concluded that despite the caveats of post hoc analyses, semaglutide significantly reduced TG levels from baseline. However, the reduction in risk of first MACE versus placebo occurred irrespective of TG subgroups.

Plasma proteomics has gained focus in the search for targeted therapies, enabling better patient stratification and prediction of treatment response, key tenets of personalized medicine. The clinical benefit of using this approach as a tool to guide-specific interventions has, however, yet to be established.  
  Recent analyses have indicated that the low-density lipoprotein cholesterol (LDL-C)-lowering response to PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition also associates with reduction in both cellular and arterial plaque inflammation, despite no change in high-sensitivity C-reactive protein levels. The current study investigated potential anti-inflammatory effects of PCSK9 inhibition using proteomic profiling data from 173 patients included in the SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events)-1 and 2 studies with bococizumab. Patients with <15% LDL-C reduction after 12 months or missing follow-up data were excluded.  
  Among patients on bococizumab, proteomic analyses showed selective reduction of PCSK9 plasma levels without any change in 30 inflammatory proteins, implying that the clinical benefits of PCSK9 inhibition solely relate to lipid-lowering pathways. Thus, despite the limited sample size, findings from this study provide further justification for the combination of targeted anti-inflammatory therapies on top of LDL-C lowering therapy to address residual inflammatory risk in high-risk patients.

Heart failure is an increasing challenge, due to increasingly aging populations worldwide. Beyond established lipid risk factors, accumulating evidence implicates elevated remnant cholesterol with increased risk of ischemic heart disease, although whether it is also an indicator for all-cause mortality in patients with heart failure is uncertain.
 
This Chinese study addressed this question using data from 2,823 patients (mean age 56.8 years, 71% men, 28% with heart failure with preserved ejection fraction) hospitalised for heart failure. Remnant cholesterol was calculated as total cholesterol (mmol/L) – high-density lipoprotein cholesterol (mmol/L) – low-density lipoprotein cholesterol (mmol/L). The primary outcome was all-cause mortality. .
 
The study showed that higher remnant cholesterol levels at baseline were independently associated with a lower risk of all-cause mortality. This association persisted in subgroup analyses including age, sex, body mass index, hypertension, diabetes, NYHA functional class, and NT-proBNP, suggesting that remnant cholesterol has a high predictive value. These findings suggest that remnant cholesterol may have application in differentiating heart failure patients with poor prognosis. The authors do, however, recognise several limitations, including study design (retrospective, observational study) and lack of information about remnant cholesterol levels after admission. Further study is merited.

Abnormal triglyceride-rich lipoprotein metabolism is associated with early in-stent neointimal atherosclerosis (neoatherosclerosis) formation in patients receiving contemporary preventive therapy including statin treatment, according to the results of this Japanese study.
 
In total, 114 statin-treated patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) with a current-generation drug eluting stent were evaluated using optical coherence tomography. Lipids including low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), triglyceride-rich lipoprotein cholesterol (TRL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and malondialdehyde-modified LDL (MDA-LDL), were measured.
 
At 12 months, 17 (14.9%) patients had developed in-stent neoatherosclerosis. While LDL-C levels did not differ between patients with and without in-stent neoatherosclerosis (77.2 vs. 69.8 mg/dL; p=0.15), those who developed neoatherosclerosis had significantly higher levels of other atherogenic lipids and lipoproteins including TG, apolipoprotein CIII, TRL-C, non-HDL-C, and MDA-LDL. In multivariate logistic regression analysis, apolipoprotein CIII, TRL-C, non-HDL-C, apolipoprotein B, and MDA-LDL levels were identified as risk factors for in-stent neoatherosclerosis. These findings implicate a role for elevated TG-rich lipoproteins in early neoatherosclerosis formation in statin-treated patients undergoing percutaneous coronary intervention.

Results from a prospective Danish general population study show that elevated remnant cholesterol increased the risk for cardiovascular and all-cause death. There was, however, no association with cancer-related death.
 
While there is extensive evidence that elevated remnant cholesterol is associated causally with an increased risk of atherosclerotic cardiovascular disease, whether it also increases risk for mortality beyond cardiovascular causes is uncertain. This study addressed this question, using data from a contemporary population-based cohort of 87,192 individuals from the Copenhagen General Population Study aged 20-69 years at baseline (2003-2015).
 
Over 13 years of follow-up, 687 individuals died from cardiovascular disease, 1594 from cancer, and 856 from other causes. Compared with individuals with remnant cholesterol <0.5 mmol/L (<19 mg/dL), those with levels ≥1.0 mmol/L (≥39 mg/dL), comprising 22% of this population, had a two-fold higher risk of death from cardiovascular disease or from other causes (hazard ratio 2.2, 95% confidence interval 1.3-3.5; and 2.1, 1.4-3.3, respectively). However, elevated remnant cholesterol had no effect on death from cancer (1.0, 0.7-1.3).
 
Although the authors recommend corroboration of these results in other studies, the findings imply that elevated remnant cholesterol increases the risk for death from cardiovascular and non-cardiovascular causes, other than cancer.

Remnant cholesterol, i.e., the cholesterol carried in triglyceride-rich lipoproteins and their remnants, has emerged as an important causal risk factor for atherosclerosis. The current study evaluated whether the presence of elevated remnant cholesterol impacted cardiovascular risk associated with elevated low-density lipoprotein cholesterol (LDL-C). Using data from a Korean national population study, researchers showed a synergistic effect between elevated remnant cholesterol and elevated LDL-C on risk for incident cardiovascular disease.
 
This study analysed data from 3,686,034 adults (46% women) aged between 40 and 70 years without a history of cardiovascular disease obtained from the Korean national health insurance database. Between 2014 and 2017, 144,004 cardiovascular events (the primary outcome) were reported. When categorised by remnant cholesterol and LDL-C levels (high or not), adults with both high LDL-C and high remnant cholesterol levels had 27% higher risk for incident cardiovascular disease (hazard ratio 1.266, 95% confidence interval (CI) 1.243-1.289; 7.9%), higher than groups with either high LDL-C alone (1.098, 95% CI 1.083-1.113), and high remnant cholesterol alone (1.102, 95% CI 1.087-1.118). Additionally, remnant cholesterol remained proportional to the risk of incident cardiovascular disease after adjustment for multiple variables, including LDL-C. The authors conclude that both elevated LDL-C and elevated remnant cholesterol should be considered to reduce the risk of incident cardiovascular disease.

Findings from the National Health Survey of Chile 2016-2017 show that nonalcoholic fatty liver disease (NAFLD) is prevalent, affecting more than one in four individuals in Chile, underlining the need for renewed emphasis on strategies for lifestyle intervention to reduce weight and improve dietary habits.
 
NAFLD, characterized by excessive fat accumulation within the liver, already affects about 25% of the global population, but it is anticipated that prevalence will increase as obesity escalates. The current study aimed to provide local information for NAFLD prevalence in the adult population in Chile, using non-invasive methods and data from 2,774 adults (21-75 years without infectious diseases or excess alcohol consumption) enrolled in the National Health Survey of Chile 2016-2017. NAFLD was identified on the basis of the Fatty Liver Index (FLI, which takes account of circulating triglycerides, circulating gamma-glutamyl-transferase, body mass index, and waist circumference), the Lipid Accumulation Product (LAP, which takes account of sex, circulating triglycerides, and waist circumference), or their combination. Overall, 39.4% of the sample had NAFLD using the FLI, 27.2% using the LAP, and 23.5% with both indices, and prevalence increased with increasing body mass index. The authors emphasized the urgent need for health promotion strategies focused on controlling body weight and promoting a healthy lifestyle to address this public health issue.

Patients recruited to randomized controlled trials of lipid lowering therapy are not sufficiently diverse to represent patients seen in real-world practice, according to this meta-analysis.
 
In this study, researchers systematically searched for large (≥1000 participants) trials of lipid-lowering therapy conducted by the Cholesterol Treatment Trialists Collaboration. Lipid lowering treatments studied in these trials were statins, ezetimibe, and PCSK9 inhibitors. In particular, the study specifically investigated inclusion criteria relating to older adults (>70 or >75years), women, other ethnicities beyond White patients, chronic kidney failure, heart failure, immunosuppression, cancer, dementia, treated thyroid disease, chronic obstructive pulmonary disease, mental illness, atrial fibrillation, concomitant chronic diseases, and polypharmacy.
 
In total, the analysis included 42 randomized controlled trials in 298,605 patients. The analysis showed that the majority of trials excluded patients with moderate or severe kidney failure (76% and 81%, respectively), or female patients (71%). Nearly two-thirds of trials excluded patients with moderate to severe heart failure or with immunosuppressant conditions (64% each). In addition, patients with cancer or dementia, older patients (11-25% of trials) or those with multimorbidities (51%) were less well represented.
 
In conclusion, the authors underline the need to consider patient inclusion criteria for future trials of lipid lowering therapy. In particular, inclusion of patients with common morbidities such as chronic kidney disease, heart failure and immunosuppression, as well as women and older adults, warrants a re-think, especially in aging societies. Addressing diversity in trial inclusion criteria should improve the generalisability of study results relating to both efficacy and safety of treatments and improve equity in cardiovascular research.

Results from this preliminary study suggest that pemafibrate may have potential in preventing disease progression in patients with nonalcoholic fatty liver disease (NAFLD) and hypertriglyceridemia.
 
This was a retrospective, multicentre study in 138 patients with NAFLD. The effect of pemafibrate treatment on liver function and fibrosis was assessed using liver function tests, biomarkers of fibrosis and the FibroScan-aspartate aminotransferase (FAST) score, calculated using the aspartate aminotransferase (AST) value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). Pemafibrate treatment significantly reduced levels of AST (p = 0.038), alanine aminotransferase (ALT) (p = 0.003), and gamma-glutamyl transferase (GGT) (p = 0.047), as well as the fibrosis markers Autotaxin (p = 0.006) and the AST-to-platelet ratio index (APRI) (p = 0.003) and improved the FAST score (p = 0.0475) at 48 weeks.
 
In conclusion, improvement in liver transaminases, fibrotic biomarkers and FAST score suggests potential for pemafibrate in NAFLD patients with hypertriglyceridemia, warranting further study.

While accumulating evidence shows that remnant cholesterol is associated with cardiovascular risk, uncertainty persists regarding a possible link with microvascular complications associated with type 2 diabetes mellitus (T2DM).
 
This question was addressed in this cross-sectional study conducted in Taiwan in 1964 patients with T2DM (mean age 64.1 years, 43% male, 35% with diabetic retinopathy [DR] and 18% with proliferative diabetic retinopathy [PDR]). Logistic regression models were used to assess the independent relationship between remnant cholesterol level and DR and PDR. Overall, there was no evidence of association between remnant cholesterol and DR or PDR based on a fully adjusted logistic regression model; however, a non-linear relationship was identified using a two-piece logistic regression model. When remnant cholesterol was <39.0 mg/dL, a 1-unit increase was associated with 2.1% greater risk of PDR (odds ratio 1.021; 95% confidence interval 1.004, 1.038).
 
These findings suggest a link between remnant cholesterol and DR in T2DM and warrant further study.

Observational and genetic studies, as well as evidence from Mendelian randomization trials, show that elevated remnant cholesterol, a measure of cholesterol contained in remnant lipoproteins, is associated with increased risk for cardiovascular disease, notably ischaemic heart disease and stroke. However, information on the prevalence and prognostic value of remnant cholesterol in acute coronary syndrome (ACS) patients is limited. These key uncertainties were addressed in this study.
 
A total of 7,479 patients admitted with ACS were recruited in two centres. All patients had data for remnant cholesterol, calculated as: total cholesterol - low-density lipoprotein cholesterol - high-density lipoprotein cholesterol, with values ≥30 considered high. Overall, median remnant cholesterol level was 28 mg/dL (interquartile range 21-39 mg/dL). Nearly half of the patients had high values (46%), and those overweight or obese had higher levels. While remnant cholesterol was not associated with in-hospital mortality (odds ratio 0.89, p = 0.21), there was evidence of an independent and linear risk of all-cause mortality and heart failure after discharge (median follow-up of 57 months). Notably, post-discharge remnant cholesterol levels >60 mg/dl were associated with a 49% increased risk of mortality (hazard ratio 1.49 95% confidence interval [CI] 1.08-2.06, p = 0.016) or cardiovascular mortality (hazard ratio 1.49 95% CI 1.08-2.06, p = 0.016), as well as increased risk of heart failure readmission (hazard ratio 1.55 95% CI 1.14-2.11, p = 0.005).
 
In conclusion, the study showed that elevated remnant cholesterol is common among patients admitted for ACS, and confers a higher long-term risk of mortality and heart failure, underpinning the need to identify and treat at discharge.

Matrix metallopeptidase 9 (MMP-9) plays a key role in vascular remodelling, development of the atherosclerotic lesion, and arterial plaque rupture, and is predictive of adverse cardiovascular events. To date, however, longitudinal data for the association between MMP9 and coronary artery disease progression are lacking. This analysis from the SMARTool Investigators aimed to address this by investigating whether MMP9 is associated with atherosclerotic plaque progression in patients with chronic coronary syndrome (CCS).
 
In the study, MMP9 serum levels were measured in 157 CCS patients (mean age 58 years, 66% male) undergoing coronary computed tomography angiography at baseline and at follow up. Progression of total, fibrous, fibro-fatty, necrotic core, and dense calcium plaque volumes (PV) were evaluated. Serum MMP9 was associated with significant annual increases in total and necrotic core PV (p= 0.017 and p = 0.038, respectively), which were independent of traditional cardiovascular risk factors, medications, and the presence of obstructive coronary artery disease. The authors concluded that MMP9 was an independent predictive marker of progression of adverse coronary plaques and proposed that measurement of blood MMP9 may have potential for identifying patients with elevated residual risk despite optimal management of classical cardiovascular risk factors.

Some reports have suggested that the prevalence of diabetic retinopathy is lower in individuals with concomitant non-alcoholic fatty liver disease (NAFLD), although others have shown no association (1,2). Whether atherogenic dyslipidemia, characterized by elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol, is a modulator of this potential association was investigated in this cross-sectional study.
 
The study analysed data from 744 patients with diabetes, 68% of whom also had evidence of NAFLD on ultrasonography, and 45% with atherogenic dyslipidemia. Overall, 66 had atherogenic dyslipidemia with no NAFLD, 235 had NAFLD without atherogenic dyslipidemia, 272 had both atherogenic dyslipidemia and NAFLD, and 171 had neither characteristic. Overall, 35% of patients without NAFLD had evidence of diabetic retinopathy. The prevalence of diabetic retinopathy was lower in patients with NAFLD, irrespective pf the presence of atherogenic dyslipidemia, decreasing by 32-47%. Ocular hypertonia and cataract were also less prevalent in diabetes patients with NAFLD than in those without.
The authors concluded that multi-level eye protection in diabetes may be linked to NAFLD independently of atherogenic dyslipidemia, meriting further study.
 
1. Song D, Li C, Wang Z, Zhao Y, et al. Association of non-alcoholic fatty liver disease with diabetic retinopathy in type 2 diabetic patients: A meta-analysis of observational studies. J Diabetes Investig 2021 Aug;12(8):1471-1479.
 
2. Zhang M, Li L, Chen J, Li B, Zhan Y, et al. Presence of diabetic retinopathy is lower in type 2 diabetic patients with non-alcoholic fatty liver disease. Medicine (Baltimore) 2019;98:e15362.

Studies conducted predominantly in Caucasian cohorts show that elevated remnant cholesterol is a risk factor for cardiovascular disease. There is, however, less evidence in Asian cohorts, specifically East Asian cohorts with type 2 diabetes. This uncertainty was addressed in this study using data from the Korean National Health Insurance Service database, which includes 1,956,452 patients with type 2 diabetes and without atherosclerotic cardiovascular disease (ASCVD).
 
Over a median follow-up of 8.1 years, 50,120 (2.56%) cases of myocardial infarction (MI) and 73,231 (3.74%) cases of ischemic stroke were reported. Individuals in the highest remnant cholesterol quartile had a 28% higher risk of MI and a 22% higher risk for ischemic stroke, compared with those in the lowest quartile. Additionally, a remnant cholesterol level ≥30 mg/dL identified patients at higher ASCVD risk irrespective of low-density lipoprotein cholesterol ≤ or >100 mg/dL. The authors concluded that their findings support a causal role of remnant cholesterol in residual cardiovascular risk in East Asian patients with type 2 diabetes.

MESA (Multi-Ethnic Study of Atherosclerosis) was initiated to study the correlates, predictors, and progression of subclinical cardiovascular disease in a diverse population without evidence of clinical cardiovascular disease at baseline. The latest findings from this study highlight the relevance of both remnant lipoprotein cholesterol (RLP-C, assessed using nuclear magnetic resonance spectroscopy [NMR]), and high-sensitivity C-reactive protein (hsCRP) to risk for incident clinical atherosclerotic cardiovascular disease.
 
This analysis included data from 6,720 MESA individuals (mean age 62.2 years, 53% female) enrolled in MESA with a median follow-up of 15.6 years. NMR-RLP-C, which includes very-low-density lipoprotein cholesterol and intermediate-density lipoprotein cholesterol, and hsCRP were measured at baseline. Data were categorized into four groups for analysis: Reference group - low RLP-C (i.e., ≤ median value of 29.14 mg/dL) and low hs-CRP (<2 mg/L); low RLP-C and high hsCRP (≥ 2 mg/L); high RLP-C (> median) and low hsCRP; and high RLP-C and high hsCRP.
 
Compared with the reference group, individuals with high hsCRP and/or high RLP-C were at elevated risk of incident atherosclerotic cardiovascular disease (ASCVD) events. The risk was increased by 20% in those with elevated hsCRP alone, by 18% in those with elevated RLP-C alone, but by 43% in those with both elevated hsCRP and RLP-C.
 
These results show that the combination of elevated RLP-C and hsCRP was associated with an increased risk of future ASCVD events. Adding to evidence from other studies, these findings highlight the need for a multi-targeted approach to ASCVD prevention, intervening against inflammation and atherogenic lipids.

This study addressed uncertainty regarding the association of remnant cholesterol with metabolic dysfunction-associated fatty liver disease (MAFLD), using data from NHANES Ⅲ, 1988-1994 and the linked mortality data (to 2015). Overall, 28.6% (1474/5156) of the cohort had MAFLD. Using multivariate logistic regression, the authors showed that individuals in the fourth quartile of remnant cholesterol levels had an increased risk of MAFLD versus those in the first quartile (odds ratio 1.714, 95% confidence interval 1.586-1.971; p <0.001). Additionally, MALFD patients with the highest remnant cholesterol levels had more than two-fold higher risk of all-cause mortality (hazard ratio 2.183, 95% confidence interval 1.825-2.407; p <0.001), and cardiovascular mortality (2.346, 95% CI: 2.046-2.885; p <0.001) than those with lower levels. The authors concluded that remnant cholesterol is a predictor of long-term cardiovascular and all-cause mortality in MAFLD.

Transition to the menopause is one of the key factors responsible for the increase in cardiovascular risk in women. While the underlying mechanisms are uncertain, declining ovarian hormones, which contribute to dysregulation of lipid metabolism and increased triglycerides, may be implicated. The angiopoietin-like proteins (ANGPTLs) play key roles in regulating lipoprotein lipase activity, which in turn impacts plasma triglyceride levels. On this basis, the study investigated the relationships between serum ANGPTL3 and ANGPTL8 and atherogenic biomarkers in healthy women during ageing, with a focus on their role in early triglyceride elevation.
 
Overall, the study included 94 women, of whom 37 were postmenopausal. Median levels of ANGPTL3 were significantly higher in postmenopausal women than premenopausal women, although ANGPTL8 levels did not differ. In postmenopausal women, ANGPTL8 and ANGPLT3 levels correlated with lipid levels (triglycerides, small dense low-density lipoprotein [sdLDL) and the ratio of triglycerides/high-density lipoprotein cholesterol). ANGPTL8 and sdLDL were the most significant predictors of early elevation in plasma triglycerides, more so than ANGPTL3 levels. Based on their findings, the authors conclude that menopausal status should be taken into account in trials of novel therapies targeting angiopoietin-like proteins.

In a registry study including over 1.5 million people, mild to moderate hypertriglyceridaemia (between 1.7 and 10 mmol/L) was associated with an increased risk of myocardial infarction (MI).
 
The CALIBER registry used linked electronic records for primary and secondary care and mortality records to include 1,530,441 patients (mean age 56.6 years, 51% female) with at least one triglyceride measurement and at least one year of follow up. Overall, the median duration of follow-up was 6.7 years (Interquartile range 3.4–10.5 years). When grouped by baseline triglyceride levels, 29% had triglyceride levels between 1.7−4.5 mmol/L, 1.9% had levels of 4.5-10 mmol/L, and 0.21% had levels >10 mmol/L (severe hypertriglyceridaemia).
 
Over the follow-up period, 84,874 (5.5%) patients had a MI. Patients with mild (1.7–4.5 mmol/L) and moderate (4.5–10 mmol/L) hypertriglyceridaemia had a modest albeit significant increase in risk for MI (7% and 17%, respectively) compared with those with triglyceride levels <1.7 mmol/L. The authors concluded that their findings from a real-world cohort support routine measurement of triglycerides for cardiovascular risk management.

There is extensive evidence that elevated levels of lipoprotein(a) [Lp(a)] associate with increased risk of ischaemic heart disease and stroke. The data regarding peripheral artery disease (PAD) outcomes, however, is less certain. To address this issue, the authors conducted a systematic review to investigate the association between elevated Lp(a) and PAD outcomes (defined as at least one of claudication, PAD progression, restenosis, death and hospitalisation for PAD, limb amputation, and lower limb revascularisation). Overall, this analysis included 15 studies with 493,650 subjects.
 
Elevated Lp(a) levels associated with a 20% higher risk of incident claudication, as well as increased risk for PAD progression (hazard ratio [HR] 1.41), restenosis (HR 6.10), death and hospitalisation related to PAD (HR 1.37), limb amputation (HR 22.75), and lower limb revascularisation (HR 1.29 and 2.90). This increased risk persisted after adjustment for traditional risk factors. Taken together, the findings provide strong support for an association of elevated Lp(a) levels with adverse PAD outcomes, highlighting the need for evaluation of Lp(a) levels in PAD patients.

Results from the REASSURE-NIRS registry (NCT04864171), show that circulating lipoprotein(a) [Lp(a)] levels are an important promoter of plaque vulnerability in patients with coronary artery disease (CAD) and diabetes.
 
The REASSURE-NIRS registry enrolled 741 CAD patients requiring percutaneous coronary intervention (PCI) under the guidance of near-infrared spectroscopy/intravascular ultrasound (NIRS/IVUS) imaging. This analysis included data for 312 patients with Lp(a) measurement, who were receiving statin therapy. The primary endpoint was the lipid-core-burden index in target lesions as measured with NIRS imaging. Lp(a) levels were significantly associated with lipid-core-burden index in patients with diabetes (p = 0.01) but not in patients without diabetes (p = 0.96). This association persisted in diabetes patients achieving low-density lipoprotein cholesterol levels <1.8 mmol/L (70 mg/dL). The findings support circulating Lp(a) as a determinant of the vulnerability of coronary atherosclerosis in patients with diabetes on statin therapy, and suggest that Lp(a) may represent a therapeutic target for modulating the lipid component of coronary atheroma in these patients.

There is extensive evidence from epidemiologic and genetic studies to support elevated lipoprotein(a) [Lp(a)] concentration as an independent cardiovascular risk factor. The current study also shows that high Lp(a) concentration is likely to be a potential biomarker for residual risk of cardiovascular events among statin-treated patients with history of acute coronary syndrome (ACS).
 
In total, 1,758 ACS patients who underwent emergency percutaneous coronary intervention (2008-2017) were enrolled, of whom 1,131 patients had Lp(a) data and were treated with statins at discharge. These patients were further categorized as either high or low Lp(a) concentration. The primary end point was major adverse cardiac events (MACEs), a composite of all-cause death and myocardial infarction. Over a 5-year follow-up period, 107 MACE (9.5%) were documented. Compared with patients in the low Lp(a) group, those with high Lp(a) concentration had a significantly higher risk of MACE (hazard ratio 1.66, 95% confidence interval 1.05 to 2.61, p = 0.03). The findings add support for consideration of elevated Lp(a) concentration as a contributor to residual risk among statin-treated ACS patients.

Already atherosclerotic cardiovascular disease poses a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Given that more than one in five people in Europe have elevated triglycerides (TG), this review considers the cost implications of targeting elevated triglycerides (TG) with icosapent ethyl, approved by the European Medicines Agency in 2021 to reduce the residual risk of cardiovascular events in adult statin-treated patients, or in high-risk patients in the primary prevention setting. Clinical studies in Europe show that between 12.5% and 23.3% of high-risk patients may benefit from this treatment.
 
This review considers clinical evidence from Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), and plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials, as well as multiple cost-utility studies. The authors conclude that icosapent ethyl is a cost-effective treatment option based on common willingness-to-pay thresholds. These findings have relevance for the clinical management of high-risk statin-treated dyslipidemic patients.

This study provides new insights into the impact of the triglyceride-glucose index (TyG index) trajectory on cardiovascular risk. The TyG index is the logarithmized product of fasting triglycerides and fasting glucose and has been proposed as an alternative marker for insulin resistance. Previous findings from the US National Health and Nutrition Examination Survey (1999–2014) showed that an elevated TyG index was indicative of more severe insulin resistance and showed a non-linear association with all-cause and cardiovascular disease (1). The current study investigated TyG index trajectories in 40,473 normal-weight adults and their association with the risk of incident cardiovascular disease. TyG index trajectories during 2006-2012 were identified by latent variable mixture modeling.
Over the follow-up period (6.74 years), 1,577 incident cardiovascular events were reported. Compared with a low-stable pattern trajectory (mean TyG index 7.84-7.93), individuals with a high stable trajectory (mean TyG index 9.91-10.07) had more than 2-fold higher risk of incident cardiovascular events (hazard ratio [HR], 2.24; 95% confidence interval [CI]: 1.73-2.90), higher than that observed for the moderate-increasing, high-decreasing pattern or moderate-stable TyG index trajectories over time. The authors concluded that their findings suggest that long-term trajectories of the TyG index may have value in cardiovascular risk prediction among normal weight individuals, based on their association with lipid and glucose metabolism.
1. Liu X, He G, Lo K et al. The triglyceride-glucose index, an insulin resistance marker, was non-linear associated with all-cause and cardiovascular mortality in the general population. Front Cardiovasc Med 2021; doi.org/10.3389/fcvm.2020.628109.

Pemafibrate is already licensed in Japan for the management of hyperlipidemia and hypertriglyceridemia and has demonstrated a favourable benefit versus risk profile. This latest study in European patients on statin therapy showed that treatment with pemafibrate robustly reduced plasma triglycerides (TG) and was well tolerated. This phase II randomized, double-blind, placebo-controlled study included 408 adults on statin therapy with fasting TG between 175 and 500 mg/dL and low plasma concentration of high-density lipoprotein cholesterol (HDL-C, ≤50 mg/dL for men and ≤55 mg/dL for women). Patients were randomized to treatment with placebo or pemafibrate (0.05 mg, 0.1 mg or 0.2 mg twice daily or 0.1 mg, 0.2 mg or 0.4 mg once daily). At week 12, pemafibrate 0.2 mg twice daily lowered fasting plasma TG by 54.4%. There was also improvement in other markers of TG-rich lipoprotein metabolism, including reductions in apolipoprotein (apo)B48, apoCIII, and remnant cholesterol, together with an increase in HDL-C levels. Pemafibrate was also well tolerated with a safety profile consistent with that observed in phase II and III trials of pemafibrate in Japanese patients with dyslipidemia, including those on statin therapy (1). The findings from this trial extend the evidence for pemafibrate as an effective SPPARMα for the management of dyslipidemia.
1. Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new Selective PPARα Modulator: Drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep 2020;22(1):5.

Findings from the Finnish Diabetic Nephropathy Study (FinnDiane) show that apolipoprotein (apo) CIII is predictive of cardiovascular events in type 1 diabetes subjects with albuminuria. FinnDiane is a prospective observational study investigating the risk factors and mechanisms of diabetic complications associated with type 1 diabetes. This latest cohort analysis is based on 3966 subjects. The primary endpoint was major adverse cardiac events (MACE), defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality. Progression of diabetic kidney disease was also evaluated using medical records.
The analysis showed that apoCIII was a predictor of MACE although this effect was not independent of remnant cholesterol (hazard ratio 1.05, 95% confidence interval 0.81-1.36, p = 0.71 with remnant cholesterol; and 1.30, 1.03-1.64, p = 0.03 without). This association was driven by individuals with albuminuria, indicative of diabetic kidney disease. Indeed, subjects with albuminuria had nearly 50% higher risk of mortality (hazard ratio 1.49, 1.03-2.16, p = 0.03). ApoCIII was also predictive of progression of diabetic kidney disease independent of sex, diabetes duration, blood pressure, HbA1c , smoking, low-density lipoprotein cholesterol, lipid-lowering medication, and remnant cholesterol. In conclusion, this analysis from FinnDiane highlights a role for apoCIII as a predictor of cardiovascular mortality and morbidity in individuals with type 1 diabetes and pre-existing diabetic kidney disease.

In this report from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, high triglycerides (TG) were identified as an independent predictor for the development of diabetic kidney disease (DKD) in individuals with new-onset type 2 diabetes.
The 4C Study is a multicentre, nationwide, population-based prospective cohort study exploring the associations of metabolic factors with incident diabetes, cardiovascular events, cancer, and all-cause mortality in Chinese individuals aged ≥40 years. The current analysis was based on 11,142 patients with new-onset type 2 diabetes with baseline estimated glomerular filtration rates (eGFR) ≥60 mL/min/1.73m2, who were followed between 2011 and 2016. Incident DKD was defined as eGFR <60 mL/min/1.73m2 at follow-up. In adjusted multivariate logistic regression analysis, patients with high TG levels at both baseline and follow-up were at higher risk of DKD compared with those with consistently normal values (odds ratio 1.65, p < 0.001). The authors concluded that therapeutic intervention to control TG levels might delay the development of DKD in patients with new-onset type 2 diabetes.

Danish researchers tested whether the contrasting results for atherosclerotic cardiovascular disease (ASCVD) risk reduction in Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH) may be at least partly attributable to the effects of the comparator oils used in each trial.
This hypothesis-testing analysis used data from over 100,000 individuals in the Copenhagen General Population Study to mimic each trial design. Based on key trial inclusion criteria, 5,684 individuals (852 with ASCVD) would have been eligible for REDUCE-IT and 6,862 individuals (697 with ASCVD) would have been eligible for STRENGTH. Combining results for changes in lipids and C-reactive protein in active and comparator groups, the hazard ratio for ASCVD was 0.88 (0.84-0.93) for the cohort mimicking REDUCE-IT versus 0.75 (0.68-0.83) in the REDUCE-IT trial. In contrast, hazard ratios for ASCVD were similar for the cohort mimicking STRENGTH versus the STRENGTH trial (0.96 versus 0.99). Thus, the authors concluded that the different effect of comparator oils (mineral vs. corn) on lipids and C-reactive protein partly explained the discrepant results of the two trials, implying the involvement of other mechanisms in the findings of REDUCE-IT.

There is accumulating evidence for Lp(a) as an independent cardiovascular risk factor and, potentially, a contributor to residual cardiovascular risk. Insights from the Copenhagen General Population Study also show that Lp(a) is independently associated with mitral and aortic valve calcification and aortic valve stenosis. Furthermore, data implicate Lp(a) as a potential biomarker in risk stratification in high-risk patients.
 
Lp(a) is associated with mitral and aortic valve calcification
Aortic valve disease is increasingly prevalent in aging societies. To date, however, there are no medical therapies that can slow the progression of disease. Elevated Lp(a) is already recognized as a risk factor for aortic valve calcification and stenosis, but it is not known if this biomarker is also associated with mitral valve calcification and disease. This analysis from the Copenhagen General Population Study included 12,006 individuals with information on mitral and aortic valve calcification, plasma Lp(a), genetic data (LPA kringle IV type 2 number of repeats, and variants rs10455872, and/or rs3798220). Overall, 1,521 (13%) individuals had mitral valve calcification, 3,018 (25%) had aortic valve calcification, and 74 (0.6%) had aortic valve stenosis (without a previous aortic valve replacement). Elevated plasma Lp(a) was causally associated with increased risk of mitral and aortic valve calcification, based on both observational and genetic data. These results therefore suggest that Lp(a) is one of several factors that facilitate the evolution of mitral and aortic valve calcification, predisposing to an increased risk of aortic valve stenosis. Indeed, aortic valve calcification mediated 31% of the effect of elevated Lp(a) on aortic valve stenosis. Taken together, these findings suggest potential for investigating the effects of novel Lp(a)-lowering therapies on mitral and aortic valve calcification.
Kaltoft M, Sigvardsen PE, Afza S, et al. Elevated lipoprotein(a) in mitral and aortic valve calcification and disease: The Copenhagen General Population Study. Atherosclerosis 2021; doi.org/10.1016/j.atherosclerosis.2021.11.029
 
High Lp(a) and risk for recurrent limb events
Peripheral artery disease (PAD) confers a high risk of cardiovascular morbidity and mortality. While therapeutic intervention targets the major risk factors - smoking, diabetes, hypertension, and hypercholesterolemia – PAD patients remain at high residual risk of cardiovascular events. This report from Athero-Express, a prospective biobank study, investigated the association of plasma Lp(a) levels with the risk of (recurrent) major adverse limb events (MALE) and major cardiovascular events in 384 patients (73% male, mean age 69 years, 43% with previous coronary artery disease) who underwent iliofemoral endarterectomy. MALE was a composite of (new) infrainguinal (endo)vascular interventions that were performed due to a loss of patency or novel stenosis/occlusion in other ipsilateral segments. These included percutaneous transluminal angiography, stent, drug coated balloon, drug coated stent, mechanical thrombectomy, atherectomy, thrombolytic treatment, bypass surgery and major (above-the-ankle) amputations. Over a median follow-up of 5.6 years, 132 patients experienced 225 MALE; only 7 patients had a first event. Patients with a MALE were more likely to be younger, with a history of peripheral intervention(s) and a significantly higher plasma Lp(a) value (median 37.2 nmol/L versus 19.4 nmol/L in those without a MALE, p = 0.017). In multivariable analysis, elevated Lp(a) was associated with increased risk of first MALE (hazard ratio 1.36, 95% confidence interval 1.02–1.82, p = 0.036) and recurrent MALE (1.36, 1.10–1.67, p = 0.004). Given this high risk of recurrent events in PAD patients, improvement in preventive tertiary measures would potentially benefit many patients. The findings from this study implicate Lp(a) as a potential blood biomarker for subsequent lower limb events in these high-risk patients, which could assist in targeting therapeutic intervention to reduce residual cardiovascular risk.
Verwer MC, Waissi F, Mekke JM, et al. High lipoprotein(a) is associated with major adverse limb events after femoral artery endarterectomy. Atherosclerosis 2021; doi.org/10.1016/j.atherosclerosis.2021.11.019
 
Lp(a) predicts recurrent events in STEMI patients
This US study provides insights into predictors of recurrent ischemic events in patients with ST-segment elevation myocardial infarction (STEMI), based on real-world cohort data. Overall, 724 STEMI patients were followed for 803 (324 to 1,394) days. The primary outcome was recurrent myocardial infarction (MI), and secondary outcomes were all-cause death, target vessel revascularization (TVR), in-stent restenosis, definite stent thrombosis and non-TVR. During follow-up, 70 patients (10.1%) experienced a primary event. Multivariable analysis indicated that serum Lp(a) was independently predictive of recurrent MI. A Lp(a) level ≥ 30 mg/dL had incremental risk stratification in patients with diabetes (increasing risk by more than 5-fold), and with both diabetes and a restenotic lesion. The authors concluded that these findings make a case for measurement of Lp(a) levels for long-term prognostic assessment in these high-risk patients.
Galasso G, De Angelis E, Silverio A, et al. Predictors of recurrent ischemic events in patients with ST-Segment Elevation Myocardial Infarction. Am J Cardiol 2021; doi: 10.1016/j.amjcard.2021.08.019.

Results from this study suggest that apolipoprotein (apo) E may be predictive of residual cardiovascular risk in patients with chronic coronary syndrome (CCS) on statin treatment. ApoE transports cholesterol and other lipids in the blood and plays a central role in lipid metabolism. Moreover, apoE is also linked to the pathogenesis of Alzheimer’s disease beyond its central roles in lipid metabolism. Whether apoE is also implicated in residual cardiovascular risk in CCS patients is indeterminate. This question was addressed in the current study.
 
In total, 1109 patients (mean age, 67 ± 10 years; 83% men) with CCS were included in this study; 552 and 557 were categorized to higher or lower apoE groups, based on median serum apoE values. All patients had low-density lipoprotein cholesterol levels <100 mg/dL on statin treatment. The primary endpoint was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal acute coronary syndrome, and target vessel revascularization.
 
Over a median follow-up of 5.1 years, 195 patients (17.6%) experienced a MACE, with a higher incidence among those with higher than lower apoE levels (Kaplan-Meier rates, 29.5% vs.23.8%, p = 0.019). Multivariable Cox hazard analysis showed that each 1 mg/dL increase in serum apoE was associated with a 15% increased risk of MACE (hazard ratio 1.15; 95% confidence interval 1.03-1.29, p = 0.013). These findings merit further study.

Hospitalized individuals with COVID-19 who also had atherogenic dyslipidemia, characterized by high triglycerides and low plasma concentration of high-density lipoprotein cholesterol (HDL-C), at admission were more likely to have severe complications, according to this report from Italy. This retrospective study analysed the clinical reports of 118 consecutive patients hospitalized for COVID-19 between March and May 2020. Atherogenic dyslipidemia at admission increased the risk of critical disease, defined as in-hospital death or the need for endotracheal intubation, more than 2-fold (odds ratio 2.53, 95% confidence interval 1.16-6.32, p = 0.018). Elevated triglycerides were significantly associated with elevated inflammatory biomarkers and a worse outcome of COVID-19 during hospitalization, both overall and for the subgroup with atherogenic dyslipidemia. The findings add to other findings, including those which suggest that the atherogenic index of plasma (calculated as base 10 logarithm of the triglyceride to HDL-C ratio) was predictive of mortality in patients with COVID-19 (1).
 
In their conclusions, the authors suggest that lipid profiling should be encouraged in patients hospitalized for COVID-19, to triage those at risk of worse outcome.
 
1. Turgay Yıldırım Ö, Kaya Ş. The atherogenic index of plasma as a predictor of mortality in patients with COVID-19. Heart Lung 2021;50:329-333.

Individuals with type 2 diabetes mellitus (T2DM) and diabetic nephropathy and elevated remnant cholesterol were at higher risk of cardiovascular death, according to this recent report.
 
This study used baseline lipid data from 2,282 adults withT2DM, chronic kidney disease (stages 3-5) and newly diagnosed diabetic nephropathy to investigate the association with risk for cardiovascular death over the following 2 years. The analysis showed that each 10 mg/dL increase in baseline low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol increased the risk for cardiovascular death (odds ratio [95% confidence interval] 1.022 [1.017-1.026] and 1.024 [1.021-1.028], respectively). Furthermore, each 10 mg/dL increment in baseline remnant cholesterol was associated with increased risk for cardiovascular death (odds ratio [95% confidence interval] 1.115 [1.103-1.127]). Notably, individuals with remnant-cholesterol levels ≥30 mg/dL were at a higher risk compared with those with lower values, especially if LDL-C was also elevated (>100 mg/dL) .
 
These findings show that higher baseline remnant cholesterol levels increased the risk for cardiovascular mortality in individuals with T2DM, chronic kidney disease and incident diabetic nephropathy. Patients with both elevated remnant cholesterol and LDL-C at baseline were at highest risk of cardiovascular death.

CAPTURE aimed to estimate the prevalence of established cardiovascular disease (CVD) and its management in adults with type 2 diabetes mellitus (T2DM). This non-interventional, cross-sectional study conducted at 214 centres across 13 countries in five continents, enrolled 9823 adults with T2DM (4502 from primary care and 5321 from secondary care). Overall median age was 64.0 years (interquartile range 56.0–71.0 years) and 45.5% were female. Most were overweight (~80% had a body mass index ≥ 25 kg/m2) and 70% had hypertension. The median HbA1c was 7.30% and diabetes duration was 10.7 years. The primary outcome was documented evidence of established CVD and atherosclerotic CVD (ASCVD), the latter defined as diagnosis of cerebrovascular disease, coronary heart disease, peripheral artery disease, or carotid artery disease. The prevalence (95% confidence interval [CI]) of CVD and ASCVD was estimated overall and for each country, as weighted estimates to account for the size of the diabetes population in each country.
 
Overall, about one in three adults with T2DM had established CVD (weighted prevalence 34.8%), with ASCVD accounting for most of this burden (31.8%). Compared with adults without CVD, these individuals were older (mean age 68 vs. 62 years), were more likely to be male (61.3% vs 50.7%) and had a longer duration of diabetes (13.0 vs. 9.8 years). In addition, T2DM patients with CVD had a higher prevalence of microvascular complications compared with those without CVD (retinopathy: 24.3% vs. 15.8%; nephropathy: 29.2% vs. 17.0%; neuropathy: 29.0% vs. 19.2%). Most patients were not managed according to guideline recommendations for CVD prevention. Overall, about half received lipid-lowering therapy (predominantly a statin), and only about one in five received either a glucagon-like peptide-1 receptor agonist or sodium-glucose cotransporter-2 inhibitor, both recommended by current guidelines for CVD prevention.
 
In conclusion, CAPTURE showed that about one in three adults with T2DM had diagnosed CVD. Most patients were managed suboptimally according to current guidelines. These findings provide a benchmark to assess the implementation of guideline recommendations for preventing CVD in T2DM.

Higher remnant cholesterol levels associated with increased risk of chronic kidney disease (CKD), according to this Chinese study.
 
Remnant cholesterol is the cholesterol contained in triglyceride-rich remnant lipoproteins, primarily very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). Plasma triglycerides are a surrogate measure of remnant cholesterol. There is accumulating evidence that elevated remnant cholesterol is associated with risk for ischaemic heart disease and stroke (1,2). Whether remnant cholesterol is also associated with CKD is more contentious.
 
The current study addressed this question using data from a general population cohort of 7356 Chinese middle-aged and elderly subjects. When analysed by quartiles, individuals with the highest remnant cholesterol levels not only had higher lipids (total cholesterol, triglycerides, and low-density lipoprotein cholesterol), but also a higher prevalence of CKD, albuminuria, and low estimated glomerular filtration rate compared with those in the lowest remnant cholesterol quartile. Based on multivariate logistic regression analysis, the risk of prevalent CKD in the highest quartile of remnant cholesterol was one-third higher than in the lowest quartile (odds ratio 1.344, 95% confidence intervals 1.097-1.648, p < 0.01).
 
Taken together, these findings suggest that remnant cholesterol may be a biomarker for CKD in a general Chinese population aged at least 40 years. Further study in other populations is warranted.
 
1. Varbo A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
 
2. Varbo A, Nordestgaard BG. Remnant cholesterol and risk of ischemic stroke in 112,512 individuals from the general population. Ann Neurol 2019;85:550-9.

Supported by extensive evidence, elevated lipoprotein(a) is now considered a causal cardiovascular risk factor, with an ongoing study testing whether lowering elevated levels reduces cardiovascular events (1). Results from the Plaque At RISK study also indicate that high lipoprotein(a) levels may associate with vulnerable plaque characteristics.
 
This study evaluated lipoprotein(a) concentration, apolipoprotein(a) KIV-2 repeats and single nucleotide polymorphisms of the LPA gene in 182 patients in the Plaque At RISK study. Imaging characteristics of carotid atherosclerosis were determined by multidetector computed tomographic angiography (n = 161) and/or magnetic resonance imaging (n = 171).
 
Lipoprotein(a) was associated with the degree of stenosis and the presence of vulnerable plaque characteristics including a lipid-rich necrotic core, thin-or-ruptured fibrous cap and intraplaque haemorrhage. The T3888P variant was associated with improved characteristics including the absence of lipid-rich necrotic core, as well as smaller maximum vessel wall.
 
In conclusion, these initial findings suggest an association between elevated lipoprotein(a) levels and vulnerable plaque characteristics, and merit further study.
 
1. Assessing the Impact of Lipoprotein (a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON). https://clinicaltrials.gov/ct2/show/NCT04023552

Diabetes prevalence in the US continues to increase. According to latest data from the National Health and Nutrition Examination Survey (NHANES) in 28,143 individuals, the age-standardized prevalence of diabetes increased by nearly 50% over the last 20 years, from 9.8% in 1999-2000 to 14.3% in 2017-2018.
Worryingly, management of key risk factors - HbA1c level, blood pressure, and low-density lipoprotein cholesterol (LDL-C) remains suboptimal. Among individuals with diagnosed diabetes, only about one in five attained goals for all three risk factors over the period 2015-2018. While there has been improvement since 1999-2002 (21.2% vs 9.0%), there is still much to do to improve risk factor management among individuals with diabetes. Guideline-recommended therapy – both pharmacologic and lifestyle – is effective in risk factor management. The ongoing challenge is implementing current guideline recommendations for diabetes management in routine clinical practice.

Approaches to global risk have tended to use a short-term focus. However, a lifetime risk perspective has the potential for added benefit, in that individuals are more readily able to understand their risk of a cardiovascular event and adjust their behaviour accordingly. Such an approach has important implications for public health given that studies have shown that lifetime risk for a cardiovascular disease event is higher than that for some common types of cancer (1).
 
Lifetime risk estimation may also have relevance for the management of residual cardiovascular risk in individuals with symptomatic atherosclerotic cardiovascular disease (ASCVD). The current study evaluated the effectiveness of intervention targeting blood pressure, lipids, and thrombosis guided by predicted lifetime benefit versus risk factor levels in 7,697 ASCVD patients in the UCC-SMART cohort. Lifetime benefit-guided intervention was based on individual estimation of gain in cardiovascular disease-(CVD)-free life years with the SMART-REACH model, whereas the risk factor-based strategy was based on targeting low-density lipoprotein cholesterol (LDL-C < 1.8 mmol/L), systolic blood pressure (<140 mmHg), and antithrombotic therapy. Effectiveness was evaluated as total gain in CVD-free life and events avoided.
 
Therapy based on a lifetime benefit approach would increase CVD-free life years by 24,243 [95% confidence interval (CI) 19,980-29,909] and avoid 940 (95% CI 742-1140) events over the next 10 years. This was substantially more than with risk-factor based treatment (increase of 18,564 CVD-free life years and avoidance of 857 events). Compared with risk-factor based treatment, the lifetime-benefit approach would result in 1871 additional quality-adjusted life years (QALYs) for the price of €36 538/QALY gained.
 
In conclusion, these findings imply that a lifetime risk approach to management of residual cardiovascular risk not only reduces the burden of disease compared with the conventional risk factor-based strategy, but also is potentially cost-effective in patients with ASCVD.
 
1. Lloyd-Jones D, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113:791–8.

Insights from the German Longitudinal Cognitive Impairment and Dementia Study indicate that the Mediterranean diet is a protective factor against memory decline and mediotemporal atrophy.
The German Longitudinal Cognitive Impairment and Dementia Study included 512 individuals, either with normal cognitive function (n=169) or at higher risk of Alzheimers Disease. In this cross-sectional study, researchers investigated associations between adherence with a Mediterraenean diet (assessed with a Food Frequency Questionnaire), brain volume outcomes (analysed using T1-MRI) and cognitive performance (evaluated using an extensive neuropsychological test battery). They showed that higher adherence with a Mediterranean diet was associated with larger mediotemporal gray matter volume (p<0.05), better memory (p=0.038), and less amyloid (p=0.008) and pTau181 pathology (p=0.004), implying favourable impact on mediotemporal atrophy. In concluding remarks, the researchers highlighted the need for longitudinal and dietary intervention studies to evaluate whether these associations might be explained by the Mediterranean diet mediating a decrease of amyloidosis and tau-pathology.

This timely review highlights dyslipidaemia as a major risk factor for cardiovascular disease. Notably, elevated low-density lipoprotein cholesterol is the most common dyslipidaemia, becoming increasingly prevalent. In 1990, this was the 15th leading risk factor for death and in 2019 is now the 8th leading risk factor for death. The review also highlights the increasing prevalence of other dyslipidaemias, in particular the combination of high triglyceride levels and low plasma levels of high-density lipoprotein-cholesterol (atherogenic dyslipidaemia) especially among patients with diabetes or metabolic syndrome. The review summarises evidence for atherogenic dyslipidaemia as a contributor to residual cardiovascular risk.

This report from the Atherosclerosis Risk in Communities (ARIC) study suggests potential for lowering hepatic apolipoprotein (apo)C-III or angiopoietin-like protein 3 (ANGPTL3) expression in older individuals with elevated triglyceride (TG)-rich lipoproteins.
 
The study analysed data from 6359 subjects (mean age 75.8 years) who were followed for up to 6 years for atherosclerotic cardiovascular events [coronary heart disease (CHD) or ischaemic stroke]. Using Cox regression modelling with adjustment for age, sex, and race, the researchers showed that remnant lipoprotein particle-cholesterol, LDL-TG, apoC-III, and ANGPTL3 were significantly associated with CHD. After adjustment for traditional risk factors and lipid-lowering therapy, only LDL-TG and ANGPTL3 were significantly associated with ASCVD events, with a 72% increase in risk per log unit increase in LDL-TG, and a 63% increase in risk per log unit increase in ANGPTL3. In conclusion, these findings provide support for monitoring TG-rich lipoproteins as part of the lipid profile in older adults.

While lipoprotein(a) is a recognized causal risk factor for atherosclerotic cardiovascular disease, its role in acute ischaemic stroke remains controversial. In this report from BIOSIGNAL, elevated lipoprotein(a) was independently associated with large artery atherosclerosis (LAA) stroke aetiology and risk of recurrent cerebrovascular events in younger patients (<60 years).
 
BIOSIGNAL was a prospective, observational, multicentre cohort study in 1733 primarily Caucasian patients with acute ischaemic stroke. Plasma lipoprotein(a) levels were measured within 24 hours of onset of symptoms. The analysis showed that lipoprotein(a) levels were independently associated with LAA stroke aetiology, with age a modifier of this association. The adjusted odds ratio for LAA stroke was 3.64 (95% confidence interval [CI] 1.76-7.52) per unit log10 lipoprotein(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off of at least 100 nmol/L. Moreover, lipoprotein(a) levels ≥100 nmol/L were associated with an increased risk for recurrent events among patients <60 years (by 2.40-fold), with LAA stroke aetiology (by 2.18-fold) or with no known atrial fibrillation (by 1.60-fold). In conclusion, these findings provide useful data on whether the frequency of first or recurrent stroke events can be reduced by lowering plasma lipoprotein(a) levels.

A key session was the Joint European Atherosclerosis Society (EAS) /International Atherosclerosis Society Session: Universal cardiovascular health – time to act. Professor Peter Libby (Brigham and Women’s Hospital, Harvard Medical School, Boston, USA) overviewed changing perspectives about triglycerides (TG) – a biomarker for TG-rich lipoproteins and remnant particles - as causal and actionable atherosclerotic cardiovascular risk factors. The see-saw between high-density lipoprotein cholesterol (HDL-C) and TG has now swung in favour of the latter (1), largely driven by insights from Mendelian randomization studies of variants in genes that play a key role in TG metabolism. These include variants in the genes for lipoprotein lipase (LpL), the central hub for TG metabolism, apolipoproteins C-III and A-V, as well as the angiopoietin-like proteins 3 and 4. Together, findings from these studies provided strong support for an association between TG-rich lipoproteins and cardiovascular risk (2-6).
 
Concomitantly, there is recognition of an evolving global profile of dyslipidaemia, driven in large part due to the dual pandemics of obesity and type 2 diabetes. In the same session, Dr. Cristina Taddei (Imperial College London, UK), discussed data from the NCD Risk Factor Collaboration collected between 1980-2018 and involving 102.6 million adult participants. Notably, the study showed that mean non-HDL-C (which captures all atherogenic lipoproteins, including TG-rich lipoproteins) in low and middle-income countries, especially in Asia, were higher than in Western countries. Elevated non-HDL-C was responsible for 3.9 million deaths from cardiovascular disease in 2017, with half of these deaths in South, East and South-East Asia (7).
 
Beyond lifestyle, current guideline-recommended therapeutic options for managing hypertriglyceridaemia include fibrates and high-dose icosapent ethyl, although both have limitations. Against a background of statin therapy, fibrates have not demonstrated significant reduction in cardiovascular events in high-risk patients, although subgroup analyses in patients with atherogenic dyslipidaemia (elevated TG and low HDL-C) indicated clinical benefit (8). Additionally, fenofibrate is associated with safety issues which include elevation in serum creatinine (albeit reversible) (9) and adverse effects on hepatic enzymes. REDUCE-IT, with high-dose icosapent ethyl supported the concept of targeting elevated TG in statin-treated patients with or at risk of atherosclerotic cardiovascular disease, although given the magnitude of TG lowering (10,11), it is likely that the significant reduction in cardiovascular events observed also involves non-lipid effects. Moreover, omega-3 fatty acids also appear to be associated with increased risk for atrial fibrillation (12).
Given the limitations of current fibrates, there is a clear need for a novel approach to targeting atherogenic dyslipidaemia. In a state-of-the art lecture, Professor Jean-Charles Fruchart (Pasteur Institute, Lille, France) discussed the rationale for a novel class of therapeutic agents, the selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα). The first of these agents – pemafibrate – was identified from screening of more than 1300 compounds for SPPARMα activity. The incorporation of benzoxazole and phenoxyalkyl sidechains to the acidic region of the fibrate structure resulted in a Y-shaped structure with enhanced fit within the ligand-binding domain of PPARα. Consequently, pemafibrate showed improved selectivity and potency for PPARα compared with fenofibric acid (the active moiety of fenofibrate) (13). Clinical trials have also demonstrated efficacy in lowering TG and remnant cholesterol, as well as a favourable safety profile with no indication of elevation in serum creatinine. There is also evidence of anti-inflammatory activity, improved glucose homeostasis and insulin sensitivity, as well as favourable effects on other metabolic markers such as fibroblast growth factor-21 (14). The true test for the SPPARMα concept is PROMINENT, which is evaluating whether treatment with pemafibrate reduces cardiovascular events in type 2 diabetes patients with atherogenic dyslipidaemia despite maximally tolerated statin therapy (15).
Beyond pemafibrate, genetic insights have been instrumental in the development of novel therapeutics targeting TG metabolism. One of these is evinacumab, a fully human monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3). Already licensed for the management of homozygous familial hypercholesterolaemia, evinacumab has also shown benefit in treating refractory hypercholesterolaemia (16). Professor Robert S. Rosenson (Icahn School of Medicine at Mount Sinai, New York, USA) reported results of a phase II trial evaluating evinacumab in 51 patients with severe hypertriglyceridaemia, with screening TG levels 500 mg/dL or higher despite a strict diet. At the end of 12 weeks treatment with evinacumab, the median TG level decreased by 80% in patients with a single mutation or no mutations in LpL pathway genes, whereas those with a double copy of mutations in these genes had essentially no benefit. In patients with no identifiable LpL mutations, there was a median TG reduction of 68.8% (17). Future studies are planned in patients with elevated TG and low-density lipoprotein cholesterol (LDL-C), a profile often seen in patients with diabetes. Finally, another key theme emerging from the Congress was inequity in treatment of dyslipidaemia. This was evident in a report from the DA VINCI study, an EU-wide observational study of lipid management in nearly 6,000 patients in primary and secondary prevention. Overall, the study demonstrated issues with attainment of low-density lipoprotein cholesterol (LDL-C) goal; only about half of patients achieved their risk-based 2016 ESC/EAS LDL-C goal and about one-third their 2019 goal (18). As reported by Professor Michal Vrablik (Charles University in Prague, the Czech Republic), LDL-C goal attainment was even lower for Central and Eastern European countries. In the secondary prevention setting, attainment of 2019 ESC/EAS LDL-C goal was about half that in Northern and Western Europe (13% versus 23% and 22%, respectively), with only about one-third of patients prescribed high-intensity statin therapy and very few on ezetimibe (19).
 
References
 
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12. Jia X, Gao F, Pickett JK, Al Rifai M, et al. Association between omega-3 fatty acid treatment and atrial fibrillation in cardiovascular outcome trials: a systematic review and meta-analysis. Cardiovasc Drugs Ther 2021; doi: 10.1007/s10557-021-07204-z.
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16. Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med 2020;383:2307-19.
17. Rosenson RS, Gaudet D, Ballantyne CM, et al. A phase 2 trial of the efficacy and safety of evinacumab in patients with severe hypertriglyceridaemia. Poster EAS Helsinki 2021.
18. Ray KK, Molemans B, Schoonen WM, et al. EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: the DA VINCI study. Eur J Prev Cardiol 2020:zwaa047.
19. Vrablik M, et al. En Europa Central y Europa del Este, ¿se logran los objetivos de C-LDL basados en el riesgo en la atención primaria y secundaria? Comparación con otras regiones de Europa del estudio observacional DA VINCI. EAS Helsinki 2021 – Virtual. Noticias clínicas de última hora.

Single nucleotide polymorphisms (variants) in the ANGPTL4 gene (encoding angiopoietin-like 4 protein) are associated with decreased risk of ischemic stroke, according to this case-control study.
 
Genotyping was performed for 360 patients with ischemic stroke and 342 controls to assess the association between ANGPTL4 variants and risk for ischemic stroke. Carriers of the rs11672433-T variant (either CT or TT variants) were at lower risk of ischemic stroke than those with the CC genotype (adjusted odds ratio 0.005; 95% confidence interval, 0.02-0.11), even after multivariable adjustment including gender, age, smoking and alcohol status, hypertension, diabetes mellitus, lipids, and uric acid. Furthermore, gene-gene interaction between this variant and the ANGPTL4 rs4076317 variant was also associated with decreased risk for ischemic stroke.

Genetic studies have demonstrated association between angiopoietin-like 3 (ANGPTL3) single nucleotide polymorphisms and the risk of cardiovascular disease, providing a basis for the development of novel therapeutics. To date, however, there is no consensus whether ANGPTL3 haplotypes, i.e., polymorphisms that are inherited together, associate with risk for cardiometabolic disease.
 
This study investigated the association of three variants of the ANGPTL3 gene (rs1748195, rs11207997, and rs10789117) with cardiovascular risk factors, including diabetes mellitus, hypertension, obesity, metabolic syndrome, and dyslipidaemia. The analysis included data for 1,002 individuals in the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort who were followed for up to 6 years.
 
Compared with the wild type genotype, individuals with the rs10789117 ANGPTL3 variant had a lower risk of obesity, hypertension, metabolic syndrome and diabetes, and those with the rs1748195 variant were at lower risk of obesity. The authors concluded that these GTC and CTC haplotypes of the ANGPTL3 gene may help identify individuals with a genetic susceptibility to cardiometabolic disease.

As key players in infection, lipids are thought to play an integral role influencing the severity of SARS-CoV-2 infection. However, evidence for the association between baseline lipid levels and prognosis in COVID 19 has been less frequently studied. This report from the STACOV (Statin Therapy and COVID-19 Infection) database aimed to investigate this further.
 
Of 2159 patients included in this database, 1305 had available lipid results (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-HDL-C and triglycerides) before the infection and 297 had lipid results measured during hospitalization. In total, 191 patients had lipid results at both timepoints. Patients with severe COVID-19 had significantly lower HDL C concentration both at baseline (median [interquartile range] 1.25[1.06 to 1.48] mmol/L versus 1.32 [1.09 to 1.58] mmol/L in those with mild infection, p=0.007) and during hospitalization (0.73 [0.59 to 0.98] mmol/L versus 0.88 [0.72 to 1.08], respectively, p<0.001). Compared with those with mild infection, patients with severe COVID-19 also had higher triglycerides levels at baseline (1.44 [1.06 to 1.99] versus 1.31 [0.95 to 1.78] mmol/L) and during hospitalization (1.94 [1.39 to 2.88] versus 1.61 [1.13 to 2.18] mmol/L, p<0.001 at both timepoints).
 
Based on their findings, the authors concluded that the presence of atherogenic dyslipidemia, i.e. low HDL-C levels and high triglyceride levels, during hospitalization was associated with increased severity of COVID-19, and thus could represent prognostic criteria to aid clinical decision making for an earlier treatment intensification.

Accumulating evidence from genetic, observational, and clinical intervention studies shows that elevated levels of cholesterol carried by triglyceride-rich lipoprotein remnants (i.e., remnant cholesterol) contributes to residual cardiovascular risk. This study provides novel information showing that elevated fasting remnant cholesterol levels are associated with atherosclerosis progression among patients with ischemic stroke.
 
This study included 1,496 patients with a history of ischemic stroke and with baseline lipids and carotid artery imaging. Fasting remnant cholesterol was calculated as total cholesterol minus [high-density lipoprotein cholesterol and low-density lipoprotein cholesterol]. Common carotid artery intima-media thickness (cIMT) was the marker of subclinical atherosclerosis, with an abnormal value defined as mean cIMT and maximum cIMT ≥1 mm. The analysis showed that high remnant cholesterol levels were associated with atherosclerosis progression, as assessed by both cIMT measures. When comparing individuals in the highest versus lowest quartile of remnant cholesterol there was about 2-fold increased risk of progression (multivariable adjusted odds ratios 2.06 (95% confidence interval 1.46-2.91) for mean cIMT and 1.70 (95% confidence interval 1.23-2.35) for maximum cIMT.
 
The authors concluded that among patients with ischemic stroke, higher remnant cholesterol levels increased the risk of atherosclerosis progression, even among individuals at low-density lipoprotein cholesterol goal.

Genetic sequencing in large studies has provided important insights into the link between lipid levels and cardiovascular disease, especially coronary heart disease. Genome-wide association studies have so far identified more than 150 independent loci associated with serum lipids, with effect sizes of common variants ranging from less than 1 mg/dL to about 15 mg/dL. These may influence either one lipoprotein, all lipoprotein levels (for example, variants in the genes CETP, TRIB1, FADS1-2-3, and APOA1), or a combination of lipoproteins. There is, however, limited information for the impact of X chromosome genetic variation on blood lipids.
 
A new study provides novel insights. The authors analysed genetic and blood lipid data from a multi-ethnic cohort of 65,322 subjects using whole X chromosome sequencing. Replication analyses were performed in 456,893 European subjects. The study showed that common alleles on chromosome Xq23 were strongly associated with lower levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, with similar effects in men and women. Furthermore, carriage of these chromosome Xq23 lipid-lowering variants was associated with reduced risk for coronary heart disease (42,545 cases and 591,247 controls), as well as type 2 diabetes mellitus (54,095 cases and 573,885 controls). These novel findings merit further study.

In this retrospective cohort analysis, acute inflammatory response biomarkers were predictive of mortality and poor outcome in stroke patients.
This study evaluated data for risk factors and inflammatory markers in 3,013 Chinese ischemic stroke patients. Stroke subtype was defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. The inflammatory biomarkers of interest were white blood cell count (WBC), neutrophils, lymphocytes, serum C-reactive protein (CRP), and interleukin-6 (IL-6). The key endpoints were all-cause mortality and three functional outcomes defined by the National Institute of Health Stroke Scale (NIHSS), the modified Rankin Scale, and the Barthel Index.
The study concluded that the neutrophils and lymphocytes counts and their ratio, together with CRP level showed the best predictive ability for outcome compared with other inflammatory markers, even after adjustment for confounding factors, including conventional risk factors and TOAST subtype. These findings underline the importance of inflammation in the progression of adverse outcome following stroke. Furthermore, these biomarkers may offer discriminative value for new therapeutic approaches targeting inflammation to prevent ischaemic stroke.

Diabetes and chronic kidney disease (CKD) are each associated with increased risk for recurrent events after myocardial infarction (MI). The current study adds new evidence, showing that the combination of these morbidities exacerbates residual cardiovascular risk.
Investigators analysed health insurance data from 162,730 patients hospitalised for an MI. Individuals were categorised as either 1) with pre-existing cardiovascular disease without diabetes or CKD (55.2%); 2) with diabetes only (28.3%); 3) with CKD only (8.3%); and (4) with both diabetes and CKD (8.2%). Over the follow-up period, the rate of recurrent events was highest among individuals with both diabetes and CKD; 171 versus 135 with prior CVD, 110 for diabetes only, and 124 for CKD only (data given per 1000 patient-years). When compared with individuals with prior CVD only, those who had both diabetes and CKD were at 18% higher risk of recurrent cardiovascular events (hazard ratio 1.18, 95% confidence interval 1.14–1.22).
These findings demonstrate the very high residual risk among patients with diabetes and CKD following MI, and underline the need for intensive risk factor interventions, as recommended by guidelines, to reduce this risk.

Despite best treatment, high-risk patients continue to experience atherosclerosis progression, culminating in clinical manifestations such as myocardial infarction and ischaemic stroke. Fibroblast growth factor (FGF) 21 is a key regulator of energy metabolism and has been shown to offer potential benefit in metabolic diseases such as type 2 diabetes, although effects in atherosclerosis are uncertain.
The current study investigated whether administration of recombinant FGF 21 protects against atherosclerosis in hypercholesterolemic APOE*3-Leiden.CETP mice, a model of atherosclerosis initiation and progression in humans. FGF 21 reduced plasma total cholesterol (and non-high-density lipoprotein cholesterol), by accelerating triglyceride-rich lipoprotein turnover due to enhanced adipose tissue thermogenesis. This in turn resulted in reduced atherosclerotic lesion formation and severity. In addition, FGF 21 reduced body fat, improved glucose tolerance and substantially reduced hepatic steatosis. These findings, albeit in an animal model, suggest that FGF 21 may offer therapeutic potential for preventing atherosclerotic cardiovascular disease.

The atherogenic index of plasma (AIP) is a derived index reflecting plasma levels of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) and is calculated as log10(TG/HDL-C). It allows for assessing atherogenic dyslipidemia as a continuous variable. The current study investigated whether AIP was predictive of progression of coronary atherosclerosis beyond conventional risk factors.
In total 1,488 adults underwent serial coronary computed tomography angiography, with a median interval of 3.4 years between scans. Rapid plaque progression was defined as change of percentage atheroma volume (PAV) ≥1.0%/year. When analysed by tertiles of AIP, individuals in the highest tertile (median 2.70, interquartile range 0.41 to 7.50), demonstrated significantly greater progression of coronary atherosclerosis (odds ratio: 1.52, 95% confidence interval: 1.02–2.26; p = 0.042), compared with those in the lowest AIP tertile, after adjusting for traditional risk factors and baseline total PAV. On this basis, AIP may offer additive predictive value for atherosclerosis progression and cardiovascular risk stratification beyond conventional lipids.

This new analysis from the Look AHEAD (Action for Health in Diabetes) Study offers two key messages. First, the metabolic syndrome is highly prevalent in individuals with type 2 diabetes. Second, atherogenic (metabolic) dyslipidemia should be considered in risk stratification in this group.
Look AHEAD was designed to evaluate the effects of intensive lifestyle interventions (achieved through healthy eating and increased physical activity) compared with the then "standard of-care" diabetes management on cardiovascular disease outcomes. Briefly, the study enrolled 5145 obese/overweight individuals aged 45 to 76 years with a self-reported diagnosis of type 2 diabetes verified by measured glucose levels, use of antidiabetic medication, or physician’s report. The current analysis, which evaluated the prevalence and cardiovascular risk associated with atherogenic dyslipidemia, reports data from 4199 individuals (mean age 58.4 years, 62% women). The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for angina.
The investigators showed that atherogenic dyslipidemia (metabolic dyslipidemia) was highly prevalent, affecting 40% of individuals in the study. Importantly, they showed that the presence of this dyslipidemia was associated with increased risk for cardiovascular events (hazard ratio 1.30; 95% CI, 1.03–1.63, p=0.025), independently of other cardiovascular risk factors. Based on their findings, the investigators concluded that triglyceride–HDL-C phenotyping may offer additional utility for cardiovascular risk stratification among individuals with type 2 diabetes.

This report from the UK Biobank reports a linear association between higher plasma levels of high-density lipoprotein cholesterol (HDL-C) and lower risk of severe COVID-19 complications.
 
The authors analysed data from 317,306 participants in this study with complete data on HDL-C at baseline (2006–2010), using follow-up data for COVID-19 status from hospitalisation records in England (16 March to 31 May 2020), and death certificates with COVID-19 as the underlying cause (1 March to 30 September 2020). Overall, there were 869 hospitalisations for COVID-19. Age- and sex-adjusted analyses showed an inverse stepwise relationship between HDL-C and COVID-19 hospitalisation; each 0.2 mmol/L increase in plasma HDL-C concentration was associated with a 15% decrease in risk for COVID-19 hospitalisation. This association was only slightly attenuated after adjustment for health behaviours, inflammatory markers, and socio-economic status. The relationship between HDL-C and death due to COVID-19 also showed an inverse association of similar magnitude. The authors speculated that the functionality of HDL, including anti-inflammatory properties, may explain these associations.

This report, using Mendelian randomization based on genome-wide association studies of over 300,000 individuals, suggests causal association between high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) and coronary artery disease (CAD) that is locus- and mechanism-specific. While Mendelian randomization has been used to investigate the association of lipid traits with CAD, findings may be compromised by pleiotropic effects of the lipid trait, such as insulin resistance, that influence lipoprotein remodelling. Lipid traits also share genetic determinants with other metabolic traits, such as body mass index and waist-hip ratio, which are also risk factors for CAD. Consequently, this study evaluated the pleiotropic effects of lipid trait genetic variants and accounted for these effects in CAD. Overall, the authors showed that low-density lipoprotein cholesterol (LDL-C), HDL-C and TG were independently associated with CAD, suggesting that each is biologically active at the arterial wall. However, the authors conclude with a caveat that while Mendelian randomization may offer insights into causal effects of these traits, it cannot accurately estimate the magnitude of effects, and therefore may have limited utility in assessing the impact of therapeutic intervention.

A Joint Statement from the World Heart Federation, American College of Cardiology, American Heart Association, and the European Society of Cardiology has highlighted the threat posed by air pollution on cardiovascular health. Epidemiological evidence shows that ambient air pollution is responsible worldwide for 6.7 million deaths per year, half of which are due to cardiovascular causes. Indeed, air pollution ranks fourth as a risk for mortality, following low-density lipoprotein cholesterol, high body mass index, physical inactivity, or alcohol use. In particular, fine and coarse particulate matter is associated with increased cardiovascular morbidity, disability and mortality. The underlying mechanisms are multiple, likely involving increased systemic vascular oxidative stress, endothelial dysfunction, and proatherogenic changes in lipoproteins. Air pollution also favours thrombus formation, by increasing coagulation factors and platelet activation. While awareness of the impact of air pollution on population health is increasing, there is still limited appreciation of air pollution as a modifiable cardiovascular risk factor among healthcare providers.
 
In this Statement, the World Heart Federation, American College of Cardiology, American Heart Association, and the European Society of Cardiology advocate for 1) further research on cardiovascular disease and air quality; 2) education to raise awareness among health care providers; 3) the development of clinical guidelines on air pollution and cardiovascular disease; and 4) lobbying of governmental agencies to control and mitigate the effects of air pollution.

Given their profile of lipid-modifying activity, this review discusses whether selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) may have a role in managing the metabolic syndrome. The authors discuss the evidence for the first SPPARMα, pemafibrate, taking into account data from animal models of hypertriglyceridemia or non-alcoholic steatohepatitis (NASH), and clinical trials in patients with atherogenic dyslipidemia. The outstanding question is whether treatment with pemafibrate significantly reduces cardiovascular events in patients with atherogenic dyslipidemia. The PROMINENT study in patients with type 2 diabetes mellitus and atherogenic dyslipidemia, is the critical test of this question, and integral to defining the therapeutic potential of SPPARMα in reducing residual cardiovascular risk.

In children and adolescents, elevated levels of remnant cholesterol could be a marker of early atherosclerotic disease, according to this report. Investigators analysed data from 767 youths (594 were overweight or obese) with lipid and carotid intima-media thickness (CIMT) measurements. Elevated CIMT was defined as ≥ 0.56 mm, based on the 90th percentile of values observed in normal-weight children.
 
Compared with the lower tertile for remnant cholesterol, those in the middle and higher tertiles had a 2.3- and 2.4-fold increased risk of elevated CIMT, even after adjustment for age, sex, pubertal stage, body mass index and apolipoprotein B. This association persisted even when the effects of overweight or obesity were taken into account. The authors suggest that measuring remnant cholesterol levels may provide a marker of early atherosclerotic disease in the young.

In another report from the Danish study group, which analysed data from the Copenhagen General Population Study and the Copenhagen City Heart Study, moderately elevated triglycerides were associated with increased risk of both non-Alzheimer’s dementia and ischemic stroke. There was no association between elevated triglycerides and Alzheimer’s dementia.
 
When the group with the highest percentile of triglycerides (median 629 mg/dL or 7.1 mmol/L) was compared with the group in the 1-50th percentile (median 89 mg/dL or 1.0 mmol/L) the hazard ratios were 1.75 (95% confidence interval 1.17-2.63) for non-Alzheimer’s dementia, 1.18 (0.73-1.91) for Alzheimer’s disease, and 1.89 (1.50-2.38) for ischemic stroke. Results were similar after adjustment for multiple risk factors, including apolipoprotein E (APOE) genotype.

This survey highlights sub-optimal lipid management of acute coronary syndrome (ACS) patients compared with the 2019 ESC/EAS lipid guideline recommendations. Data on lipid profile, medications, follow-up visit planning, and screening for familial hypercholesterolaemia were collected by an on-line questionnaire for 2775 ACS patients from seven European countries. While almost all (93%) ACS patients received lipid-lowering therapy during hospitalization, only one-third were discharged on high-intensity statin treatment. Moreover, less than one-quarter (23%) had low-density lipoprotein cholesterol levels <70 mg/dL (<1.8 mmol/L) at first follow-up. The findings of this survey are consistent with other studies showing that lipid management of very high-risk patients, including those with ACS, is far from optimal.

Results of this kinetic study concluded that the PCSK9 (proprotein convertase subtilisin/kexin 9) monoclonal antibody evolocumab had only minor effects on lipoproteins that are involved in triglyceride (TG) transport (i.e., chylomicrons and very low-density lipoprotein [VLDL1]). In contrast, PCSK9 inhibition had a profound impact on lipoproteins that carry cholesterol (VLDL2, intermediate-density lipoprotein [IDL], and low-density lipoprotein [LDL]). Triglyceride transport and the metabolism of apolipoproteins (apo) B48, B100, C-III, and E were investigated in 13 subjects with type 2 diabetes mellitus, after a fat-rich meal, before and on evolocumab treatment. While treatment with evolocumab did not influence the kinetics of apoB48 in chylomicrons or apoB100 or TG in VLDL1, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-TG were increased by about 45%. Furthermore, LDL-apoB100 was also markedly reduced by evolocumab treatment. The findings provide insight into the metabolic effects of PCSK9 inhibition in atherogenic dyslipidaemia associated with type 2 diabetes.

CANTOS previously demonstrated in a proof-of-concept study that inhibiting the interleukin (IL)-1β innate immunity pathway reduced the risk of recurrent cardiovascular events in patients with previous myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hs-CRP). The current multicentre study investigated the association between admission IL-1β level and all-cause mortality in 1,398 patients with acute ST-segment elevation MI who underwent primary percutaneous coronary intervention. Admission IL-1β concentration was associated with all-cause mortality at 90 days, with an adjusted hazard ratio of 1.47 (95% confidence interval [CI] 1.16 to 1.87; p<0.002) per one standard deviation (SD) increase. Irrespective of hs-CRP concentration, patients in the highest tertile for admission IL-1β concentration had higher mortality rates at 90 days (adjusted hazard ratio 2.78, p = 0.0002) and at 1 year (adjusted hazard ratio 1.93, p = 0.005). The authors concluded that admission IL 1β concentration was prognostic for risk of early mortality in MI patients.

In a pilot study, treatment with pemafibrate for 3 months improved markers of hepatic inflammation, function and fibrosis in 38 patients with dyslipidemia and non-alcoholic fatty liver disease (NAFLD). Specifically, there was improvement in alanine aminotransferase, a marker of hepatic inflammation, as well as decreases in alkaline phosphatase and γ-glutamyl transpeptidase and improvement in the albumin-bilirubin score. This is the first clinical study evaluating the effect of pemafibrate in patients with NAFLD.

Peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor integral to lipid metabolism and inflammation, may affect the initiation and progression of atherosclerosis by reducing inflammatory responses. In a model of atherosclerosis (LDLR knockout pigs with balloon injury), the selective peroxisome proliferator-activated receptor alpha modulator pemafibrate was associated with the inhibition of inflammatory responses in the coronary artery.

Emerging data have highlighted triglyceride-rich lipoproteins (TGRLs, for which triglycerides are a surrogate marker), lipoprotein(a), and C-reactive protein as a measure of inflammation, as potential contributors to residual cardiovascular risk among individuals with well controlled low-density lipoprotein cholesterol levels. This latest review appraises the data and puts it into context. Novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development, and major prospective studies testing these will be crucial to determining their role in reducing residual cardiovascular risk.

In an animal model of apolipoprotein CIII deficiency (apoCIII knockout [KO] rabbits), there was improvement in triglyceride (TG)-rich lipoprotein metabolism and reduction in atherosclerosis compared with wild type rabbits. These findings suggest that therapeutic approaches to inhibit apoCIII expression may offer potential for treating hyperlipidemia and reducing atherosclerosis.
 
Compared with wild type rabbits, apoCIII KO rabbits fed a normal diet had reduced TG levels, accompanied by reduction in levels of very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins. On a cholesterol-rich diet, apoCIII KO rabbits had lower levels of plasma total cholesterol and TG than wild type rabbits, due to reduction of β-VLDL. Both aortic and coronary atherosclerosis were significantly reduced in apoCIII KO rabbits compared with WT rabbits.

Competing risks analysis showed that remnant cholesterol was a strong independent risk factor for cardiovascular mortality but not for death due to cancer or other causes. Investigators used this analysis tool to evaluate data from two prospective studies including 5729 subjects. Overall, there were 861 (15%) deaths, 234 (27%) due to cardiovascular disease, 245 (27.5%) due to cancer, 271 due to other causes (31.5%) and 111 unknown causes of death (12.8%). Remnant cholesterol was only a strong risk factor for cardiovascular death; levels ≥1.29 mmol/L were associated with more than 2-fold increase in risk (risk 2.54, 95% confidence interval 1.21 to 5.34). These findings provide further support to strengthen the case for remnant cholesterol as a residual cardiovascular risk factor.

A report from the Copenhagen General Population Study provides support. The authors evaluated data from 25,480 subjects who were not on lipid-lowering therapy and had no history of myocardial infarction (MI) at study entry. Cholesterol and triglyceride contents of very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and low-density lipoproteins (LDL) were measured using the Nightingale Health nuclear magnetic resonance spectroscopy platform. Briefly, the study showed that for each 1 mmol/L (39 mg/dL) increase in VLDL-cholesterol content, the hazard ratio for MI was 2.07 (95% confidence interval 1.81-2.36), whereas for VLDL-triglyceride, the corresponding hazard ratio was 1.19 (95% confidence interval 1.14-1.25). Increasing LDL cholesterol by 1 mmol/L was associated with a hazard ratio of 1.86 (95% confidence interval 1.62-2.14) and for IDL cholesterol, the hazard ratio was 5.38 (3.73-7.75). Based on their findings, the authors concluded that VLDL-cholesterol explained 46% of the risk of MI from elevated levels of apolipoprotein B-containing lipoproteins.

In individuals with atherosclerotic cardiovascular disease (ASCVD) on statin therapy, the presence of diabetes confers a higher residual cardiovascular risk, according to this report. The analysis used data from 3271 statin-treated patients with ASCVD (40% with diabetes) in the AIM-HIGH study, to evaluate the excess risk of first and total recurrent ASCVD events associated with diabetes over a 3-year follow-up period. The presence of diabetes conferred a 21% increase in the risk for first events (p = 0.038) and a 23% increase in the risk of total recurrent events (p = 0.012). On this basis, the authors concluded that for statin-treated patients with ASCVD, the presence of diabetes confers a significantly greater residual risk for initial and total ASCVD events.

Individuals with very high triglycerides (>1,000 mg/dL) are at high risk of acute pancreatitis. In a preliminary report, pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), decreased triglycerides to <250 mg/dL in three individuals with baseline triglycerides ranging from 1,326 mg/dL to 2,300 mg/dL. This proof-of-concept study suggests potential for pemafibrate for the management of patients with severe hypertriglyceridaemia.

This meta-analysis including over 130,000 patients investigated whether the intensity of lipid lowering impacts inflammation, as measured by high-sensitivity C-reactive protein (hsCRP), in turn reducing major cardiovascular events (MACE). The analysis included data from 14 trials evaluating more versus less intensive lipid lowering, involving comparison of statins, ezetimibe, or PCSK9 inhibitors with placebo or active controls. While more intensive lipid lowering did not influence hsCRP levels (p=0.31), this approach did significantly reduce the risk of MACE, compared with less intensive lowering (p<0.001). However, there appears to be a persistent residual inflammatory risk despite intensive reduction in levels of low-density lipoprotein cholesterol.

CANTOS provided proof of the concept that reducing residual inflammatory risk with the interleukin (IL)‑1β inhibitor canakinumab reduced time to first major adverse cardiovascular events in patients with prior myocardial infarction (MI). However, from a societal perspective, the impact of canakinumab on the total burden of cardiovascular events is more relevant. This was the focus of the latest analysis from this study. The primary endpoint was serious cardiovascular events, a composite of myocardial infarction, stroke, coronary revascularization, and cardiovascular death.
 
The CANTOS investigators showed that treatment with canakinumab reduced the rate of total serious cardiovascular events, from 10.4 per 100 person-years in the placebo group, to 8.4, 8.3 and 8.2 per 100 person-years in the 50 mg, 150 mg, and 300 mg canakinumab groups, respectively. This translated to between 20% and 22% relative reduction in the rate of total serious cardiovascular events compared with placebo. These findings reaffirm the benefit of targeting residual inflammatory risk to reduce the total burden of cardiovascular events in high-risk patients.

High-density lipoprotein (HDL) cholesterol is known to be inversely associated with cardiovascular disease. Trials of drugs that raise HDL cholesterol have, however, failed to show clinical benefit, and are further supported by genetic insights. This ‘HDL paradox’ has called into question the role of HDL cholesterol as a surrogate for HDL.
 
Interest has focused on the pleiotropic functions of HDLs, including a role in promoting reverse cholesterol transport and its anti-inflammatory, antithrombotic, and anti-oxidative effects. The JUPITER (Justification for the Use of Statins in Prevention: An Intervention Evaluating Rosuvastatin) trial has previously investigated a number of HDL-related biomarkers of risk. This latest report relates to the HDL inflammatory index (HII), a putative measure of HDL anti-inflammatory function. This was measured at baseline and after 12 months on the study treatment in this nested case-control study of the JUPITER trial. The investigators showed a nonlinear relationship between HII and incident cardiovascular events. Compared with the reference group (HII 0.5–1.0) with the lowest event rates, subjects with baseline HII ≤0.5 were at increased risk of cardiovascular disease or death (adjusted hazard ratio, 1.53; 95% confidence interval 1.06–2.21; p=0.02). Additionally, the HII modified the beneficial association between HDL particle number and cardiovascular events; only individuals with optimally functioning anti-inflammatory HDLs demonstrated this inverse relationship. These findings offer insights into the role of HDL that may help to explain the ‘HDL paradox’.

Much of the research surrounding high-density lipoproteins (HDL) has centred on a potential atheroprotective role. It is, however, evident from failures of trials evaluating treatments aimed at raising HDL cholesterol, as well as genetic insights, that a low HDL cholesterol level is a marker rather than a risk factor for atherosclerotic cardiovascular disease (ASCVD). Emerging evidence suggests that HDLs might be involved in the development of diseases beyond ASCVD, notably, infection, autoimmune disease, cancer, kidney disease, and lung disease. These novel findings are discussed in this latest review.

inhibition of lipoprotein lipase and hepatic very low-density lipoprotein (VLDL) uptake, and increased hepatic VLDL secretion. In addition, apoCIII promotes VLDL formation and assembly and has proinflammatory and prothrombotic effects. Mendelian randomization studies have indicated a causal association between apo CIII and cardiovascular disease, as carriers of loss-of-function mutations in APOC3 had 40% lower TG levels and a 40% reduction in risk of coronary artery disease. These findings were also supported by prospective observational studies linking apoCIII levels and incident coronary artery disease. However, whether this association is also applicable to postprandial apoCIII levels is uncertain. This study addressed this, by investigating changes in apoCIII concentration after a standardized oral fat load test and whether both fasting and postprandial apoCIII levels predict disease progression in coronary artery disease patients, comparing native versus chylomicron-free serum.
 
The study included 195 patients from the prospective Homburg Cream and Sugar study, 92 with a prior cardiovascular event. Almost all (97%) were treated with a statin. There were no significant changes in apoCIII concentration after the oral fat load test. Importantly, apoCIII concentration in chylomicron-free serum was independently associated with event-free survival in coronary artery disease patients in both fasting (Hazard ratio 2.09, 95% confidence interval 1.32-3.32, p = 0.002), and postprandial (Hazard ratio 1.67, 1.06–2.29, p = 0.028) states. On the basis of their findings, the authors proposed that apoCIII, measured in chylomicron-free serum, may have utility as a risk marker to predict residual cardiovascular risk.

Atherogenic dyslipidaemia, characterised by elevated triglycerides and low plasma levels of high-density lipoprotein cholesterol (HDL-C), is implicated as a contributor to lipid-related residual cardiovascular risk. This post hoc analysis of high-risk primary prevention patients in Mexico showed that the CNIC (Centro Nacional de Investigaciones Cardiovasculares) polypill, a fixed dose combination of aspirin, the ACE-inhibitor ramipril and simvastatin, also favourably impacted atherogenic dyslipidaemia in this group.  
In total, 533 patients included in a prospective registry were evaluated for blood lipids at baseline (usual care) and after 12 months of treatment with the CNIC-polypill. After one year of treatment, there were significant reductions (p<0.001) in levels of total cholesterol (by 22%), triglycerides (by 29%), and non-HDL-C (by 29%) (all p < 0.001). In addition, atherogenic dyslipidaemia-related ratios including remnant cholesterol and the atherogenic index, were also significantly lower with the polypill treatment. Moreover, patients were seven-fold more likely to attain desirable TG levels with this treatment, given in a real-world primary prevention setting.

The ongoing pandemics of obesity, metabolic syndrome and type 2 diabetes have led to escalation in the global prevalence of nonalcoholic fatty liver disease (NAFLD). Worldwide it is estimated that NAFLD affects 25% of the population, with the highest prevalence in the Middle East and South America. Multiple comorbidities are associated with NAFLD, including dyslipidaemia. The clinical profile of pemafibrate, a selective peroxisome proliferator activated receptor α modulator (SPPARMα), evident from clinical trials in patients with dyslipidaemia, including improvement in liver function, suggests potential benefit with this agent in the setting of NAFLD. This pilot study aimed to investigate pemafibrate in patients with NAFLD.
 
The study included 20 patients with NAFLD and dyslipidaemia, who received pemafibrate 0.1 mg twice daily. After 12 weeks, treatment with pemafibrate resulted in reduction in serum alanine aminotransferase (ALT) levels, from 75.1 IU/L at baseline to 43.6 IU/L at week 12 (p=0.001). There were also significant improvements in plasma triglycerides and high-density lipoprotein cholesterol levels. On the basis of their findings, further evaluation of pemafibrate for management of NAFLD with dyslipidaemia is merited.

According to this analysis from the Verona Heart Study, elevated plasma levels of apolipoprotein CIII (apoCIII) confer an increased risk of acute ischaemic cerebrovascular events (stroke and transient ischaemic attack, TIA).
 
The Verona Heart Study aims to identify new risk factors for coronary artery disease (CAD) in individuals undergoing coronary angiography. The current analysis included data from 950 people (median age 65 years, 31% female) with (n=774) and without (n=176) angiographically defined CAD. The primary endpoint was acute nonfatal ischaemic cerebrovascular events (ischaemic stroke or TIA). After a median follow-up of 130 months (interquartile range, 69–189 months), 95 (10%) individuals had a primary endpoint. These individuals also had higher plasma levels of apoCIII at entry to the study compared with those who did not experience a stroke/TIA (11.4; interquartile range: 9.3–14.4 mg/dL versus 8.7–13.0 mg/dL). Moreover, individuals with apoCIII levels above the median (>10.6 mg/dL) had a 2-fold increased risk of future stroke/TIA, which persisted even after adjustment for potential confounders including sex, age, hypertension, atrial fibrillation, oral anticoagulant treatment, and plasma lipids. The authors suggest that this association might be mediated by enhancement of the coagulation cascade and thrombin generation due to elevated apoCIII levels. However, they acknowledge that further study is needed to establish whether measurement of apoCIII plasma levels has a potential role in patient management in routine practice.

The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial was designed to investigate treatment strategies in patients with diabetes and stable ischaemic heart disease. The study showed no significant difference in the primary endpoint (a composite of death, myocardial infarction and stroke, i.e. major cardiovascular events) in cohorts allocated to prompt revascularization or medical therapy. The investigators recognised, however, that despite best treatment, including statins, these patients have a high residual cardiovascular risk of recurrent events.
 
Accumulating evidence from mechanistic and genetic studies has implicated elevated triglycerides (TG), a marker of TG-rich lipoproteins and their remnants, as a contributor to this high residual cardiovascular risk. Consequently, this analysis from the BARI 2D study investigated the association between TG levels and risk for major cardiovascular events in 2,307 patients with type 2 diabetes and coronary artery disease. At baseline, median TG levels were 148 mg/dL; 18% of patients had TG levels 150-199 mg/dL, 28% 200-499 mg/dL and 3% ≥500 mg/dL. In adjusted analyses, every 50 mg/dL increase in TG level was associated with a 3.8% (Hazard ratio 1.038, 95% confidence interval [CI] 1.004-1.072, p <0.001) increase in the primary composite outcome. Subgroup analyses showed no interaction according to female sex, additional non-coronary atherosclerotic disease, chronic kidney disease or low plasma levels of low-density lipoprotein cholesterol (<100 mg/dL). These findings therefore support an independent association between elevated TG and adverse cardiovascular outcomes in patients with type 2 diabetes and established coronary artery disease.

This analysis of the MEDIDIET study investigated the effect of different diets on remnant cholesterol levels in patients with metabolic syndrome, as well as the association between NAFLD and remnant cholesterol. In total, 237 individuals were randomly assigned to the Mediterranean diet (MD), Low Glycaemic Index diet (LGID), or Low Glycaemic Index Mediterranean diet (LGIMD). Remnant cholesterol was calculated as [total cholesterol-low density lipoprotein cholesterol (LDL-C)-high density lipoprotein cholesterol (HDL-C)]. Liver ultrasound was performed at baseline, 3 and 6 months to assess the NAFLD score. All three dietary interventions reduced levels of remnant cholesterol at 3 and 6 months; the effect was stronger among the group assigned to the LGIMD. Remnant cholesterol was independently associated with the severity of NAFLD. In conclusion, the Mediterranean dietary pattern may be a useful strategy for reducing remnant cholesterol and the severity of NAFLD in patients with metabolic syndrome.

Despite best evidence-based management including well-controlled low-density lipoprotein cholesterol levels (LDL-C), high-risk patients continue to be at risk of cardiovascular events. This implies that there are other drivers of residual risk, which are often unrecognized and therefore not addressed in clinical practice. This review discusses the contribution of inflammatory, pro-thrombotic, and metabolic pathways to residual cardiovascular risk. Among the potential contributors to residual metabolic risk, the focus is on triglyceride-rich lipoproteins and their remnants, lipoprotein(a) and diabetes. The authors underline the need for a personalized approach to risk prediction and subsequent treatment of high-risk patients in routine practice.

Beyond lipids, inflammation may be an important contributor to residual cardiovascular risk in type 2 diabetes patients, according to this analysis. The study evaluated data from 511 type 2 diabetes patients, stratified for statin use, attainment of low-density lipoprotein cholesterol (LDL-C) goal and the presence of diabetes complications. Residual inflammatory risk was defined as persistent circulating levels of high sensitivity C-reactive protein (hs-CRP) >2 mg/L despite well controlled LDL-C levels (<70 mg/dL or <1.8 mmol/L). In this group, 39.2% of type 2 diabetes patients had residual inflammatory risk, and prevalence was even higher among patients with diabetic nephropathy. Glucose-associated variables were strongly associated with residual inflammatory risk in patients at LDL-C goal. Overall, the findings suggest that glycaemic control, insulin resistance, non-LDL-C lipid variables and central obesity are implicated in residual inflammatory risk in type 2 diabetes patients with well controlled LDL-C levels.

Future treatments for prevention of atherosclerotic cardiovascular disease should target both inflammation and additional cholesterol reduction, according to this latest analysis from the Cardiovascular Inflammation Reduction Trial (CIRT). CIRT tested whether the addition of low-dose methotrexate 15 mg/day reduced major adverse cardiovascular events (MACE) in patients with stable coronary artery disease (CAD) and either diabetes mellitus or metabolic syndrome or both. The topline results of the trial did not shown any benefit from this intervention, with no reduction in interleukin (IL)-1β, IL-6, or high-sensitivity C-reactive protein (hs-CRP). A major factor was that CIRT did not mandate high residual inflammation as an entry criterion for the study.

This subsequent analysis from CIRT compared baseline levels of IL-6, hs-CRP and low-density lipoprotein cholesterol (LDL-C) as markers of residual risk in 4168 patients enrolled in the study. Baseline levels of IL 6, hs-CRP, and LDL-C were all predictors of major recurrent cardiovascular events. Adjusted hazard ratios [HR; 95% confidence interval (CI)] for increasing quartiles of IL-6 were 1.0 (referent), 1.66 (1.18-2.35), 1.92 (1.36-2.70), and 2.11 (1.49-2.99), p<0.0001); for increasing quartiles of hs-CRP were 1.0 (referent), 1.28 (0.92-1.79), 1.73 (1.25-2.38), and 1.79 (1.28-2.50; p<0.0001) and for increasing quartiles of LDL-C were 1.0 (referent), 1.12 (0.78-1.62), 1.25 (0.87-1.79), and 2.38 (1.72-3.30; p<0.0001). Patients with both elevated levels of LDL-C and inflammation were at highest risk. The authors concluded that targeting both inflammation and LDL-C is needed to reduce cardiovascular risk.

This timely review discusses the evidence for remnant lipoprotein particles as a contributor to residual cardiovascular risk. Remnant lipoproteins are derived from the lipolysis of very low-density lipoproteins (VLDL, containing apolipoprotein B100) and chylomicrons (containing apolipoprotein B48). These lipoprotein particles vary in size and composition, and are enriched in cholesteryl esters and apolipoprotein E. The authors highlight the need for a generally accepted definition of remnant lipoproteins, as well as standardisation in their measurement. Both are essential to understanding the role of remnant lipoproteins in promoting atherosclerotic cardiovascular disease.

Data from the Beijing Longitudinal Study of Aging indicate that the ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is associated with future risk of type 2 diabetes mellitus in the Chinese population. This analysis included data from 1,460 subjects (733 men and 727 women, mean age at baseline 68.8 years) followed for up to 25 years. Overall, the cumulative incidence of new-onset type 2 diabetes mellitus was 8.42 per 1000 person-years. Individuals with a time-dependent TG/HDL-C ratio of 1.31–1.74 and ≥1.75 had a 2.75- and 2.84-fold higher risk of developing type 2 diabetes mellitus, respectively, compared with those with a ratio <0.87. These findings indicate that the TG/HDL-C ratio is an independent risk factor for developing type 2 diabetes mellitus. The authors concluded that lowering the TG/HDL-C ratio may be a preventive measure against the development of type 2 diabetes mellitus in the general population, re-emphasizing the importance of monitoring the lipid profile in clinical practice.

Elevated triglycerides are one of the common risk factors contributing to both chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus, according to this report. This cross-sectional study evaluated common and unique risk factors for CKD and NAFLD in 1,992 subjects with type 2 diabetes mellitus. The common risk factors associated with both CKD and NAFLD were age, triglycerides, and uric acid; unique risk factors were albumin and HbA1c for CKD, and body mass index, white blood cell count, serum glutamic pyruvic transaminase level (aka alanine aminotransferase ) and smoking for NAFLD. The analysis also confirmed a causal relationship between NAFLD and CKD in this patient group.

New insights from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study showed that fibrate treatment in the initial trial period was associated with a legacy benefit in terms of improved survival during the post-trial follow-up. Patients completing the ACCORD Lipid study, a randomized controlled trial of 5,518 participants allocated simvastatin plus fenofibrate or simvastatin plus placebo, were invited to enter an extended follow-up study (ACCORDION). This analysis focused on 940 (17.0%) patients with dyslipidemia (484 assigned to fenofibrate-simvastatin therapy), which was defined as the combination of the highest tertile of triglycerides (204 mg/dL) and lowest tertile of high-density lipoprotein cholesterol (34 mg/dL) at baseline in the ACCORD Lipid. Overall, 765 of these patients entered the ACCORDION study. Over a median extended follow-up of 4.9 years, patients treated with fenofibrate in the ACCORD trial had lower incidences of cardiovascular mortality, nonfatal myocardial infarction, congestive heart failure and major coronary heart disease compared with the group allocated simvastatin alone. Furthermore, allocation to the combination of fenofibrate and simvastatin was associated with a beneficial legacy effect on all-cause mortality during the post-trial follow-up (adjusted Hazard ratio 0.65, 95% confidence interval 0.45–0.94, p= 0.02). This was achieved despite similar lipid profiles in both groups during the extended follow-up.

About one in four statin-treated adults have triglycerides ≥150 mg/dl (≥1.7 mmol/L), according to the latest data from the US National Health and Nutrition Examination Survey (NHANES, 2007–2014). Elevated triglycerides are recognized as a risk factor for atherosclerotic cardiovascular disease. While guidelines recommend statins as a first treatment option, this may be insufficient in a substantial proportion of patients. These new survey data aimed to evaluate the prevalence of elevated triglycerides ≥150 mg/dL (recommended as the upper limit for desirable triglyceride levels) among US statin-treated patients, using data from NHANES. Overall, the results showed that 25.9% of statin-treated patients have triglycerides ≥150 mg/dL; this translates to 12.3 million people in the USA. These findings underline the need for new approaches to address this unmet clinical need and reduce the residual cardiovascular risk associated with elevated triglycerides in these patients.

New insights from the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT) show that the benefit observed in the trial may be mediated by eicosapentaenoic acid (EPA) levels. REDUCE-IT stunned the clinical community in late 2018 when it reported that treatment with 4 g icosapent ethyl was associated with a 25% reduction in the primary endpoint, a composite of cardiovascular death, myocardial infarction (MI), stroke, coronary revascularization and unstable angina compared to placebo (p<0.00000001), as well as a 26% reduction in the key secondary ‘hard endpoint’ of cardiovascular death, MI and stroke. There was, however, much debate as to what drove this benefit, as the relative reduction in risk was similar in patients with baseline triglycerides ≥ or <150 mg/dL. Moreover, adjusting for triglycerides over time showed that reduction in triglyceride levels only accounted for a small fraction of the benefit. In this new analysis, the REDUCE-IT Investigators showed that higher on-treatment EPA levels were associated with a lower risk of the primary and key secondary endpoint (p<0.001), as well as a lower risk of outcomes of any MI, stroke, coronary revascularization or unstable angina.

Professors Shizuya Yamashita, Daisaku Masuda and Yuji Matsuzawa overview preclinical data and evidence from clinical trials with pemafibrate in this review. Specifically, they highlighted the favourable safety profile with pemafibrate, compared with current fibrates such as fenofibrate, for liver and kidney function, including lack of effect on serum creatinine or estimated glomerular filtration rate, as well as reduced propensity for drug-drug interactions.
 
Additionally, an experimental study investigated the effect of pemafibrate on microglial cells. Microglia are the primary innate immune effector cells of the central nervous system; they act as sensors of pathology and can develop into brain macrophages and perform immunological functions. In this study, pemafibrate suppressed the microglia via inhibition of NF-κB phosphorylation and cytokine expression. These effects were also observed with fenofibrate. However, the pathways mediating this effect appear to differ, involving distinct PPARα and SIRT1-dependent pathways.
Ogawa K, Yagi T, Guo T et al. Pemafibrate, a selective PPARα modulator, and fenofibrate suppress microglial activation through distinct PPARα and SIRT1-dependent pathways. Biochem Biophys Res Commun 2020; doi: 10.1016/j.bbrc.2020.01.118. [Epub ahead of print]

This post hoc analysis from the ODYSSEY DM-DYSLIPIDEMIA trial investigated the efficacy of alirocumab, a PCSK9 monoclonal antibody, in the management of patients with type 2 diabetes mellitus and mixed dyslipidemia. The investigators defined mixed dyslipidemia as the combination of baseline triglycerides ≥200 mg/dL and high-density lipoprotein cholesterol (HDL-C) <40 mg/dL in men or <50 mg/dL in women. Alirocumab was compared with background usual care (ezetimibe, fenofibrate, omega-3 fatty acids, niacin, and no additional lipid-lowering therapy). Of the 413 individuals included in the main trial, 186 individuals randomized to alirocumab (n = 128) or usual care (n = 58) were included in this analysis. Treatment with alirocumab led to significant reductions (p<0.0001) from baseline to week 24 in non-HDL-C (least square mean difference − 35.0%) and apoB (− 34.7%). Alirocumab reduced triglycerides to a greater extent than usual care overall, ezetimibe, or no lipid lowering therapy (adjusted mean difference − 5.0% versus usual care; − 18.2% versus vs ezetimibe; − 13.5% versus no lipid lowering therapy), although alirocumab was less effective than fenofibrate (adjusted mean difference 9.6%). Alirocumab also significantly increased HDL-C compared with usual care. Despite the limitations associated with post hoc analysis, these findings suggest that alirocumab may be a therapeutic option for individuals with type 2 diabetes mellitus and mixed dyslipidemia.

A preclinical study has highlighted potential for a dual apolipoprotein (apo) C-II mimetic and apoC-III antagonist in the management of elevated triglycerides. ApoC-II plays a critical role in the metabolism of triglyceride-rich lipoproteins, by acting as a cofactor of lipoprotein lipase (LPL), the main enzyme that hydrolyses triglycerides carried by these lipoproteins. There have been rare cases of genetic deficiency in apo C-II; affected individuals have very high triglycerides and are at risk of pancreatitis. These findings, together with mechanistic studies, suggest that apoC-II may be a potential target for novel approaches to manage hypertriglyceridemia. The current study reports data with a novel agent, D6PV, which activates LPL and antagonizes the triglyceride-raising effect of apoC-III. In experimental models (apoC-II-deficient mice and hAPOC3-transgenic mice), D6PV markedly lowered triglycerides by more than 80% within a few hours of dosing, as well as lowering apoC-III in the latter model. D6PV was also shown to act independently of LPL, as it lowered triglycerides by 50% in whole-body inducible LPL knockout mice. These promising findings merit further investigation of this agent as a potential treatment for hypertriglyceridemia.

Consideration of triglycerides level, a surrogate for triglyceride-rich lipoproteins and their remnants, as a contributor to lipid-related residual cardiovascular risk, has gained new focus. This review discusses the available evidence from population-based and secondary prevention studies, genetic insights, and Mendelian randomization studies which support triglycerides as a causal risk factor for atherosclerotic cardiovascular disease. Mendelian randomization analysis suggests that the benefit of genetic lowering of triglycerides and low-density lipoprotein cholesterol is similar per unit change in apolipoprotein-B. Divergent results from recent major outcomes studies with omega-3 fatty acids - REDUCE-IT, STRENGTH and VITAL, underline the need to take account of dose, as well as potential cardiovascular benefits through non-lipid pathways.

This new statement takes account of the results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which evaluated the effects of icosapent ethyl 4 g/day on major adverse cardiovascular events in selected high- or very high-risk, statin-treated patients with elevated triglycerides. Treatment with icosapent ethyl was associated with 25% relative reduction (95% confidence interval 17%-32%, p <0.001) in the primary outcome of first major adverse cardiovascular event (cardiovascular death, MI, stroke, coronary revascularization and hospitalization for unstable angina) compared with placebo. The National Lipid Association recommends icosapent ethyl 4 g/day for patients aged at least 45 years with clinical atherosclerotic cardiovascular disease, or aged ≥50 years with diabetes mellitus requiring medication plus at least one additional risk factor, with fasting triglycerides 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy (± ezetimibe).

Following the recommendation from an Independent Data Monitoring Committee, the Phase III STRENGTH trial for Epanova (containing both eicosapentaenoic acid and docosahexaenoic acid, 4 g/daily) has been stopped due to its low likelihood of demonstrating a benefit to patients with mixed dyslipidemia who are at increased risk of cardiovascular disease.
 
STRENGTH was a large-scale, global cardiovascular outcomes trial designed to evaluate the safety and efficacy of Epanova compared to placebo (corn oil), in patients on optimal statin therapy with mixed dyslipidemia and at high risk for cardiovascular disease (atherosclerotic cardiovascular disease, history of diabetes mellitus, or aged >50 years [men] or >60 years [women] with at least one cardiovascular risk factor). Mixed dyslipidemia was defined as the combination of triglycerides ≥180 and <500 mg/dL and high-density lipoprotein cholesterol <42 mg/dL for men or <47 mg/dL for women. A total of 13,086 patients were enrolled at 675 sites in 22 countries. The primary outcome was first occurrence of major adverse cardiovascular events, defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), nonfatal stroke, emergent/elective coronary revascularization, or hospitalization for unstable angina. The key composite outcome was first occurrence of cardiovascular death, non-fatal MI and non-fatal stroke. Full findings are awaited.

Marine omega-3 supplementation lowers the risk of cardiovascular events, including cardiovascular death, but dose is critical. This is the conclusion of an updated meta-analysis incorporating data from 127,477 subjects in 13 randomized controlled trials. The key outcomes in this meta-analysis were myocardial infarction, coronary heart disease (CHD) death, total CHD events, total stroke, cardiovascular death, total cardiovascular disease events and major vascular events. Excluding data from REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), marine omega-3 supplementation was associated with significant reduction in the risk of the key outcomes: for myocardial infarction (rate ratio [95% confidence interval] 0.92 [0.86, 0.99] p=0.020); CHD death 0.92 [0.86, 0.98] p=0.014); total CHD events 0.95 [0.91, 0.99] p=0.008; cardiovascular death (0.93 [0.88, 0.99] p=0.013), and total cardiovascular disease events 0.97 [0.94, 0.99] p=0.015). These associations were strengthened when data from REDUCE-IT were included in the analysis. The authors did, however, note that in the setting of high to very high-risk patients treated with best evidence-based therapy, a high dose of marine omega-3 supplementation may be needed to attain clinical benefit. These findings are also in line with the different outcomes of the REDUCE-IT vs. STRENGTH studies (discussed in a recent editorial on the R3i website).

This report, based on a recent joint consensus panel of the European Atherosclerosis Society and the European Federation of Clinical Chemistry and Laboratory Medicine, provides practical guidance on the measurement of atherogenic lipoproteins. According to this consensus, the main lipid panel for estimating risk of cardiovascular disease should include total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and calculated non-HDL-C, and should be measured nonfasting. LDL-C (either directly measured or estimated) is the primary target of lipid-lowering therapies. Lipoprotein(a)-cholesterol should be estimated at least once in all patients at risk of cardiovascular disease. The residual risk of cardiovascular disease in individuals on optimal LDL-lowering treatment should be assessed using non-HDL-C or apolipoprotein B100, especially in patients with mild-to-moderate hypertriglyceridemia (2–10 mmol/L). This report provides practical guidance for laboratories and clinicians for the measurement of atherogenic lipoproteins.

A recent report has reviewed PPARalpha (peroxisome proliferator-activated receptor alpha) polymorphisms. PPAR polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, as well as single nucleotide polymorphisms which have a less defined biological role. The L162V variant has been associated with lipid changes [increases in total and low-density lipoprotein cholesterol, and triglycerides, low plasma levels of high-density lipoprotein cholesterol, and elevated lipoprotein (a)], although it is not clear whether this lipid profile is also associated with increased cardiovascular risk. The V227A variant has been associated with reduced hepatic steatosis and an increase in glutamyl transpeptidase levels in non-drinking Asians. These PPAR polymorphisms may offer potential in explaining the variability in response to specific pharmacotherapeutic approaches.

A low plasma level of high-density lipoprotein cholesterol (HDL-C), which is a marker of average high triglycerides (TG)/remnant cholesterol, could be used to monitor TG levels long-term, according to this report. This cross-sectional study evaluated data from 108,731 individuals, including 1313 individuals with lipid measurement at ten repeated visits, and 10,479 individuals with two lipid measurements 10 years apart. There was a close inverse association between HDL-C and TG/remnant cholesterol. Among individuals with data at baseline and 10 years, those with the highest TG and corresponding lowest HDL‑C initially, had similar levels 10 years later. Prospectively, individuals with increased TG/remnant cholesterol were also at increased risk of myocardial infarction, consistent with HDL-C monitoring findings. The authors suggest that HDL-C may have a role in follow-up of TG levels long-term.

About one in four US adults, nearly one-third on statin treatment, have elevated fasting triglycerides (TG ≥1.69 mmol/L or 150 mg/dL), and are at increased risk of cardiovascular events, according to this real-world analysis. The investigators analysed data from two large patient databases, the National Health and Nutrition Examination Survey (NHANES) database (2007-2014) and the Optum Research Database, as well as electronic medical records from two Kaiser Permanente regions. In the NHANES data analysis, the prevalence of hypertriglyceridemia (TG ≥1.69 mmol/L) was ~26% of US adults, including nearly one-third of statin users, and was even higher among those with diabetes (~40%). The Optum analyses showed that individuals with TG levels ≥1.69 mmol/L on statin treatment had a 26% increase in risk of major cardiovascular events (hazard ratio 1.26, 95% confidence interval [CI] 1.19-1.34; p < 0.001) compared with those with lower TG levels. This increased risk conferred an increased burden in terms of healthcare utilization and direct healthcare costs (hazard ratio 1.12, 95% CI 1.08-1.16; P < 0.001). Furthermore, analyses of the Kaiser Permanente records showed that patients with diabetes and TG levels between 2.26-5.64 mmol/L had 30% higher risk of non-fatal MI (rate ratio 1.30, 95% CI 1.08-1.58; P = 0.006), 23% higher risk of non-fatal stroke (rate ratio 1.23; 95% CI 1.01-1.49; p = 0.037) and 21% higher risk of coronary revascularization (rate ratio 1.21; 95% CI 1.02-1.43; p = 0.027), compared with those with lower TG levels. These real-world data highlight the need to manage this TG-associated residual cardiovascular risk.

Results from this preclinical study suggest that pemafibrate, a novel SPPARMα (Selective Peroxisome Proliferator-Activated Receptor Alpha Modulator), may prevent pathological neovascularization in this mouse model of retinopathy. Using an oxygen-induced retinopathy model, researchers treated the mice with vehicle, pemafibrate or fenofibrate by oral gavage. Administration of pemafibrate, but not fenofibrate, significantly reduced pathological angiogenesis in this model. After pemafibrate dosage, there was upregulation of fibroblast growth factor 21 (FGF21), together with reductions in retinal hypoxia-inducible factor-1α and vascular endothelial growth factor A. These preliminary data warrant further study.

In statin-treated patients with pre-existing coronary artery disease (CAD), higher remnant cholesterol levels were associated with greater coronary atheroma progression and higher 2-year rates for major adverse cardiovascular events (MACE), according to the results of this study. This report describes a post hoc analysis of 5,754 CAD patients (mean age 58.1 years, 28% women) from 10 trials who underwent serial intravascular ultrasonography. Almost all (96%) were treated with a statin. Remnant cholesterol was calculated as: non-high-density lipoprotein cholesterol – low-density lipoprotein cholesterol (estimated using the Hopkins–Martin equation)). The key variables were 1) the change in percentage atheroma volume (PAV) and 2) 2-year MACE event rates. On-treatment remnant cholesterol levels were significantly correlated with PAV progression (p<0.001), even after adjustment for clinical trial duration, baseline PAV, on-treatment low-density lipoprotein cholesterol, apolipoprotein B, high-density lipoprotein cholesterol, C-reactive protein and other clinical risk factors. 2-year MACE rates increased progressively with increasing remnant cholesterol levels, from 14% in patients with remnant cholesterol <17.8 mg/dL to 23% in patients with remnant cholesterol >32.7 mg/dL, p<0.001. The authors conclude that the findings from this analysis support further investigation of therapeutic strategies targeting remnant cholesterol in statin-treated patients with persistent residual atherosclerotic cardiovascular disease risk.

Variants of the ANGPTL3 gene, encoding angiopoietin-like 3 protein, can contribute to susceptibility to ischaemic stroke in the Chinese population via effects on the regulation of lipid metabolism. This case-control study included 989 cases of ischaemic stroke (54% aged ≥60 years, 63% male, 45% with hypercholesterolaemia), confirmed by clinical history and neurological examination, and 990 matched controls. Single-nucleotide polymorphisms (SNPs) within the ANGPTL3 gene were selected using criteria of minor-allele frequency >5% in the Chinese Han population, with linkage disequilibrium r2 values <0.8 for candidate SNPs. Four candidate SNPs (rs12048208, rs6690733, rs12563308, and rs72641123) were included. Logistic regression analysis was used to calculated odds ratios and 95% confidence intervals (CI) for the association between polymorphisms of the ANGPTL3 gene and risk of ischaemic stroke, adjusted for age, sex, smoking and drinking status, body-mass index, hypertension, diabetes, and hypercholesterolaemia. The study showed that two ANGPTL3 SNPs - rs6690733 (C vs A alleles: odds ratio 1.34, 95% CI 1.13–1.59; p=0.001) and rs12563308 (C vs T alleles: odds ratio 0.77, 95% CI 0.64–0.93, P=0.007) were significantly associated with susceptibility to ischaemic stroke. Carriers of the minor allele of SNP rs6690733 also had higher levels of total and low-density lipoprotein cholesterol, whereas carriers of the rs12563308 SNP had lower levels of both parameters, when compared with controls. These findings add support for ANGPTL3 as a novel therapeutic target in to reduce the residual risk of cardiovascular events.

Recovery from the metabolic syndrome resulted in a corresponding decreased risk for major adverse cardiovascular events (MACE), according to a recent report. This study included 9,553,042 patients (aged ≥20 years) sampled from the National Health Insurance Database of Korea, who were screened from 2009 to 2014. None had a pre-existing history of cardiovascular disease. Metabolic syndrome was defined as the presence of three or more of the following components: elevated triglyceride level or use of a relevant drug, increased waist circumference, elevated blood pressure or use of an antihypertensive medication, reduced high-density lipoprotein cholesterol or use of a relevant drug, and elevated fasting glucose level or the use of an antidiabetic drug. Individuals were categorized based on metabolic syndrome status at three follow-up visits. MACE was defined as revascularization, acute myocardial infarction and/or acute ischaemic stroke. During follow-up, individuals who had the metabolic syndrome at the first visit but not at the second and third visits had a lower risk for MACE (incidence rate, 4.55 per 1,000 person-years) compared with those with the metabolic syndrome at all three visits (incidence rate, 8.52 per 1,000 person-years). In addition, individuals who developed the metabolic syndrome during the study had about a three-fold higher risk for MACE than those who did not (incidence rates, 6.05 per 1,000 person-years vs1.92 per 1,000 person-years; adjusted incidence rate ratio = 1.36; 95% CI, 1.33-1.39). According to the researchers, the results of the study make the case for renewed efforts directed at prevention and recovery from the metabolic syndrome to reduce the socioeconomic burden of cardiovascular disease.

Despite advances in best treatment targeting blood pressure, low-density lipoprotein (LDL) cholesterol and glycaemia (for microvascular disease), individuals with type 2 diabetes continue to experience cardiovascular events. Therapeutic strategies aimed at additional targets are clearly needed. One approach is to target the nuclear peroxisome proliferator-activated receptor alpha (PPARα), which exerts both positive and negative control on genes involved in fatty acid oxidation, lipoprotein metabolism and inflammation. In particular, effects including increased HDL production, very-low-density lipoprotein (VLDL) clearance and LDL particle size, as well as reduction in VLDL production and LDL particle concentration, imply a key role for PPARα agonism in managing atherogenic dyslipidaemia (high plasma triglycerides, low HDL cholesterol, small-dense LDL particles, and elevated apolipoprotein B and C-III), a key lipid trait associated with type 2 diabetes. Current PPARα agonists are limited by low potency and side effects. Clinical studies with these agents have also failed to show definitive benefit in reducing cardiovascular events, against a background of best evidence-based treatment including statin. New approaches are needed. This comment from internationally renowned leaders in cardiovascular disease prevention makes the case for the SPPARMα (Selective Peroxisome Proliferator-Activated Receptor Alpha Modulator) concept. This new class of pharmacological agents aims to maximize favourable effects associated with PPARα activation while simultaneously limiting the propensity for unwanted effects. This concept is being tested in the cardiovascular outcomes study PROMINENT. SPPARM alpha may offer the key to addressing residual cardiovascular risk.

A new review makes the case for stricter control of eligibility criteria, particularly among patients with elevated triglycerides, when testing novel therapeutics in the setting of residual cardiovascular risk. The authors make the point that recruitment of an inappropriate patient population likely explains the failure of past cardiovascular outcomes studies. For example, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study testing the effect of fenofibrate in statin-treated type 2 diabetes patients, there were no specific inclusion criteria for elevated triglycerides. The failure to show impact on residual cardiovascular risk is therefore a direct consequence of enrolling high-risk patients with normal or near normal lipid levels and not patients with "true" dyslipidaemia. The authors conclude that future trials of novel lipid-modifying drugs should have stringent lipid selection criteria for eligible patients to be a true test of intervention against lipid-related residual cardiovascular risk.

Findings from a systematic review and meta-analysis of 31 prospective studies reaffirmed that elevated triglycerides are associated with increased risk of cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM). Researchers interrogated the literature database for studies published until June 2018 that evaluated the association between triglycerides and cardiovascular disease in T2DM. In total, 31 studies involving 132,044 T2DM individuals with 10,733 incident cardiovascular events (follow-up duration 1-13 years) were identified. Stepwise increases in triglycerides were associated with a stepwise increase in incident cardiovascular disease. For each 1 mmol/L increase in triglycerides, the pooled maximum-adjusted relative risk (95% CI) for incident cardiovascular disease in T2DM was 1.30 (1.18, 1.42). The researchers make the point, however, that triglycerides levels are a surrogate marker for triglyceride-rich lipoproteins and their remnants, the true target of therapeutic intervention.

Genetic studies played an integral role in elucidation of the role of PCSK9 (proprotein convertase subtilisin/kexin type 9) in cholesterol homeostasis and as a potential therapeutic target, subsequently validated by cardiovascular outcomes studies. Now, genetic insights link PCSK7, another member of the subtilisin-like proprotein convertase family, with dyslipidaemia and severity of liver disease in high-risk individuals. In the latest study, the effects of genetic variation in PCSK7 expression on non-alcoholic fatty liver disease-related traits were evaluated in 1,801 individuals from the Liver Biopsy Cohort, 500,000 individuals from the UK Biobank Cohort, and 4,580 from the Dallas Heart Study. The PCSK7 rs236918 C variant was associated with higher triglycerides and aminotransferase levels, and more severe hepatic inflammation in the Liver Biopsy Cohort (p < 0.05), as well as hypercholesterolaemia and liver disease in the UK Biobank Cohort. PCSK7 missense variants were also associated with circulating lipids in the Dallas Heart Study cohort. In vitro studies showed that the PCSK97 rs236918 C variant upregulates a new "intra-PCSK7" long noncoding RNA, which correlates with plasma triglycerides in vivo (p = 0.04). These findings suggest that the potential of PCSK7 targeting in non-alcoholic fatty liver disease may merit investigation.

Remnant cholesterol is associated with significant coronary atherosclerotic burden even among patients with well-controlled low-density lipoprotein cholesterol (LDL-C) levels, according to this report. This was a multicentre study involving 587 patients (mean age 61 ± 12 years) with suspected coronary artery disease, who underwent computed tomography coronary angiography and a fasting lipid profile within 3 months. Remnant cholesterol was calculated as: total cholesterol – (LDL-C + high-density lipoprotein cholesterol [HDL-C]). Overall, 134 (23%) patients had LDL-C levels <1.8 mmol/L and most of these (82%) were on a statin. In this subgroup, multivariable analysis adjusting for HDL-C and traditional cardiovascular risk factors showed that remnant cholesterol was predictive of significant coronary atherosclerotic burden, as defined by a computed tomography-Leaman score >5 (odds ratio 3.87, 95% confidence interval 1.34-7.55, p = 0.004). These findings add further support for the rationale of therapeutic targeting of elevated remnant cholesterol to reduce the residual atherosclerotic risk.

Studies have shown that calculated remnant cholesterol in triglyceride-rich lipoproteins is causally associated with increased risk of ischaemic heart disease, although what this represents (as direct measurement) as a proportion of total circulating plasma cholesterol is unclear. Results from the Copenhagen General Population Study provide insights. Researchers evaluated total cholesterol, free- and esterified cholesterol, triglycerides, phospholipids, and particle concentration using nuclear magnetic resonance spectroscopy in 9,293 individuals. Remnant lipoproteins were defined as the combination of very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL). Mean nonfasting remnant cholesterol concentration was 1.84 mmol/L (72 mg/dL), equivalent to 32% of total plasma total cholesterol. These results reaffirm that triglyceride-rich remnant lipoproteins contain a substantial proportion of circulating cholesterol and therefore represent a key target for therapeutic intervention.

In metabolically healthy individuals, the presence of non-alcoholic fatty liver disease (NAFLD) was independently associated with coronary artery calcification, according to this report from the CArdioPulmonary bioImage Study (SCAPIS). This population-based Swedish cohort study evaluated data from 1015 subjects aged 50-64 years (51.2% women). NAFLD was defined as computed tomography liver attenuation ?40 Hounsfield Units, excluding other causes of liver fat, and the coronary artery calcification score (CACS) was assessed using the Agatston method. Metabolic status was based on assessments of glucose homeostasis, serum lipids, blood pressure and inflammation. The presence of NAFLD was significantly associated with CACS after adjustment for confounders and metabolic risk factors (odds ratio 1.77, 95% CI 1.07-2.94), with the strongest association observed in subjects with few metabolic risk factors (odds ratio 5.94, 95% CI 2.13-16.6). Surprisingly, however, there was no association between the presence of NAFLD and evidence of carotid plaques or intima-medial thickness, assessed by ultrasound.

Global studies which aim to identify the genetic basis of variation in blood lipid traits and extreme lipid phenotypes have been predominantly performed in European Caucasian populations. The current study addressed the lack of information regarding genetic variation in lipids in Arab populations. Investigators performed a genome-wide association study in Arab individuals in Kuwait (discovery cohort including 1,353 subjects and a replication cohort of 1,176 subjects). The study identified six variants that were recessive for high triglycerides at the genome-wide significance level, and a further six variants that were associated at borderline significance. All 12 variants were novel. These findings in an Arab population complement international efforts to identify genetic regulation of lipid traits across different ethnicities.

Findings from the standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study implicate serum triglycerides as a predictor of future cardiovascular events in statin-treated individuals with diabetes mellitus and retinopathy. EMPATHY is a multicentre, prospective, randomized, open-label, blinded-endpoint study evaluating standard versus intensive statin therapy in subjects with diabetes mellitus. The current analysis included data from 5,042 subjects who were followed for a median of 3 years. The key outcomes of interest were 1) major adverse cardiac events, a composite of myocardial infarction, stroke, or cardiac death; and 2) cardiovascular disease, a composite of myocardial infarction, unstable angina, ischemic stroke, large artery disease or peripheral arterial disease. Using Cox-regression hazard modelling, each 10 mg/dL increase in serum triglycerides was associated with a 2.1% relative increase in major cardiac events (adjusted hazard ratio 1.021, 95% confidence interval [CI] 1.007-1.035, p?=?0.0025) and a 2.3% relative) increase in cardiovascular disease (adjusted hazard ratio 1.023, 95% CI 1.013-1.034, p?=?0.0000077). Compared with the lowest quintile for serum triglycerides (<79 mg/dl), individuals in the top quintile (>185?mg/dl) were at 89% increased risk for major cardiac events (p?=?0.04) and 90% increased risk for cardiovascular disease (p?=?0.007). This increased risk was independent of low-density lipoprotein cholesterol levels and statin treatment. In conclusion, these findings suggest that measurement of serum triglycerides may offer additional information for risk prediction in individuals with diabetes mellitus and retinopathy.

Despite well controlled low-density lipoprotein cholesterol (LDL-C) levels on statin treatment, individuals with elevated triglycerides are at high residual risk, according to this report. In this study, adults with diabetes with LDL-C levels between 40 and 100 mg/dL and with established cardiovascular disease or at least one other cardiovascular risk factor were identified from the Kaiser Permanente database. Individuals were categorized by high (200-499 mg/dL, n=5,542) or normal (<150 mg/dL, n=22,411) triglycerides. The primary outcomes were non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina or coronary revascularization. When compared with individuals with normal triglycerides, those with high triglycerides had a 30% higher incidence of nonfatal MI (p=0.006), 23% higher rate of non-fatal stroke (p=0.037), 21% higher rate of coronary revascularization (p=0.027), and 33% higher rate of unstable angina, although this was not statistically significant (p=0.185). These findings provide further evidence linking elevated triglycerides with increased residual risk of cardiovascular events against a background of well controlled LDL-C levels.

Evidence from a retrospective study, presented at the 2018 European Society of Cardiology Congress, Munich, Germany supports a possible link between elevated triglycerides and risk for peripheral artery revascularization. This longitudinal administrative claims analysis evaluated data from 46,362 adults (?45 years) in the Optum Research Database with diabetes and/or atherosclerotic cardiovascular disease who had a statin prescription filled in 2010. Subjects with triglycerides ? 1.69 mmol/L or ? 150 mg/dL (median 2.23 mmol/L) were matched with those with lower triglycerides levels (median 1.11 mmol/L). The key endpoint was peripheral artery revascularization.
 
At 5 years, the probability of peripheral artery revascularization was 6.9% in subjects with elevated triglycerides versus 4.9% in those with lower triglycerides. Compared with subjects with lower triglycerides, those with elevated triglycerides had a 37% higher rate of peripheral artery revascularization and a 26% higher risk for a first cardiovascular event. These higher rates of cardiovascular events translated to higher health care costs and a longer initial inpatient hospital stay compared with the group with lower triglycerides. These findings implicate elevated triglycerides as a factor to consider to reduce the risk of cardiovascular events, including interventions for peripheral artery disease.

Topline results of the REDUCE-IT trial show that high doses (4-g daily) of eicosapentaenoic acid (EPA) led to a 25% relative reduction in major adverse cardiovascular events (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization) over a median follow-up of 4.9 years. Results will be reported at the American Heart Association Scientific Sessions this November.

The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial did not show any incremental clinical benefit of extended-release niacin in 3414 statin-treated patients with cardiovascular disease and low baseline levels of high-density lipoprotein cholesterol (HDL-C). However, the most recent analysis from this group suggests that niacin may confer benefit in patients with atherogenic dyslipidaemia by reducing remnant lipoprotein cholesterol and increasing HDL2-C.
In this new analysis, investigators evaluated the relationship between niacin treatment, lipoproteins and their subfractions, and cardiovascular outcomes in 2457 patients in the AIM-study at baseline and after 1 year of treatment. Overall, they showed that apoliprotein(apo) B-containing lipoproteins and their subfractions decreased and HDL-C and its subfractions increased more in patients treated with niacin than placebo. Among the subgroup with atherogenic dyslipidaemia (elevated triglycerides and low HDLC) treated with niacin, the data suggested that a reduction in levels of remnant lipoprotein cholesterol (very low-density lipoprotein cholesterol and its subfractions and total remnant lipoproteins) at 1 year, and an increase of HDL subclass HDL2-C were associated with reduced cardiovascular risk. The AIM-HIGH investigators make the case, however, that this post hoc analysis is solely hypothesis-generating and requires further evaluation.

In the Dyslipidemia International Survey-China survey, over 50% of patients had persistent atherogenic dyslipidaemia despite attainment of low-density lipoprotein cholesterol (LDL-C) goal on statin therapy. This report analysed data from 22,039 patients receiving statin monotherapy, enrolled at 122 hospitals in China. Atherogenic dyslipidaemia was defined as triglyceride levels ?1.7mmol/L and/or low levels of high-density lipoprotein cholesterol (men: <1.0mmol/L; women: <1.3mmol/L). Based on the US National Cholesterol Education Program Adult Treatment Panel III criteria, of 13,088 patients who attained LDL-C goals, 7,134 patients (55%) had residual atherogenic dyslipidaemia. Results were similar using the Chinese guideline for the management of dyslipidemia: 13,551 patients reached LDL-C goal, of whom 7,719 (57%) patients had atherogenic dyslipidaemia. The intensity of statin therapy did not affect the prevalence of atherogenic dyslipidaemia. These findings highlight the need for renewed awareness of atherogenic dyslipidaemia in this region.

A state-of-the art review suggests potential for novel genome-editing techniques, such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated 9), which make it feasible to permanently alter target genes in vivo. CRISPR-Cas9 may offer specific advantages over other genome-editing technologies, as this can be redirected to any genomic site. Indeed, in several proof-of-concept studies, permanent disruption of PCSK9 with genome editing was achieved in an in vivo mouse model. Future gene targets for this approach may include ANGPTL3 and APOC3. However, before this approach can be translated to humans, a number of issues need to be addressed. First, the precision of the technique needs to be improved. Additionally, the potential for unintended consequences at the target site such as insertion of undesired sequences, large deletions, and chromosomal rearrangements, off-target mutagenesis, and efficacy and safety need to be assessed. If proven to be effective and safe, genome-editing therapies could offer advantages for long-term management of atherogenic dyslipidaemia.

The PREDIMED study has been retracted, and then republished after concerns were raised about baseline data distributions which may have led to misinterpretation or statistical error. The study evaluated the effect of the Mediterranean diet supplemented with extra-virgin olive oil, nuts or control (advice to reduce dietary fat) on cardiovascular outcomes in 7447 subjects (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no clinically evident cardiovascular disease at enrollment. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). In this republished version, absolute event rates after a median follow-up of 4.8 years were 3.8% in the group assigned to a Mediterranean diet with extra-virgin olive oil, 3.4% in the group assigned to a Mediterranean diet with nuts, and 4.4% in the control group. In intention-to-treat analyses, there was a 31% relative reduction in the primary endpoint (hazard ratio 0.69, 95% confidence interval [CI], 0.53 to 0.91) in the group assigned a Mediterranean diet with extra-virgin olive oil, and 28% reduction in the group assigned a Mediterranean diet with nuts (hazard ratio 0.72, 95% CI, 0.54 to 0.95), compared with the control diet. The results were similar when data from 1588 subjects in whom study-group assignment was known or with protocol variations were excluded. These new findings were generally similar to those previously reported. The overall process, however, has raised concerns about other errors in the data that may not have been properly accounted for in the analysis.

A number of posters added to the information about this novel lipid-modifying agent. As a follow-up to the clinical study in dyslipidaemic patients with elevated triglycerides, reported by Ishibashi et al,¹ pemafibrate was shown to reduce the particle number of triglyceride-rich chylomicrons, very low-density lipoproteins (VLDL) and small low-density lipoproteins (LDL), but increased large LDL and antiatherogenic high-density lipoproteins (HDL).²
A pooled analysis of phase II/III trials in 1255 patients, 957 treated with pemafibrate, showed a favourable safety profile consistent with that reported in other trials. The incidence of adverse events was comparable with placebo with no indication of any increase in adverse events with increasing dose, and there were no clinically meaningful changes in liver or renal function tests.³ In another study in 189 patients with a spectrum of renal function based on estimated glomerular filtration rate (ranging from <45 to ?90 ml/min/1.73 m2) there was no change in renal function in any cohort of patients over 52 weeks treatment with pemafibrate 0.2 mg twice daily.⁴
Furthermore, in separate studies, pemafibrate exposure was not dependent on the severity of renal dysfunction,⁵ and there was no need for dose adjustment in individuals with fatty liver disease.⁶ Concomitant treatment with pemafibrate and statins had no clinically meaningful effect on the systemic exposure on either agent.⁷
 
References
1. Ishibashi S et al. Effects of K-877, a novel selective PPAR? modulator (SPPARM?), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.
2. Yamashita S et al. Effect of selective PPAR? modulator K-877 on particle numbers of lipoprotein subclasses in dyslipidemic patients: analysis by HPLC and NMR lipoprofile 2 and 3. P1-095
3. Arai H et al. A pooled analysis of pemafibrate phase II/III clinical trials showed no significant increase in incidence of adverse events compared with placebo. P5-029
4. Yokote K et al. Long-term pemafibrate treatment was well tolerated in patients with dyslipidemia including those with kidney dysfunction. P5-049.
5. Hosford D, et al. The plasma concentration and pharmacokinetic parameters of pemafibrate did not increase in a creatine clearance-dependent manner. Poster P5-036
6. Hosford D et al. Dose adjustment should be considered for the administration of pemafibrate in patients with hepatic cirrhosis. Poster P5-037
7. Hounslow N et al. Pemafibrate minimally affected the systemic exposure of statins, and vice versa, in healthy male volunteers. Poster P5-052.
 
One key focus of the meeting was the role of visceral obesity in health, relating to cardiovascular disease and beyond. The R3i covered the Joint International Atherosclerosis Society (IAS)-International Chair on Cardiometabolic Risk (ICCR) satellite symposium on visceral adiposity and related atherogenic hypertriglyceridemia; check back for the highlights report from this key meeting.

New findings from the Shiga Diabetes Clinical Survey implicate obesity as a driver of poorer glycaemic and triglycerides control among Japanese individuals with diabetes. The study evaluated 12-year trends of increasing obesity based on data from adult diabetes subjects in 2000 (n=14,205), 2006 (n=14,407) and 2012 (n=21,449). The survey showed an increasing prevalence of overweight (body mass index [BMI] 25-30 kg/m2) and obesity (BMI ?30 kg/m2) over this period: 27.0% and 5.1% in 2000, 28.9% and 7.3% in 2006 and 30.9% and 10.0% in 2012. While overall control of glycaemia, blood pressure and lipids improved over 12 years, management of glycaemia and triglycerides was insufficient in younger obese patients aged <65 years. These findings highlight the need for more active weight-control interventions especially in younger patients with diabetes.

Increasing obesity rates in China has led to increases in the prevalence of elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C). This report was based on data from a national representative survey in 163,641 adults aged >18 years living in mainland China between 2013 and 2014. Overall, the population-weighted means of total cholesterol, HDL-C, and low-density lipoprotein cholesterol (LDL-C), and median of triglycerides were 4.70, 1.35, 2.88, and 1.49 mmol/L, respectively. Notably, the prevalence of low HDL-C and high triglycerides was about 2-fold higher than for high LDL-C (20.4% and 13.8% versus 8.1%, respectively). These findings highlight the need to improve the management of dyslipidaemia, which is prevalent in China.

This timely review has highlighted the potential of therapeutic approaches targeting angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) to reduce triglyceride-rich lipoproteins and related residual cardiovascular risk. Ongoing research has led to new biologicals that suppress the expression or inhibit the function of these two key proteins. These include human monoclonal antibodies or antisense oligonucleotides. This article reviews the mechanisms of action of ANGPTL3 and apoC-III, and why intervening against these targets may offer future promise for reduction in residual cardiovascular risk.

This sub analysis from the ANCHOR study showed that treatment with 4 g/day icosapent ethyl, a pure prescription eicosapentaenoic acid ethyl ester, showed benefit in women with type 2 diabetes mellitus (T2DM) and elevated triglycerides (TGs). The ANCHOR trial randomized 702 statin-treated patients (73% with diabetes; 39% women) at increased cardiovascular risk with elevated TGs (200-499 mg/dL) despite controlled low-density lipoprotein cholesterol (LDL-C, 40-99 mg/dL) to treatment with icosapent ethyl 2 g/day, 4 g/day, or placebo. This post hoc analysis focused on 146 women with T2DM (mean age 62 years) randomized to icosapent ethyl 4 g/day (n = 74) or placebo (n = 72). In this group, icosapent ethyl significantly reduced TGs (by 21.5%; p < 0.0001) without increasing LDL-C, and also had favourable effects on other potentially atherogenic lipids, lipoproteins, and inflammatory parameters versus placebo. Treatment was also well tolerated. These findings are relevant in the context of the ongoing Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial (REDUCE-IT) cardiovascular outcomes trial.

This post hoc analysis of the Treating to New Targets (TNT) study showed that reduction in triglyceride-rich lipoprotein-cholesterol (TRL-C) with atorvastatin reduced the risk of major adverse cardiovascular events. After a run-in phase on atorvastatin 10 mg/day, the TNT study randomized patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) <130 mg/dL to treatment with atorvastatin 10 mg/day (n=5006) or atorvastatin 80 mg/day (n=4995). The primary study endpoint was a composite of coronary heart disease death, non-fatal myocardial infarction, resuscitated cardiac arrest, or stroke (MACE). This analysis investigated the impact of both doses of atorvastatin on TRL-C, calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. Treatment with atorvastatin 10 mg/day reduced TRL-C by 10.7%; the higher dose led to an additional 15.4% reduction in TRL-C. In adjusted analyses, a 1 standard deviation percentage reduction in TRL-C with atorvastatin led to a lower risk of MACE (Hazard ratio 0.93, 95%CI 0.86-1.00, p=0.0482). This effect was independent of the reduction in LDL-C and of similar magnitude to that observed per 1 standard deviation reduction in LDL-C (HR 0.89, 95%CI 0.83-0.95, p=0.0008). In conclusion, this analysis provides evidence that the cardiovascular benefit of statin therapy is associated with reduction in both LDL-C and TRL-C.

Presentation of top-line results from ODYSSEY Outcomes, showed that treatment with the PCSK9 inhibitor alirocumab improved major adverse cardiovascular events and also had a benefit on all-cause mortality in patients with a recent acute coronary syndrome (ACS). ODYSSEY Outcomes randomized 18,924 ACS patients (median age 58 years, 25% female, 19% with a prior myocardial infarction (MI), 29% with diabetes, mean baseline low-density lipoprotein cholesterol [LDL-C] 87 mg/dl); 9,462 patients each received alirocumab or placebo. The majority of patients (89%) were on intensive statin therapy at entry to the study. The primary study endpoint of major adverse cardiovascular events (MACE) was a composite of first coronary heart disease (CHD) death, nonfatal MI, ischaemic stroke or unstable angina requiring hospitalization.
 
After a median follow-up of 2.8 years, treatment with alirocumab substantially lowered LDL-C levels and this was associated with a significant 15% relative reduction in the primary endpoint (hazard ratio 0.85, 95% CI 0.78-0.93, p=0.0003). There were also significant beneficial effects on secondary outcomes including a 15% reduction in all-cause death. A post hoc analysis showed that patients with higher LDL-C levels at baseline derived greater clinical benefit from alirocumab treatment. Importantly, the study also provided reassuring safety data for this therapeutic strategy.
 
Full publication of the results is still awaited; the study will be discussed as a Landmark Trial when published.
 
For the presentation slides: https://accscientificsession.acc.org/features/2018/03/video-sanofi-regeneron
 
CANTOS: canakinumab did not affect rates of incident diabetes in people with prediabetes
 
This pre-specified analysis follows the primary CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) publication last year.1 The investigators hypothesized that since type 2 diabetes mellitus is thought to be related to inflammatory processes, treatment with canakinumab may slow or prevent the progression from prediabetes to diabetes.
 
This analysis2 focused on 4,960 patients with prediabetes at the start of the study. Despite large reductions in high-sensitivity C-reactive protein (hsCRP) and interleukin-6, canakinumab did not reduce the incidence of new onset diabetes over a median period of 3.7 years (rates per 100-person years in the placebo, 50mg, 150mg, and 300mg canakinumab groups were 4.2, 4.2, 4.4, and 4.1, respectively). The hazard ratio for incident diabetes comparing all canakinumab doses to placebo was 1.02 (95% CI 0.87-1.19, p=0.82). While canakinumab reduced HbA1c during the first 6-9 months of treatment there was no consistent long-term benefits on HbA1c or fasting plasma glucose. While there was no effect on diabetes progression, patients with prediabetes derived the same benefits from canakinumab in terms of cardiovascular outcomes.
 
ANCHOR: Icosapent ethyl in patients with elevated triglycerides and inflammatory markers
 
The 12-week ANCHOR study randomized 702 statin-treated patients at increased cardiovascular risk with triglycerides (TGs) 200-499 mg/dL despite statin treatment. This post hoc subanalysis3 of the ANCHOR Study focused on 246 patients with elevated TGs and hsCRP ?2.0 mg/L; 126 were allocated to icosapent ethyl 4 g/day and 120 to placebo.
 
Treatment with icosapent ethyl 4 g/day to statin therapy significantly reduced TGs by 20% without increasing levels of low-density lipoprotein cholesterol (LDL-C). Notably, there was also an 18% reduction of hsCRP versus placebo over 12 weeks (p=0.02).
 
Real-World Data: elevated triglycerides increase cardiovascular risk and healthcare costs
 
This retrospective, longitudinal administrative claims analysis4 evaluated data from the Optum Research Database which included patients aged ?45 years with diabetes and/or atherosclerotic cardiovascular disease who had a statin prescription filled in 2010, continuous medical/pharmacy coverage, and had data from 6 months pre-index and ?6 months from index date (or less if due to death) up to March 2016. The analysis focused on patients with TGs ?150 mg/dL (median 197 mg/dl, n=23,181) and a propensity-matched comparator cohort (median TGs 98 mg/dl). Patients with elevated TGs had a 26% (95% CI 16-34%) increase in risk for major adverse cardiovascular events (p<0.001). This increase in risk was driven by a 32% (95% CI 1.20-1.45) increase in risk of non-fatal MI (p<0.001) and a 46% (95% CI 1.33-1.61) increase in risk of coronary revascularization (p<0.001). From the payer’s perspective, this increased cardiovascular risk associated with elevated TGs led to a 12% higher average total healthcare cost (95% CI 1.08-1.16), as well as 13% higher rate of occurrence of initial inpatient hospital stay (95% CI 1.10-1.17).
 
References
 
1. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-1131.
2. Everett BM, Donath MY, Pradhan AD et al. Anti-Inflammatory Therapy with Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol 2018; doi: 10.1016/j.jacc.2018.03.002. [Epub ahead of print]
3. Miller M, Ballantyne CM, Bays HE et al. Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) Reduces Potentially Atherogenic Lipid, Lipoprotein, Apolipoprotein, and Inflammatory Parameters in High-Risk, Statin-Treated Patients With Persistent Elevated Triglycerides and High-Sensitivity C-reactive Protein: A Post hoc Subanalysis of the ANCHOR Study,” Poster presentation. 1287-251. http://www.abstractsonline.com/pp8/#!/4496/presentation/38983
4. Toth P, Granowitz C, Hull M et al. Triglycerides ? 150 mg/dL Associated With Greater Risk of Cardiovascular Events, Costs, and Resource Utilization in High-Risk Statin-Treated Patients With Controlled Low-Density Lipoprotein Cholesterol: A Real-World Analysis. Poster presentation. 1290-303. http://www.abstractsonline.com/pp8/#!/4496/presentation/39282

Finally, there is a report from the Midlife in the U.S. study that persistently high levels of psychological well-being measures may favourably impact lipids, specifically reducing the likelihood of the atherogenic dyslipidaemic profile.
 
The authors measured longitudinal profiles of psychological well-being over 9–10 years in 1054 subjects, aged 34 to 84 years, 55% of whom were female. Psychological well-being was evaluated on six scales: autonomy, environmental mastery, personal growth, positive relations with others, purpose in life, and self- acceptance. Each scale consisted of three items, with a mix of positive and negative items. Subjects indicated the extent from 1 (strongly agree) to 7 (strongly disagree) to which the statements described them. Negative items were reverse coded so that higher scores reflected more positive appraisal.
 
Subjects with persistently high levels of environmental mastery and self-acceptance had significantly higher levels of HDL-C and lower levels of triglycerides than those with lower levels. Indeed, the 2–5 mg/dl increase in HDL-C observed in subjects with higher than lower well-being scores predicted a 4–10% reduction in coronary heart disease, comparable with that expected from lifestyle interventions. In contrast, longitudinal trajectories of psychological well-being were not linked to variations in low-density lipoprotein cholesterol levels.
 
Although there were limitations to this study, the findings add to emerging literature linking psychological well-being with lipid profiles and merit further study.

Serum levels of C-peptide, an important risk factor for cardiovascular disease, are known to increase with age. This population-based cross-sectional study showed a strong association between serum C-peptide and elevated triglycerides and low plasma concentration high-density lipoprotein cholesterol (HDL-C) suggesting that C-peptide may be implicated in the residual cardiovascular risk associated with atherogenic dyslipidaemia in the elderly.
 
The study included 3,091 elderly subjects aged ?65 years. Serum triglycerides and HDL-C levels were significantly associated with changes in serum C-peptide levels, independent of insulin levels. Additionally, there was evidence of a significant dose-response association in both men and women.

This new study underlines the economic impact of complications of type 2 diabetes in Germany, based on nationwide data from316,220 patients. Both cardiovascular and microvascular complications were associated with significant cost to the healthcare system, both in the short- and long-term. Specifically, estimated costs (in the 3 months subsequent to the event) were:
diabetic foot €1,293, amputation €14,284, retinopathy €671, blindness €2,933, nephropathy €3,353, end-stage renal disease (ESRD) €22,691, nonfatal stroke €9,769, fatal stroke €11,176, nonfatal myocardial infarction (MI)/cardiac arrest (CA) €8,035, fatal MI/CA €8,700, nonfatal ischemic heart disease (IHD) €6,548, fatal IHD €20,942, chronic heart failure €3,912, and angina pectoris €2,695. In the subsequent quarters, costs ranged from €681 for retinopathy to €6,130 for ESRD.
 
These data highlight the need for early intervention to prevent the debilitating consequences of complications of type 2 diabetes.

Data from the Dyslipidemia International Survey-China study highlight a high prevalence of atherogenic dyslipidaemia among individuals attaining low-density lipoprotein cholesterol (LDL-C) goal with statin monotherapy. In this survey, atherogenic dyslipidaemia was defined as triglyceride levels ?1.7 mmol/L and/or low levels of high-density lipoprotein cholesterol (men: <1.0 mmol/L; women: <1.3mmol/L).
 
The survey included 22,039 patients receiving statin monotherapy, of whom 13,088 attained LDL-C goal according to the American National Cholesterol Education Program Adult Treatment Panel III recommendations. Yet among those at LDL-C goal, 54% had atherogenic dyslipidaemia as residual comorbidity, highlighting an unmet clinical need in this population. Incidentally, the prevalence of atherogenic dyslipidaemia was not influenced by the intensity of statin therapy.

Results from this analysis of the Atherosclerosis Risk in Communities study indicate that the severity of metabolic syndrome, estimated by Z-scores, may offer a means to estimate and track coronary heart disease (CHD) risk in individuals with type 2 diabetes.
 
The study included data from 1419 subjects with diabetes and 7241 without diabetes, who were followed in four visits for adjudicated CHD diagnoses over a 20-year period. Metabolic syndrome severity was calculated as a Z-score using sex- and race- based formulae, based on the five traditional components (waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure and fasting glucose). Subjects with diabetes not only had the highest metabolic syndrome severity at baseline, but also during follow-up, whereas those without diabetes had low severity during follow-up. In the diabetes cohort, there were 1446 cases of CHD. Each 1-standard deviation unit increase in metabolic syndrome severity score was associated with 29% increase in risk of future CHD events.
 
The authors make the point that tracking metabolic syndrome severity over time using this approach may help to motivate individuals with diabetes to change their lifestyle to reduce their risk of CHD.

Findings from this large general population study indicate a U-shaped relationship between plasma high-density lipoprotein cholesterol (HDL-C) concentration and mortality.
 
The study included 37,059 subjects (mean age 57.7±11.9 years;47% men) who were recruited from the Health Survey for England and Scottish Health Survey. Individual subject data were linked with the British National Health Service Central Registry to record mortality.
 
Over 326,016 person-years of follow-up, there were 2250 deaths, 649 due to cardiovascular disease. When compared with the reference group (1.5–1.99 mmol/L), individuals with the lowest (<1.0 mmol/L) or highest (?2.5 mmol/L) HDL-C levels had the highest cardiovascular risk; Hazard ratios (95% confidence interval) for all-cause death were 1.23 (1.06-1.44) and 1.25 (0.97 - 1.62), respectively. However, for cardiovascular death, subjects with the lowest HDL-C levels had the highest risk (hazard ratio 1.49 (1.15 - 1.94). These findings suggest a disconnect between concentration and function in individuals with high HDL-C levels, although further study is merited.

Empagliflozin, a potent and highly selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor of the proximal tubule, has previously been shown to significantly reduce major adverse cardiovascular events and mortality in patients with type 2 diabetes from the EMPA-REG OUTCOME study (1). The mechanisms behind these rapid-onset benefits, are likely to be multifactorial, possibly involving favourable effects on insulin sensitivity. This study investigated whether treatment effects on remnant cholesterol are associated with a change in insulin resistance in patients with type 2 diabetes.
 
In total 109 type 2 diabetes patients were allocated to treatment with empagliflozin (n=58) or placebo (n=51) for 12 weeks. Blood glucose and lipid control were similar in both groups at baseline. Treatment with empagliflozin led to significant decreases in HbA1c, body weight, systolic blood pressure, plasma triglycerides, liver transaminases and estimated glomerular filtration rate, and also increased high-density lipoprotein cholesterol. Empagliflozin was also associated with decreases in remnant cholesterol and HOMA-R. In multiple regression analysis, the change in HOMA-R was significantly associated with the change in remnant cholesterol in the empagliflozin group (p=0.00241).
 
In conclusion, this study shows that empagliflozin decreased remnant cholesterol and that this was associated with amelioration of insulin sensitivity in patients with type 2 diabetes. Although confirmation is needed in larger studies, these findings provide a possible (part) explanation for the cardiovascular benefit of empagliflozin in patients with diabetes.

According to this study, individuals with diabetes mellitus have a more advanced arterial plaque phenotype than those without diabetes, and these differences continue to progress despite similar low-density lipoprotein cholesterol (LDL-C) control. These differences may, at least partly, explain the higher cardiovascular morbidity and mortality in diabetic individuals.
 
The authors evaluated changes in plaque volume and plaque phenotype during lipid-lowering therapy in 61 patients with stable angina pectoris (17 with diabetes mellitus) included in the PREDICT trial (ClinicalTrials.gov identifier NCT01773512). Only those patients with intravascular ultrasound-virtual histology (IVUS-VH) of a native coronary artery with ?50% lumen stenosis at baseline; imaged vessels free of severe calcification; and with sufficient quality baseline and follow-up data were evaluated. At baseline, 14 (82%) diabetic patients and 34 (77%) non-diabetic patients were on a statin; mean LDL-C levels were comparable (2.42 and 2.46 mmol/L).
 
Despite attaining similar LDL-C levels, diabetic patients had evidence of greater progression of plaque area (0.47 ± 1.15 mm2 vs. 0.21 ± 0.97 mm2 in patients without diabetes, p = 0.001) and percent atheroma volume (0.7 ± 2.8% vs. ? 1.4 ± 2.5%, p = 0.007), and had more locations with thin-cap fibro-atheroma plaque phenotype (20.3% vs. 12.5%, p = 0.01). These findings imply that currently-achieved LDL-C lowering is insufficient for stabilizing atherosclerotic plaque in diabetes patients, and that other lipid and non-lipid parameters should be considered.

This study implies that increased levels of triglycerides in middle-aged individuals may be implicated in the subsequent pathology of Alzheimer’s disease. This was a longitudinal cohort study of 318 individuals with normal cognitive function at baseline (mid-life, mean age 54 years) and fasting lipid levels both at baseline and 20-year follow-up (mean age 73 years), as well as data for beta-amyloid and tau, implicated in Alzheimer’s disease pathology. At follow-up, both beta-amyloid and tau pathology were evident in 16% of subjects. Importantly, higher levels of triglycerides in midlife were independently associated with abnormal beta-amyloid and tau pathology in later life, even after adjustment for age, sex, APOE beta4, education, and multiple vascular risk factors. In addition, the authors showed that increased levels of medium and large low-density lipoprotein subfractions were significantly associated with abnormal beta-amyloid distribution based on positron emission tomography imaging, whereas large high-density lipoprotein particles were associated with decreased risk of abnormal beta-amyloid distribution.
 
Thus, while elevated triglycerides, a marker for high triglyceride-rich lipoproteins and remnant cholesterol, have been shown to be causal for cardiovascular disease, this study also suggests a potential role in cognitive function in later life.

The concept of raising high-density lipoprotein (HDL) cholesterol using pharmacological intervention to reduce cardiovascular risk has been discredited with a string of failed studies and investigational agents. However, the spotlight has not shifted completely from HDL cholesterol, with new evidence adding support for a role for HDLs in immunity.
 
A key study (1) reported novel findings based on data from 97,166 individuals in the Copenhagen General Population Study and 9,387 from the Copenhagen City Heart Study with measurements of HDL cholesterol at baseline. The primary endpoint of both studies was any infectious disease requiring hospital admission, ascertained in the Danish health registries from baseline in 2003–13 or 1991–94 through 2014.
 
Overall, 9% of individuals in the Copenhagen General Population Study and 31% in the Copenhagen City Heart Study experienced one or more infectious disease events. There was a U-shaped association between HDL cholesterol concentration and risk of any infection. Notably, an HDL cholesterol <0.8 mmol/L (31 mg/dL) and >2.6 mmol/L (100 mg/dL) had a higher risk for any infection compared with a value of 2.2–2.3 mmol/L (85–95 mg/dL). Hazard ratios and 95% confidence interval [CI] were 1.75, 1.31–2.34 and 1.43, 1.16–1.76, respectively, for the Copenhagen General Population Study, and 2.00, 1.16–3.43 and 1.13, 0.80–1.60, respectively, for the Copenhagen City Heart Study. These findings are relevant given that, in the general population, 21% of subjects had low HDL cholesterol and 8% had high HDL cholesterol levels.
 
Furthermore, the authors also showed that variants of genes encoding hepatic lipoprotein lipase, LIPC, and cholesterol ester transfer protein, CETP, were consistently associated with a reduced risk for infections.
 
The association between low HDL cholesterol and increased risk of infectious events is supported by experimental studies which have shown that HDLs plays a role in the development of immune cells, modulation of immune cell function and activity, as well as the neutralization and clearance of endotoxins. In contrast, the mechanism(s) for the association between high HDL cholesterol levels and increased risk for infection is less clear. It may be that these individuals with higher HDL cholesterol have higher levels of functionally defective HDLs as a consequence of different co-morbidities; of relevance, estimated glomerular filtration rate, indicative of reduced kidney function, was lower in individuals in the Copenhagen General Population Study with HDL cholesterol levels >2.6 mmol/L, and might partly explain this association.
 
In the second report (2), HDL functionality, specifically its cholesterol efflux capacity, was shown to be significantly impaired in older subjects with sepsis. This was a prospective study in patients with sepsis (n=10, mean age ± standard deviation 80?±?2 years) who were enrolled within the first 24?hours of admission to the emergency department, and 10 healthy controls (77?±?2 years). Compared with controls, patients with sepsis had significantly lower mean percent cholesterol efflux (24.1?±?1.2% versus 31.5?±?1.0%, p? 
These two studies implicate a role for HDLs in infection; further study is clearly merited.
 
1. Madsen CM, Varbo A, Tybjærg-Hansen A et al. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. Eur Heart J 2017; doi:10.1093/eurheartj/ehx665. [Epub ahead of print]
 
2. Guirgis FW, Leeuwenburgh C, Grijalva V et al. HDL cholesterol efflux is impaired in older patients with early sepsis: a subanalysis of a prospective pilot study. Shock 2017; doi: 10.1097/SHK.0000000000001030. [Epub ahead of print]

Increasingly it is thought that the functionality of high-density lipoprotein (HDL) may have a pathophysiologically important impact in delaying the progression of atherosclerosis. This study shows that anti-inflammatory properties of HDLs are impaired in type 2 diabetes mellitus (T2DM) patients, even those with generally acceptable metabolic control. The study included 40 subjects with T2DM (median duration 5 years), none of whom were treated with insulin or statin, and 36 non-diabetic subjects. HDL anti-inflammatory capacity was determined as the ability to suppress tumor necrosis factor-? (TNF-?) induced vascular cell adhesion molecule-1 (VCAM-1) mRNA expression in endothelial cells in vitro, thus reflecting a critical early event in atherogenesis, i.e. the recruitment of macrophages into developing atherosclerotic lesions. T2DM was associated with impaired HDL anti-inflammatory capacity (by more than 3-fold in the test system), as well as decreased paraoxonase-1 activity, and enhanced low grade chronic inflammation. This impaired functionality of HDL may contribute to the increase in risk of atherosclerotic cardiovascular disease associated with T2DM.

This multicenter registry cohort study in Taiwan shows that failure to achieve recommended low-density lipoprotein cholesterol (LDL-C) goal, rather than the intensity of statin therapy, was associated with increased risk of cardiovascular events. The study evaluated data from 4,099 patients with atherosclerotic cardiovascular disease (ASCVD) in the Taiwan Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) registry; 183 were on high-intensity statin, 2,338 (57%) on moderate-intensity statin, 412 on low-intensity statin and 1166 (28%) did not receive a statin. Overall, 1,781 (43%) patients failed to achieve the target LDL-C level of < 100 mg/dl (2.6 mmol/L). Over a median follow-up of 2 years, major adverse cardiovascular events occurred in 109 patients. Irrespective of the intensity of statin use, failure to attain the LDL-C target level was associated with a higher risk of major cardiovascular events compare with those patients who attained target LDL-C levels (hazard ratio 1.66, 95% CI 1.04 - 2.63, p = 0.03 for those on statins; and 2.04 95% CI 1.06 -3.94, p = 0.03 for those not on statins). These findings underline the need for improvement in lipid management in the real-world, with a specific focus on attainment of lipid goals.

APOC3 encodes apolipoprotein (apo) C-III, a critical inhibitor of triglyceride lipolysis and remnant triglyceride rich lipoprotein clearance. Genetic studies have investigated the association between APOC3 variants and risk for ischaemic heart disease, paving the way for new therapeutic approaches to managing elevated triglycerides.
 
This report details the mechanism of lowering of triglyceride-rich lipoproteins by the APOC3 Ala43Thr (A43T) variant, the only missense variant in APOC3 reported to lower triglycerides and protect against ischaemic heart disease. In mice expressing human APOC3 A43T, marked reduction in plasma apoC-III levels was due to impaired binding of A43T apoC-III to lipoproteins and accelerated catabolism of free apoC-III, as well as accelerated clearance of circulating triglyceride-rich lipoproteins. These findings have been the driver for the development of new therapeutic approaches to reduce apoC-III levels and the burden of triglyceride-rich lipoproteins.

Selective peroxisome proliferator-activated receptor alpha modulators (SPPARM?) may offer a novel therapeutic approach to the management of atherogenic dyslipidaemia. The concept of SPPARM? is that by modulating the unique receptor–cofactor binding profile of PPARalpha, it is possible to improve potency and selectivity while at the same time avoiding unwanted side effects of the fibrates.
 
This review summarizes the experimental and clinical evidence for pemafibrate (K-877), a novel SPPARM?. In clinical trials, treatment with pemafibrate led to marked reduction of triglycerides, remnant cholesterol and apolipoprotein CIII, together with an increase in high-density lipoprotein cholesterol. Whether pemafibrate, against a background of intensive statin therapy, is able to reduce the residual risk of cardiovascular events in patients with type 2 diabetes and atherogenic dyslipidaemia, will be addressed by the PROMINENT (Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs) study. PROMINENT aims to recruit 10,000 patients with type 2 diabetes mellitus, with and without cardiovascular disease, who will be randomized to treatment with pemafibrate 0.4 mg/day or placebo. The primary study outcome is a composite of nonfatal myocardial infarction, nonfatal ischaemic stroke, hospitalization for unstable angina requiring unplanned coronary revascularization, or cardiovascular death. Results are not expected until 2022.

Type 2 diabetes prevalence in China has escalated by more than 10-fold over the last 30 years, with recent estimates indicating that over 90 million people are affected. This report from the China Health and Nutrition Survey, based on risk factor data for the period 1991-2011 shows that high BMI is a key driver of this increase. High BMI was responsible for 43.8 million diabetes cases in 2011, with a population-attributable fraction of 46.8%. Other modifiable risk factors, including physical inactivity, high blood pressure, dietary factors, the consumption of sugar-sweetened beverages and smoking, were also associated with this increased diabetes burden. The authors make the case for renewed efforts directed to primary prevention strategies, education and awareness to reduce the escalation in diabetes prevalence in China.

The current study corroborates previous findings that obesity accentuates the effects of common genetic susceptibility variants that regulate levels of triglycerides. Using data from the Women's Genome Health Study, investigators evaluated the impact of changes in body mass index (BMI) and waist circumference on a weighted genetic risk score (based on 40 published triglyceride-associated variants). They showed differential association of body mass index (BMI) with the genetic risk score and effects on triglycerides; in overweight (BMI ? 25 kg/m2) women, each unit increase of the risk score was associated with 1.013% increase in triglycerides (compared with 1.011% triglyceride increase in normal weight women, p for interaction = 0.014). These findings were confirmed in meta-analyses combining results for this study with four Scandinavian cohorts, thus reaffirming the link between obesity and genetic risk for elevated triglycerides.

Pemafibrate is a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARM?) with higher activity and selectivity for the PPAR? receptor than the fibrate drugs. Pemafibrate has been shown to significantly reduce triglycerides in individuals with hypertriglyceridaemia or atherogenic dyslipidaemia, and has recently received regulatory approval for the management of dyslipidaemia in Japan.
 
The current study compared the effect of pemafibrate (0.0005%) or fenofibrate (0.05%), in a mouse model of diet-induced hypertriglyceridaemia. Treatment with pemafibrate was shown to decrease postprandial levels of triglycerides and apolipoprotein B-48, as well as reduce the postprandial accumulation of triglyceride-rich lipoproteins and chylomicron remnants. These findings suggest that pemafibrate may have potential benefit in attenuation of postprandial hypertriglyceridaemia, a risk factor for cardiovascular disease.

Emerging data suggest a link between triglyceride-rich lipoproteins, inflammation and atherogenesis. This study adds to this, suggesting that increased number of triglyceride-rich lipoproteins and dysfunctional high-density lipoproteins (HDL) may represent the missing link between inflammation and lipids in rheumatoid arthritis.
 
This prospective study measured inflammatory mediators, paraoxonase-1 (PON1) activity, and serum total antioxidant capacity in 113 patients with rheumatoid arthritis, 113 healthy controls, and 27 dyslipidaemic subjects. Overall, 26% (29/113) rheumatoid arthritis patients had atherogenic dyslipidaemia, characterised by high fasting triglycerides and low HDL-C. These patients also had significantly increased serum levels of inflammatory mediators (including tumour necrosis factor alpha and monocyte chemotactic protein, both p=0.004), and leptin, p <0.001) but decreased PON1 and antioxidant activity. Moreover, the high triglycerides/low HDL-C profile was also associated with poor clinical response to tumour necrosis factor-? blockade.
 
These data suggest the importance of atherogenic dyslipidaemia beyond the setting of residual cardiovascular risk, to also include management of inflammatory disease such as rheumatoid arthritis.

There is a growing body of evidence supporting atherogenic dyslipidaemia, the combination of elevated fasting triglycerides and low plasma concentration of high-density lipoprotein cholesterol (HDL-C), as a contributor to residual cardiovascular risk. Added to this, this prospective cohort study showed that the nonfasting triglycerides/HDL-C ratio could be a valuable predictor of cardiovascular events after percutaneous coronary intervention (PCI) in patients treated with statins.
 
The study enrolled 1170 patients with acute coronary syndrome or stable angina between January 2005 and December 2015, who subsequently continued statin therapy after successful PCI. Patients were categorised on the basis of a nonfasting TG/HDL-C ratio 3 months after PCI: 1.37 ± 0.38 (group 1, n=390), 2.60 ±0.34 (group 2, n=390) and 5.60 ± 2.29 (group 3, n=390). The three groups did not differ with respect to high intensity statin use (73-76% of patients). The primary endpoint was major adverse cardiovascular events (MACE), defined as cardiac death, nonfatal myocardial infarction, or revascularization due to new stenosis or restenosis.
 
Over a median follow-up of 47 months, there was a higher incidence of MACE in the group with the highest nonfasting TG/HDL-C ratio: 156 (40.0%) versus 73 (18.7%) in Group 1 and 114 (29.2%) in Group 2. Cox proportional hazards regression analysis indicated that the nonfasting TG/HDL-C ratio was significantly correlated with the incidence of MACE (1.09, 95% confidence interval 1.05-1.13, p<0.001). In conclusion, this study shows that the nonfasting TG/HDL-C ratio is a valuable predictor of incident cardiovascular events after PCI in statin-treated patients. Ideally, clinicians should aim for a nonfasting TG/HDL-C ratio less than 2.00 in this patient group.

This study from Taiwan provides valuable insights into the relevance of different residual cardiovascular risk factors in a prospective cohort of 5,483 patients with atherosclerotic cardiovascular disease (ASCVD), of whom 2,117 (39%) had diabetes. Overall, mean age was 66.4 years, 73% were male and 89% had coronary heart disease. Patients with diabetes were more likely to be older, female, have higher systolic blood pressure, and a higher rate of coronary artery disease and prior intervention for coronary or peripheral artery disease (p<0.05). At baseline, 69.5% of diabetes patients versus 65.5% of those without diabetes were treated with a statin (p<0.01), although the use of high-intensity statin did not differ between the two groups (<5%).
 
Compared with patients without diabetes, those with diabetes had lower levels of low-density lipoprotein cholesterol (LDL-C, mean ± SD: 92.7 ± 31.8 vs. 100.6 ± 35.1 mg/dL) and non-high-density lipoprotein cholesterol (non-HDL-C, 121.6 ± 37.5 vs. 126.9 ± 37.2 mg/dL), but higher triglycerides (152.2 ± 109.7 vs. 135.1 ± 83.4 mg/dL, all p < 0.001).
 
Over a median follow-up of 2.7 years, the incidence of recurrent major adverse cardiovascular events (MACE) was 1.6 per 100 person-years in diabetes patients versus 1.0 per 100 person-years in those without diabetes. The non-HDL-C level was the most significant lipid predictor among the lipid profile for recurrent MACE in patients with diabetes, irrespective of statin treatment. In diabetes patients treated with a statin, a non-HDL-C level between 100 and <130 mg/dl was associated with nearly 3-fold higher residual risk compared with those with a level <100 mg/dl (Hazard ratio 2.98, 95% CI 1.15-7.71, p<0.05), and those with a value of ?130 mg/dl had more than 4-fold higher risk. In conclusion, the study reinforces the need for improved lipid management, especially of non-HDL-C, a marker of total atherogenic apolipoprotein B-containing lipoproteins, in diabetes patients treated with a statin to reduce residual cardiovascular risk.

Composite endpoints are conventionally used in clinical outcomes studies to increase statistical power and precision. More recent outcomes studies in diabetes have tended to predominantly use a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (i.e. major adverse cardiovascular events or MACE), with or without the addition of hospitalization for unstable angina. This report argues that inclusion of this additional endpoint may be problematic, specifically with respect to subjective variability in its ascertainment and a lower prognostic relevance compared with the MACE outcomes, and thus the MACE outcomes may be more clinically relevant when evaluating treatment effects. Ultimately, there is no gold standard for a specific endpoint (either single or composite) for cardiovascular outcomes studies.

Omega-3 polyunsaturated fatty acids (PUFAs) represent one therapeutic option for managing lipid-related residual cardiovascular risk. These treatments have a number of beneficial effects beyond their triglyceride-lowering action, including inhibition of platelet aggregation, anti-inflammatory effects, improvement in vascular endothelium function, and anti-hypertensive action. However, given conflicting clinical trial results, it may be that PUFAs levels need to exceed a threshold for anti-arteriosclerotic efficacy, which may depend on the EPA/arachidonic acid (AA) ratio at baseline (pre-treatment). This hypothesis was tested in a prospective, randomised clinical trial to investigate the effect of the additional administration of EPA (1800 mg/day, n=50) versus control (n=50) on the EPA/AA ratio in statin-treated stable coronary artery disease patients.
 
At 6 months, the achieved EPA/AA ratio was more reliable as an independent and significant predictor of reduction in non-high-density lipoprotein cholesterol (non-HDL-C), a measure of total atherogenic lipoproteins cholesterol load, than the absolute change in the EPA/AA ratio. There were also significant negative correlations between the baseline level and absolute change in non-HDL-C and triglyceride-rich lipoproteins. The authors concluded that the achieved EPA/AA ratio could be useful in risk stratification in statin-treated patients with a high non-HDL-C level.

This review highlights accumulating evidence which suggests a link between dysfunctional insulin signalling and glucose metabolism in the brain and subsequent development of Alzheimer’s dementia. Indeed, recent studies have suggested the importance of controlling blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia. The authors draw attention to therapeutic efforts targeting oxidative stress which could have potential in reducing amyloid Beta-induced neurotoxicity and improving neurological outcome in patients with Alzheimer’s dementia.

Action is needed to improve the care of type 2 diabetes patients with cardiovascular disease (CVD) to reduce their high risk of recurrent events.
 
TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) was a multi-national, double-blind randomised placebo-controlled study of sitagliptin versus placebo in adults with type 2 diabetes and CVD (N=13,616). The primary report of this study conducted to meet the requirements of the FDA showed that the addition of sitagliptin to evidence-based usual care did not increase the risk of major adverse cardiovascular events, hospitalisation for heart failure or other adverse events over a mean follow-up of 3 years. This subsequent retrospective analysis evaluated attainment of five secondary prevention parameters—aspirin use, lipid control (low-density lipoprotein cholesterol [LDL-C] <70 mg/dL or statin therapy), blood pressure control (<140 mmHg systolic, <90 mmHg diastolic), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and non-smoking status in the intention-to-treat TECOS cohort.
 
The results show the need for much work on goal attainment in high risk patients: less than one-third (29.9%) attained all five secondary prevention parameters. These patients had a 40% lower risk of a recurrent event compared with patients with control of ?2 parameters (adjusted hazard ratio 0.60, 95% CI 0.47-0.77). The biggest challenge was blood pressure control (only 57.9% attained guideline recommended goals).
 
This report underlines the need for improvement management of secondary prevention patients to optimise reduction in their risk of a recurrent event; however, even with this, a substantial residual cardiovascular risk persists.

According to the latest report from the EURIKA study, one in five patients without a history of cardiovascular events, have elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C) or both. The prevalence of atherogenic dyslipidaemia is even higher in high risk patients, including those with type 2 diabetes.
 
EURIKA (European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice) is a cross-sectional observational study of primary and secondary prevention care across Europe. Given that atherogenic dyslipidaemia is an important contributor to lipid-related residual cardiovascular risk, especially in patients with insulin resistant conditions, the current report investigated the prevalence of this dyslipidaemia among primary prevention patients in Europe. In total, data from 7,641 patients (52% female, almost all Caucasian) were evaluated. Atherogenic dyslipidaemia was defined according to guideline recommendations for desirable levels of triglycerides and HDL-C.
 
Over 20% of these patients had either elevated triglycerides or low HDL-C levels consistent with atherogenic dyslipidaemia. Despite this, more than half of these patients (55%) were not receiving lipid lowering therapy.
 
These data clearly show the unmet clinical need for management of atherogenic dyslipidaemia across Europe, which warrants urgent attention.

(Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showing that each study had met its primary endpoint (1,2).
 
On June 22, Novartis confirmed that the CANTOS study met the primary endpoint, showing that when used in combination with standard of care, canakinumab (a monoclonal antibody to interleukin 1?) reduced the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, in patients with a prior myocardial infarction and inflammatory atherosclerosis.
 
Added to this, five days later Merck announced that the REVEAL study met its primary endpoint, significantly reducing major coronary events (defined as the composite of coronary death, myocardial infarction, and coronary revascularization) with the addition of the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib compared to placebo in patients at risk for cardiac events who were already on optimised low-density lipoprotein cholesterol lowering treatment. The safety profile of anacetrapib was generally consistent with that observed in recent CETP-inhibition studies. Anacetrapib is the last of the CETP inhibitors in clinical development, following the termination of evacetrapib after the failure of ACCELERATE.
 
We wait for the full results at the European Society of Cardiology Congress in Barcelona, Spain, this August.
 
1. Press release, Novartis 22 June 2017. https://www.novartis.com/news/media-releases/novartis-phase-iii-study-shows-acz885-canakinumab-reduces-cardiovascular-risk
 
2. Press release, Merck, 27 June 2017. http://www.mrknewsroom.com/news-release/research-and-development-news/merck-provides-update-reveal-outcomes-study-anacetrapib

Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. The wealth of data relating to this peptide suggests that it may be an excellent target in therapeutic management of diabetes and cardiovascular disease associated with obesity. While a novel agent targeting FGF21, the analogue PF-05231023, reduced plasma triglycerides this was also associated with increased blood pressure and heart rate.
This study enrolled 107 obese, hypertriglyceridaemic subjects treated with atorvastatin, with or without type 2 diabetes. These individuals were randomly allocated to PF-05231023 or placebo intravenously once-weekly for 4 weeks. At day 25, PF-05231023 treatment was associated with reduction in plasma triglycerides (by 33-43%) and an increase in high-density lipoprotein cholesterol concentration (by 15-28%), without significant changes in body weight. However, treatment was also associated with dose-related increases in blood pressure and heart rate. These results call into question the potential of this therapeutic approach for managing elevated triglycerides associated with obesity.

This new review discusses recent advances in the field of remnant lipoproteins and remnant cholesterol, specifically focused in their role in cardiovascular disease risk. There is now accumulating evidence from observational, genetic, and mechanistic studies linking remnant lipoproteins with the development of atherosclerotic cardiovascular disease, suggesting that this could be a contributor to lipid-related residual cardiovascular risk. While there are encouraging findings from small studies and post hoc analyses, large prospective studies are still needed to definitively evaluate whether reduction in remnant cholesterol levels translates to reduction in cardiovascular risk.

Insights from genetic studies have proved critical in investigating the causality of triglycerides in cardiovascular disease risk. This new review discusses the evidence from recent Mendelian randomization studies.
Meta-analyses of cohorts and population-based sequencing studies have investigated whether genes for lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and the angiopoietin-like proteins 3 and 4, are associated with cardiovascular disease risk. The evidence to date shows that triglyceride-raising variants of these genes showed generally strong associations with clinical cardiovascular endpoints. However, these findings are confounded by the association of elevated triglycerides with low high-density lipoprotein cholesterol (HDL-C). Thus, while the evidence from these genetic studies points to a potential causal association with cardiovascular risk, further study is needed to tease out this confounding with low HDL-C. Ultimately, what is needed to resolve this uncertainty is outcomes studies with novel agents specifically aimed at targeting elevated triglycerides via inhibition of apoCIII or angiopoietin-like protein 3. This week’s Landmark study offers new hope.

This Chinese study highlights the importance of triglycerides and high-density lipoprotein cholesterol (HDL-C), components of atherogenic dyslipidaemia, as well as apolipoprotein B (apoB) levels as independent predictors of coronary heart disease (CHD) in individuals referred for coronary angiography. This cross-sectional study included 1,941 patients of whom 1,363 patients had confirmed evidence of CHD. After adjustment for age, sex, body mass index, diabetes, hypertension, smoking and alcohol intake, in nonstatin users there was an independent association between triglycerides, HDL-C and apoB levels and incident CHD (p for trend = .001, .005, and .003, respectively). Given the relatively high prevalence of hypertriglyceridaemia and low HDL-C concentration in this region (both lipid abnormalities were observed in 22% of patients in this study), the study highlights the need to consider appropriate lipid-modifying strategies beyond low-density lipoprotein cholesterol to reduce incident CHD.

The results from this study based on data from two large European cohorts (HUNT3, Lifelines, 144,082 individuals aged at least 20 years) suggests that this may be the case. The authors modelled road traffic noise exposure for 2009 using a simplified version of the Common Noise Assessment Methods in Europe. Annual ambient air pollution (particulate matter 10 (PM10), nitrogen dioxide) was estimated for 2007 using a Land Use Regression model. Based on pooled data, higher day-time noise (by interquartile range 5.1 dB) was associated with higher high-sensitivity C-reactive protein, triglycerides, and high-density lipoprotein cholesterol (HDL-C); the association with HDL-cholesterol was robust after adjustment for air pollution. Additionally, higher particulate matter (2.0 µg/m3) or nitrogen dioxide concentration (7.4 µg/m3) was associated with higher triglycerides (by 1.9%, 95% confidence interval 1.5-2.4% and 2.2%, 95% confidence interval 1.6-2.7%, respectively), independent of adjustment for noise. In conclusion, these findings suggest that long-term exposure to road traffic noise and ambient air pollution was associated with detrimental changes in blood biochemistry, including higher triglycerides, suggesting a link with cardiometabolic disease risk.

Women living in the Arabian Gulf, especially those at very high cardiovascular risk, were much less likely to attain recommended lipid goals according to this analysis of the Centralized Pan-Middle East Survey on the undertreatment of hypercholesterolemia (CEPHEUS). The analysis included 4,384 high and very high risk patients (mean age 57±11 years and 40% women) on lipid lowering therapy in six Arabian Gulf countries. Compared with male patients, females in this study were at higher cardiometabolic risk, as shown by a higher prevalence of diabetes (84% vs 71%; p<0.001) and metabolic syndrome (49% vs 35%; p<0.001), but were less likely to achieve their recommended lipid goals, for low-density lipoprotein cholesterol (LDL-C) (28% vs 32%; p = 0.002), high-density lipoprotein cholesterol (HDL-C) (42% vs 50%; p<0.001), and apolipoprotein B (38% vs 42%; p = 0.015). Among the very high risk cohort, only 1 in five women attained LDL-C goal and about 1 in three attained non-HDL-C goals, significantly lower than in men. These data, from a large prospective study, highlight an unmet clinical need to improve lipid management in high risk patients of both sexes, but especially very high risk women, in this region.

Although experimental studies suggest that lipoproteins directly affect beta cell function, evidence from clinical studies is less consistent. This question was investigated in a cross sectional, observational prospective multicentre study including 1,016 non-diabetic subjects (aged 30-60 years and with body mass index 20.0-39.9 kg/m2). The study measured fasting lipids, fasting insulin and Oral Glucose Tolerance Test (OGTT)-induced insulin secretion and clearance, and peripheral insulin sensitivity (by the euglycemic clamp) at baseline and after 3.5 years. There was no association between low-density lipoprotein cholesterol levels and fasting or stimulated insulin secretion or clearance. However, low levels of high-density lipoprotein (HDL) cholesterol and elevated triglycerides were associated with abnormalities in insulin secretion characteristic of the pre-diabetic state, independent of changes in body weight or plasma glucose.

Non-alcoholic fatty liver disease (NAFLD) encompasses the spectrum of diseases ranging from pure steatosis (i.e. uncomplicated fatty liver) to non-alcoholic steatohepatitis (NASH), and ultimately cirrhosis. The optimal pharmacological treatment for people with NAFLD remains uncertain.
 
This timely review discusses the potential of novel therapies targeting peroxisome proliferator-activated receptors (PPARs) for modulation of NAFLD. Notably, PPAR-alpha is closely linked to the transcription of genes related to hepatic beta-oxidation, such as CPT-1 and is highly expressed in the liver. In experimental studies, activation of PPAR-alpha by fenofibrate markedly ameliorated hepatic insulin resistance due to upregulation of enzymes involved with beta-oxidation, and upregulation of genes involved in hepatic lipid oxidation, as well as inhibition of de novo lipogenesis and gluconeogenesis enzymes, resulting in a significant decrease in hepatic steatosis. Whether these experimental findings translate to the clinical setting merits further evaluation.

Two new trials add to evidence of robust reduction in triglycerides when this new selective peroxisome proliferator-activated receptor alpha (SPPARMalpha) agonist is added to statin therapy. In one trial, 188 patients treated with pitavastatin were randomized to add-on treatment with pemafibrate 0.1, 0.2, and 0.4 mg/day for 12 weeks; the other trial evaluated pemafibrate either as a fixed dose of 0.2 mg/day, or with the possibility of up-titration (0.2 mg/kg increasing to 0.4 mg/day) in combination with any statin for 24 weeks in 423 patients. Compared with statin monotherapy, pemafibrate add-on therapy was associated with reduction in triglycerides, remnant cholesterol and apolipoprotein B48 by about 50%, as well as improvement in the atherogenic lipoprotein profile. Pemafibrate also appeared to be well tolerated with no signal for any increase in unexpected adverse events compared with statin monotherapy.

Attention has refocused on remnant cholesterol, transported by triglyceride-enriched precursors to low-density lipoproteins, as a contributor to cardiovascular risk. There is compelling evidence from several Mendelian randomization studies that remnant cholesterol is causal in atherosclerotic cardiovascular disease, as well as supportive findings from cross-sectional and prospective studies. There is also biological plausibility for such a link, given that at least some of the group of remnant lipoproteins, such as intermediate density lipoproteins, which contain far more cholesterol per particle than LDL, are able to traverse the arterial wall to elicit changes that predispose to or exacerbate atherosclerosis. Added to this, new evidence indicates that there is an important inflammatory component to the atherogenicity of remnant cholesterol.
 
This study evaluated arterial wall inflammation and bone marrow activity using 18F-FDG PET/CT (18F- fluoro-2-deoxy-d-glucose positron emission tomography–computed tomography) and monocyte phenotype with flow cytometry in 17 patients with familial dysbetalipoproteinaemia (characterized by increased total cholesterol and triglyceride levels) and 17 matched controls. Compared with controls, there was a 20% increase in 18F-FDG uptake in the arterial wall, as well as increased lipid accumulation and higher expression of surface integrins (CD11b, CD11c, and CD18) in patients with familial dysbetalipoproteinaemia. In addition, data from the Copenhagen General Population Study validated the correlation between remnant levels and hematopoietic activity, as well as the strong correlation with leukocyte counts. These findings support an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in these patients.

This year’s ACC Sessions highlighted PCSK9 inhibition, with evidence from two studies with PCSK9 monoclonal antibody therapy - FOURIER and SPIRE-2 with the prematurely terminated bococizumab – that lowering low-density lipoprotein cholesterol (LDL-C) levels far beyond current LDL-C targets reduces cardiovascular events in very high risk patients (1,2). As shown by the SPIRE-2 study, the magnitude of benefit appeared to be greater in patients with higher LDL-C levels at baseline, and thus at higher LDL-related risk, consistent with the regression line shown for statin therapy in the Cholesterol Treatment Trialists’ Collaboration meta-analysis (3). While FOURIER was an event-driven trial, the short duration of follow-up (median 2.2 years) has led to some controversy regarding the lack of benefit on cardiovascular mortality. Additionally, it is relevant that adding evolocumab to maximally tolerated lipid lowering therapy did not eliminate the risk of cardiovascular events in very high risk patients, thus underlying the importance of other risk factors, both lipid and non-lipid related, that contribute to this residual risk. Data are also awaited on subgroup analyses evaluating the effects of evolocumab added to maximal lipid-lowering therapy in diabetes patients.
 
Regarding other lipids and lipoproteins, there was disappointing news (yet again) for targeting high-density lipoprotein (HDL) from the proof-of concept CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) study (4). Short-term treatment with the HDL mimetic CER-001 did not produce a significant effect on coronary disease progression, as measured by intravascular ultrasonography (IVUS), against a background of contemporary therapy in the acute coronary syndrome (ACS) setting. Thus these findings from CARAT suggest that CER-001 is not a promising strategy for ACS patients. Whether HDL-targeted therapy can impact plaque or clinical events remains a persistent question for researchers.
 
References
1. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017 Mar 17. doi: 10.1056/NEJMoa1615664. [Epub ahead of print]
2. Ridker PM, Revkin J, Amarenco P et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017 Mar 17. doi: 10.1056/NEJMoa1701488. [Epub ahead of print]
3. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016 Nov 19;388(10059):2532-56.
4. Nicholls SJ, Andrews J, Kastelein JJP et al. Results of the CARAT Study. Effect of serial infusions of CER-001, a pre-beta high-density lipoprotein mimetic on coronary atherosclerosis. Available at http://clintrialresults.org/Slides/ACC2017/CARAT_Nicholls.pdf

Data from the Partners Healthcare CT Registry in consecutive patients undergoing enhanced cardiac computed tomography angiography (CTA) at the Massachusetts General Hospital or the Brigham and Women’s Hospital from 2004–2011, showed an increased prevalence, extent, and severity of coronary artery disease (CAD) for individuals with body mass index (BMI) > 25 kg/m2. This analysis included data from 1,118 individuals (mean age 57 years, 58% male, 40% with diabetes and 33% with metabolic syndrome). Over a median follow-up of 3.2 (interquartile range 1.9–4.5) years, there were 46 (4.1%) all-cause deaths, 21 (1.9%) cardiovascular deaths, 13 (1.2%) non-fatal myocardial infarction (MI), 13 (1.2%) unstable angina without revascularization, and 34 (3.1%) late coronary revascularizations. Univariate analysis showed that BMI was associated with the presence, extent, and severity of CAD. There was a 3% increase in risk of any CAD for each 1 kg/m2 increase in BMI (odds ratio 1.03, 95% CI 1.01–1.05, p = 0.012), although in multivariable analyses adjusted for age, gender, smoking and each individual metabolic syndrome component, this was no longer significant. In multivariable analyses, both BMI and the presence of the metabolic syndrome were significantly associated with major cardiovascular events (hazard ratios 1.04, 95% CI 1.01–1.08, p=0.02; and 1.88, 95% CI 1.15–3.08, p=0.01, respectively). Thus, while BMI is a marker of CAD risk, this is mostly mediated by the presence of other metabolic risk factors.

This call for action paper from a panel of experts from Iraq, Kuwait, Lebanon, Oman, Saudi Arabia and United Arab Emirates (UAE) has highlighted the high prevalence of atherogenic dyslipidaemia in this region, affecting up to 70% of individuals. Experts make the case for research in this region to obtain better understanding of this often neglected dyslipidaemia; education of public and healthcare professionals; preventive programmes for dyslipidaemia and other cardiovascular risk factors; as well as the development of local guidelines relevant to this region.

A report in JAMA supports a causal association between abdominal adiposity and the development of type 2 diabetes and coronary heart disease (CHD). This Mendelian randomization study (a ‘natural’ randomized trial) investigated whether a genetic predisposition to increased waist-to-hip ratio adjusted for body mass index (BMI) was associated with cardiometabolic quantitative traits (i.e., lipids, insulin, glucose, and systolic blood pressure), type 2 diabetes and CHD, using a polygenic risk score based on 48 single-nucleotide polymorphisms for these cardiometabolic traits. Estimates for cardiometabolic traits were based on a combined data set from 4 genome-wide association studies including up to 322,154 participants, as well as individual-level, cross-sectional data from the UK Biobank including 111,986 individuals. The study showed that a 1-standard deviation increase in waist-to-hip ratio mediated by this risk score was associated with 27 mg/dL higher triglyceride levels, 4.1 mg/dL higher 2-hour glucose levels, and 2.1 mmHg higher systolic blood pressure (each p?<0.001), and more than 50% higher risk of type 2 diabetes (odds ratio 1.77 [95% CI, 1.57-2.00]) and CHD (odds ratio 1.46 [95% CI, 1.32-1.62]). These findings suggest that body fat distribution, beyond BMI, may explain part of the variation in risk of type 2 diabetes and CHD observed in different populations, such as South Asians.

Among the highlights, the R3i has identified key sessions:

• 
  FOURIER – In the Opening Late-Breaking Clinical Trials Session on March 17th, this long-awaited cardiovascular outcomes study evaluating the PCSK9 inhibitor evolocumab will report its results. In a press release earlier this month,1 the Sponsor (Amgen) announced that treatment with evolocumab met both its primary composite endpoint (cardiovascular death, non-fatal myocardial infarction [MI], non-fatal stroke, hospitalization for unstable angina or coronary revascularization) and the key secondary composite endpoint (cardiovascular death, non-fatal MI or non-fatal stroke). No new safety issues were observed. Additionally, EBBINGHAUS, a cognitive function study of patients enrolled in the FOURIER trial showed no differences between evolocumab and placebo;1 full details will be reported at the Late Breaking Clinical Trials session on March 18th. 1. Amgen Announces Repatha® (Evolocumab) Significantly Reduced The Risk Of Cardiovascular Events In FOURIER Outcomes Study. Available at https://www.amgen.com/media/news-releases/2017/02/amgen-announces-repatha-evolocumab-significantly-reduced-the-risk-of-cardiovascular-events-in-fourier-outcomes-study/
• 
  CARAT study: The CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) is an imaging trial investigating the impact of infusing an engineered pre-beta HDL mimetic containing sphingomyelin and dipalmitoyl phosphatidlyglycerol (CER-001) on coronary atheroma volume in patients with a recent acute coronary syndrome. The primary endpoint is the nominal change in percent atheroma volume. This trial will be reported at a Late-Breaking Clinical Trials Session on March 18th.
• 
  CVD-REAL Study: There will also be a report of real-world data on rates for hospitalization for heart failure among new users of SGLT-2 inhibitors in a Featured Clinical Research III session on Sunday 19th March.

This report shows that the functionality of high-density lipoproteins (HDL) was impaired in the acute post myocardial infarction (MI) setting. This prospective study included 111 patients, 41 with non-ST-segment elevation MI (NSTEMI), 37 with STEMI and 37 non-MI patients. In vitro HDL functionality was evaluated using standard experimental approaches, notably measurement of cholesterol efflux from macrophage foam cells; the ability of HDL to prevent low-density lipoprotein oxidation; and the ability of HDL to inhibit TNF-?-induced vascular adhesion molecule-1 expression in endothelial cells. HDL from STEMI patients exhibited reduced cholesterol efflux and decreased anti-inflammatory functionalities (p<0.001), although antioxidative properties were not significantly modified. This reduced HDL function was associated with significant increases in MI risk; patients in the fourth quartile had more than 5-fold increase in MI risk compared with those in lower quartiles (odds ratio [OR], 5.66; 95% confidence interval [CI], 1.26-25.00; p = 0.024; and 5.53; 95% CI, 1.83-16.73; p = 0.002, respectively). These findings may offer some explanation for the lack of benefit observed in the dal-OUTCOMES trial with the cholesteryl ester transfer protein inhibitor dalcetrapib.

Results from this Chinese study reinforce the importance of targeting atherogenic dyslipidaemia earlier. The study evaluated data from a longitudinal cohort of 3,325 subjects (aged 20–74 years) followed for a mean of 4.2 years. Data for fasting blood lipids, and fasting and 2-hour serum glucose and insulin, were obtained at two time points. The researchers used cross-lagged path analysis to assess the temporal relationship between dyslipidaemia and insulin resistance (IR). According to this model, if the relationship between dyslipidaemia and IR was bidirectional, they would predict each other, and their cross-lagged path coefficients would not differ significantly. However, if IR and dyslipidaemia have an underlying causal relationship, the causal variable should predict the consequent variable, and the cross-lagged path coefficient of the causal variable should be significantly greater. The analysis showed that the path coefficients from baseline triglycerides and high-density lipoprotein cholesterol (HDL-C) to follow-up 2-hour insulin were significantly greater than those from baseline 2-hour insulin to follow-up triglycerides and HDL-C (p<0.001 for each analysis). These findings provide strong evidence that dyslipidaemia probably precedes peripheral IR, and should therefore be targeted sooner.

Results from this study indicate economic benefit from treating diabetic patients with combination lipid therapy targeting both elevated cholesterol and elevated triglycerides compared with statin monotherapy. The researchers used data from an observational cohort study of 184,932 patients with diabetes mellitus with 2 triglycerides measurements (between January 2012 and June 2013, with a follow-up measurement 3 to 15 months later) to identify 4 therapy groups: statin monotherapy, triglyceride-specific monotherapy, statin/triglyceride-specific combination therapy, or no therapy. These groups were stratified by percent change in triglycerides (increase ?5%, ?4.9%, decrease 5% to 29%, or decrease ?30%). After adjustment for covariates, the greatest cost reduction was seen among patients on statin/triglyceride-specific combination therapy who had ?30% reduction in triglycerides (decrease by $2,859). Therefore, not only is there clinical evidence for targeting elevated triglycerides, in addition to high cholesterol, but these findings also provide an economic rationale for the benefits of this approach.

A lower triglycerides/high-density lipoprotein cholesterol ratio (TG/HDL-C) was a predictor of poorer outcome at 3 months after ischaemic stroke, according to this study. In total, 1,006 patients (median age 68.5 years; 58% male) admitted with acute ischaemic stroke (2011-2014) were included in this analysis. Three end-points were defined according to the modified Rankin scale (mRS) score at 3 months after symptom onset: excellent outcome, mRS 0-1; good outcome, mRS 0-2; and death, mRS 6. Higher TG, non-HDL-C and TG/HDL-C were strongly associated with the three end-points after adjustment: excellent [odds ratio (OR) = 1.39, OR 1.89 and OR 2.34, respectively] and good (OR 1.48, OR 2.90 and OR 4.12) outcomes, and death (OR 0.59, OR 0.29 and OR 0.26). Patients with a TG/HDL-C <0.87 had about 3-fold higher risk of death (95% confidence interval 1.89-4.55) compared with those with a TG/HDL-C ?0.87.

One in eight very high risk patients remain at high risk of cardiovascular events despite statin therapy, according to this report using real-world data. This retrospective observational study analyzed data from 27,330 patients treated with statins (50% male, mean age 68 years). Of these, 770 patients attained a low-density lipoprotein-cholesterol (LDL-C) value below current recommended goals. Despite this, these patients remained at high risk of a cardiovascular event, with incidence rates of 1.3±1.0 per patient per year for moderate cardiovascular risk, 4.1±2.6 for high risk, and 12.5±11.0 for very high risk patients. Compared with moderate risk patients, very high risk patients with a controlled LDL-C value had about 5-fold increase in risk of a (recurrent) event (hazard ratio 4.97, 95% confidence interval 1.36-18.2). Despite the limitations of a retrospective design, these findings highlight the high residual cardiovascular risk that persists in statin-treated patients with controlled LDL-C levels in a real-world setting.

Lipids were very much in the news at this year’s meeting. Not only was there a report from GLAGOV, the first intravascular ultrasound study evaluating the effects of treatment with a PCSK9 monoclonal antibody on top of statin on progression of coronary atherosclerosis (see Landmark study), but there was also news of other approaches to targeting PCSK9. In the ORION study in high risk patients with elevated low-density lipoprotein cholesterol (LDL-C), 1 or 2 subcutaneous injections of the PCSK9 RNA interference agent inclisiran reduced LDL-C levels by 55-60%. This approach has obvious benefits for adherence, offering the possibility in the future of a single depot injection per year to manage elevated LDL-C levels.
 
On the downside, there were disappointing results from the MILANO-PILOT Study. In this study, infusion of the apoA-IMilano high-density lipoprotein (HDL) mimetic did not significantly change the percent atheroma volume (PAV) in acute coronary syndrome patients, leading to termination of this agent. However, some may question why the placebo response in this study differed with that observed in GLAGOV; in the MILANO-PILOT Study there was -0.8% change in PAV (vs. -0.5% with active drug) whereas in GLAGOV, there was +0.05% change with placebo vs. -0.95% with active drug. Perhaps a case of throwing the baby out with the bathwater?
 
Furthermore, there were early clinical (Phase I) data with Ionis-angptl3-lRx, an antisense inhibitor to angiopoietin-like protein 3 (ANGPTL3). Genetic studies have previously identified ANGPTL3 variants that were associated with very low plasma levels of LDL-C, triglycerides and HDL cholesterol. Together with other evidence, there was a strong rationale that ANGPTL3 may be a novel target for managing dyslipidaemia, with multiple beneficial effects on lipoprotein metabolism. These findings were the catalyst for the development of Ionis-angptl3-lRx. In a phase I study in healthy volunteers with elevated triglycerides, there were significant mean reductions in triglycerides (by 66%), apolipoprotein CIII (by 68%), and LDL-C (by 35%). Safety data were also encouraging.

Emerging evidence shows that loss-of-function mutations in the gene encoding apolipoprotein CIII (APOC3), are associated with a decrease in plasma triglycerides levels and clinical benefit in patients at high cardiovascular risk. This study provides molecular evidence for this association. The authors identified a common APOC3 variant (rs4225) in the microRNA-binding site (miR-4271 binding) which affects its expression and the risk of coronary heart disease. The T allele but not the G allele of this variant suppressed APOC3 by facilitating miR-4271 binding. Furthermore, individuals with the TT genotype not only had lower plasma triglycerides than those with the GG allele (p=0.03), but also evidence from a case-control study suggested that the TT genotype was associated with 11% (2-23%) reduction in coronary heart disease risk [p?=?0.009]. These findings add to accumulating evidence for apolipoprotein CIII or APOC3 as a potential therapeutic targets.

In this analysis of the PreterAx and DiamicroN modified-release controlled evaluation (ADVANCE) trial and the ADVANCE-ON post-trial study, major peripheral artery disease (lower-extremity ulceration or amputation, and peripheral revascularization) increased the risk of all-cause mortality and cardiovascular events in patients with type 2 diabetes. In addition, lower-extremity ulceration or amputation was associated with an increased risk of severe retinopathy. These findings underline the close associations between macrovascular and microvascular risk in type 2 diabetes.
In this report, 11,140 type 2 diabetes patients were followed for a median of 5.0 (in-trial), 5.4 (post-trial), and 9.9 (overall) years. Overall, 516 (4.6%) patients had major peripheral arterial disease at baseline; 300 (2.7%) had lower-extremity chronic ulceration or amputation alone, 190 (1.7%) had peripheral revascularization alone, and 26 (0.2%) had both presentations. Over the follow-up period, 2265 (20.3%) died (all causes), 2166 (19.4%) had major cardiovascular events of whom 988 (8.9%) died, and 807 (7.2%) had major clinical microvascular events. Overall, major peripheral artery disease was associated with 35% (15-60%) increased risk of death (p = 0.0004), 47% (23-75%) increased risk of major cardiovascular events (p <0.0001), 75% (39-221%) increased risk of cardiovascular death (p < 0.0001), and 58% (19-209%) increased risk of myocardial infarction (p = 0.001). There was also a trend toward an association between baseline peripheral artery disease and risk of major clinical microvascular events [hazard ratio 1.31, 95% CI 0.96–1.78, p = 0.09], specifically diabetic retinopathy. In conclusion, these findings emphasize that type 2 diabetes patients with major peripheral artery disease have poor survival and cardiovascular outcomes and underline the need for routine screening for peripheral artery disease to improve prognosis.

This post hoc pooled analysis of three randomized trials of serial coronary intravascular ultrasound (REVERSAL, ASTEROID and SATURN) suggests that women with coronary disease derive greater benefit from high intensity statin therapy than male patients. The analysis evaluated data from 451 women and 1190 men. On-treatment levels of mean low-density lipoprotein cholesterol [LDL-C] (68 ± 24 vs. 67 ± 22 mg/dl) and apolipoprotein B (77 ± 23 vs. 76 ± 20 mg/dL) were similar in both sexes, although triglycerides were higher in women than men [median (interquartile range):122 (95, 158) vs. 114 (89, 154) mg/dl, p=0.012]. Additionally, C-reactive protein was also higher in women than men [1.7 (0.9, 3.8) vs. 1.1 (0.6, 2.7) mg/l, p < 0.001]. While women had significantly lower baseline percent atheroma volume (PAV) than men (34.8 ± 8.7 vs. 38.3 ± 8.8%, p < 0.001), they derived significantly greater regression in atheroma (Change in PAV -1.07 ± 0.26 vs. -0.66 ± 0.23%, p=0.02), especially with on-treatment levels of LDL-C <64 mg/dl, apolipoprotein B <73 mg/dl, and non-high-density lipoprotein cholesterol [non-HDL-C] <88.8 mg/dl. Furthermore, these apparent sex-related differences in plaque regression with high intensity treatment seem to relate more to lower achieved atherogenic lipoprotein levels (as typified by LDL-C and non-HDL-C) than lower inflammatory levels (as typified by C-reactive protein). These findings emphasize the need for aggressive lipid lowering strategies in women with established atherosclerosis.

In the German DIVE (DIabetes Versorgungs-Evaluation) and the DPV (Diabetes-Patienten-Verlaufsdokumentation) database including more than 350,000 individuals, only a minority (26.7%) were treated with lipid modifying therapy, highlighting the need for further action to address this issue. <
 
This analysis included data from 363,949 individuals with type 2 diabetes. Of those who received lipid modifying treatment, the most commonly prescribed was statin (84%). While control of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) was significantly better (p<0.001) in these patients than in those not on a statin (median LDL-C 100.5 vs. 114.0 mg/dl in those not treated, and non-HDL-C 131.0 vs. 143.1 mg/dl, respectively), plasma triglycerides were significantly higher (160.3 vs. 152.0 mg/dl; p < 0.001). Thus, despite the availability of multiple guidelines, lipid management, particularly of triglycerides, lags behind in this high risk group.

According to a press release, GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound), a serial intravascular ultrasound imaging study, met its primary endpoint, showing significant change in percent atheroma volume from baseline to week 78 with evolocumab compared to placebo. There were also significant changes in secondary outcomes of atheroma measurement. GLAGOV is due to be presented at this year’s Scientific Sessions of the American Heart Association.

In the Spanish healthcare setting, the polypill (aspirin 100 mg, atorvastatin 20 mg, ramipril 10 mg) is a cost-effective approach to reducing residual cardiovascular risk in adults with a history of myocardial infarction, compared with individual monotherapies. Using Markov modelling, use of the cardiovascular polypill instead of its monocomponents would avoid 46 nonfatal and 11 fatal cardiovascular events per 1000 patients treated over a 10-year period. Moreover, this analysis showed that the polypill would be a cost-effective strategy compared with multiple monotherapy at a willingness-to-pay threshold of 30 000 euros per quality-adjusted life year.

Although statins significantly reduce vascular event rates, lipid-related residual cardiovascular risk remains high in many patient groups. The SPIRE outcomes studies will offer the opportunity to test whether the level of low-density lipoprotein cholesterol (LDL-C) at study entry is a determinant of clinical benefit with the PCSK9 inhibitor bococizumab. There are two outcomes studies with bococizumab: SPIRE-1 (NCT01975376) and SPIRE-2 (NCT01975389). These event-driven studies will assess the efficacy and safety of bococizumab in reducing the residual risk of cardiovascular events in high-risk patients on statin, with and without clinical cardiovascular disease, and with LDL-C levels ?70 mg/dL or 1.8 mmol/L (SPIRE-1, n = 17,000) or ?100 mg/dL or 2.6 mmol/L (SPIRE-2, n = 11,000). SPIRE-2 has now completed recruitment. These trials, together with the outcomes studies with alirocumab and evolocumab, will test whether lowering LDL-C levels by PCSK9 inhibition beyond current targets will provide significant reduction in the residual risk of cardiovascular events in patients receiving best evidence-based treatment including statins.

A study using Mendelian randomization highlighted an association between elevated triglycerides and increased coronary artery disease risk; in contrast, higher triglycerides were associated with lower risk of type 2 diabetes. The study used data from genome-wide association studies, comprising 130 single-nucleotide polymorphisms (SNPs) for low-density lipoprotein cholesterol (LDL-C), 140 SNPs for triglycerides and 140 SNPs for high-density lipoprotein cholesterol (HDL-C), to construct genetic risk scores. A 1 standard deviation (SD) genetic increase in LDL-C levels (~38 mg/dL) and triglyceride levels (~89 mg/dL) increased coronary artery disease risk by 68% (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.51-1.87) and 28% (OR 1.28, 95% CI, 1.13-1.45), respectively. In contrast, 1 SD increase in HDL-C (~ 16-mg/dL) decreased risk by 5% (OR 0.95, 95% CI, 0.85-1.06). However, the study showed that all three lipid traits were associated with a lower risk of type 2 diabetes, decreasing risk by 21% (for LDL-C), 17% for HDL-C and 17% for triglycerides per 1 SD increase. These genetic data raise a number of questions for the design of studies evaluating the effects of therapeutic modulation on risk for diabetes and cardiovascular disease.

A triglyceride/high-density lipoprotein cholesterol (TG/HDL) ratio ?1.76 is an independent predictor for multivessel coronary artery disease in patients with acute coronary syndrome (ACS), according to this report from a national ACS registry in Portugal.
 
The investigators included 9,345 patients in this registry between June 2011 and November 2015; 2,163 were excluded from this analysis because of previous coronary artery disease. Among evaluable patients who underwent angiography, 45.5% had multivessel coronary artery disease. Patients with a TG/HDL ratio ?1.76 were younger, had a higher body mass index and were more frequently males, smokers, diabetics and had more hyperlipidaemia. These individuals also had a significantly higher incidence of multivessel disease (47.5% vs. 37.6%, p<0.001), even after adjustment for other predictors (odds ratio 1.59, 95% CI 1.38–1.83, p<0.001).

In a key Hotline session, the effects of higher levels of systolic blood pressure (SBP) and low density lipoprotein cholesterol (LDL-C) were shown to be independent and cumulative, providing a clear rationale for targeting both simultaneously.
 
Using a 2x2 factorial Mendelian randomization study, the investigators incorporated genetic and cardiovascular risk-factor data from 102,773 subjects included in 14 prospective cohort or case-control studies. These data were used to calculate genetic risk scores for each patient based on single nucleotide polymorphisms known to be associated with LDL-C or SBP. Combined exposure to lower LDL-C and lower SBP was significantly greater than the effect of lower LDL-C alone (P=1.4x10-14) and significantly greater than the effect of lowering blood pressure alone (P=1.8x10-23). Combined exposure to 1 mmol/L lower LDL-C and 10 mm Hg lower SBP was associated with an 86.1% lower risk of cardiovascular disease events, as well as an 84% reduction in coronary heart disease mortality. The effect was similar in men and women, smokers and nonsmokers, people with and without diabetes, as well as those with normal blood pressure and cholesterol levels.

An update to the 2011 Joint Guidelines for management of Dyslipidemia was launched at this year’s Congress. The key messages for clinicians are:
• Lifestyle is the fundamental first step in cardiovascular disease prevention and should be supported by clinicians
• Low-density lipoprotein cholesterol (LDL-C) is the primary lipid target for intervention to reduce cardiovascular risk; the guidelines give both targets and per cent reduction required for high and very high risk patients
• Nonfasting lipid measurement is recommended for routine screening.

The R3i has previously discussed the proposal that the presence of microvascular complications is predictive of cardiovascular events (1). This report adds to this argument, showing that coronary atherosclerosis and plaque vulnerability are more severe in individuals with diabetic retinopathy.
 
This study evaluated the extent and severity of coronary atherosclerosis in 57 diabetes patients with coronary artery disease, either with (n=15) or without (n=42) diabetic retinopathy. The extent of coronary atherosclerosis (yellow plaques) in at least one coronary artery was quantitated, and the severity assessed by colour rating (1 = light yellow; 2 = yellow, or 3 = intense yellow). Over a mean follow-up of 7.1 ± 3.3 years, patients with diabetic retinopathy not only had more coronary atherosclerosis (mean yellow plaques per vessel 2.08 ± 1.01 vs.1.26 ± 0.77, p = 0.002), but also more severe coronary atherosclerosis (mean rating 2.40 ± 0.74 vs. 1.90 ± 0.82, p = 0.044) compared with those without. In addition, the incidence of acute coronary syndromes (ACS) was significantly higher in those with diabetic retinopathy (p = 0.004), with nearly 7-fold higher risk of ACS (adjusted hazard ratio 6.943, 95% confidence interval, 1.267–38.054; p = 0.026). The finding that coronary atherosclerosis is more prevalent and more severe in patients with diabetic retinopathy suggests a link between diabetes-related microvascular complications and macrovascular plaque vulnerability.
 
1. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 2011;218:13-8.

The gliptins or dipeptidyl peptidase 4 (DPP4) inhibitors, are widely accepted therapy for the management of type 2 diabetes, although their effects on cardiovascular outcomes so far remains uncertain. In this small cohort, one of these agents, anagliptin, was shown to have beneficial effects on arterial stiffness in patients with type 2 diabetes, independent of glucose lowering effects. This study included 50 patients (mean age 72.5±9.5 years, 66% male) who were randomized to treatment with anagliptin (n=26) or glimepiride (n=24) for 6 months. Arterial stiffness was measured by the cardio-ankle vascular index at baseline and the end of treatment. Anagliptin significantly reduced both low-density lipoprotein cholesterol and remnant-like particle cholesterol, as well as hepatic enzymes (alanine aminotransferase). Multiple regression analysis showed that the absolute change in remnant cholesterol was an independent predictor of the change from baseline to 6 months in the cardio-ankle vascular index. These findings suggest a potential benefit of anagliptin on arterial stiffness, possibly mediated by reduction in atherogenic remnant cholesterol.

Follow-up of the NIPPON DATA 90 prospective general population cohort study showed an association between non-high-density lipoprotein cholesterol (non-HDL cholesterol) and risk for death from coronary heart disease.
 
NIPPON-DATA 90 (National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1990-2005) is a large cohort study of cardiovascular disease in the general population in Japan. This report investigated whether non-HDL cholesterol, which includes low-density lipoprotein (LDL) cholesterol, was predictive of cardiovascular mortality in 8383 subjects followed up for 20 years. In 6701 subjects with lipid data aged <75 years and without a history of cardiovascular disease, 69 died from coronary heart disease and 112 from stroke over this period. Compared with subjects with non-HDL cholesterol <3.9 mmol/L, the risk of coronary heart disease death increased by 27% with non-HDL cholesterol levels of 3.9-4.3 mmol/L (hazard ratio 1.27, 95% confidence interval 0.65-2.49), by 81% in those with levels of 4.4-4.8 mmol/L (hazard ratio 1.81, 95% confidence interval 0.92-3.55), and by 240% in those with levels ?4.9 mmol/L (hazard ratio 2.40, 95% confidence interval 1.30-4.43). This association remained significant after adjustment for other cardiovascular risk factors (P trend=0.010). However, there was no significant association between non-HDL cholesterol and stroke.
 
These findings reaffirm the importance of non-HDL cholesterol as a predictor of future coronary heart disease death, as reported from analyses in Caucasian subjects.

This timely perspective highlights the unmet clinical need due to non-low-density lipoprotein abnormalities that contribute to residual cardiovascular risk in high risk patients. In particular, the report highlights the marked increase in the prevalence of atherogenic dyslipidaemia, characterised by hypertriglyceridaemia, low plasma concentration of high-density lipoprotein (HDL) cholesterol, and qualitative changes in LDL particles. The increase in the prevalence of this dyslipidaemic profile has been especially notable in Latin and South America and South East Asia, in line with adoption of a sedentary lifestyle and Westernised diet on top of high habitual carbohydrates intake. This review discusses the underlying pathophysiology contributing to the development of this dyslipidaemia, current therapeutic options, as well as novel therapeutic strategies that target elevated triglyceride-rich lipoprotein particles which may offer promise in reducing the high residual cardiovascular risk.

Volanesorsen, a second generation antisense inhibitor of apolipoprotein (apo) CIII, substantially reduced plasma apoC-III and triglycerides in type 2 diabetes patients with elevated triglycerides (>200 and <500 mg/dL). Treatment was also associated with marked improvement in insulin sensitivity. This randomized, double-blind, placebo-controlled trial enrolled 15 type 2 diabetes patients (mean age 56.5 years, 73% women, mean HbA1c 7.9%, baseline triglycerides 249 mg/dL). Patients were allocated to treatment with volanesorsen 300 mg or placebo administered subcutaneously on days 1, 3, 5, 8, 15, 22, 29, 35, 42, 49, 56, 63, 70, 78, and 85 (15 doses). Insulin sensitivity was assessed using a two-step hyperinsulinaemic-euglycaemic clamp procedure, before and after study treatment. Eleven of the 15 patients received all 15 doses. Compared with placebo, treatment with volanesorsen resulted in significant reductions in apoCIII by 88% and triglycerides by 69% (p<0.05), and also increased high-density lipoprotein cholesterol by 42% (p<0.05). Intriguingly, there was also significant improvement in whole-body insulin sensitivity (by 57%, p<0.001), in relation to changes in both apoCIII and triglycerides (p=0.03 and p=0.01, respectively). On the strength of these findings, albeit in a small sample of patients treated for a short duration, further investigation of the efficacy of volanesorsen to better define those patients most likely to benefit from treatment is merited.

AIM-HIGH failed to show that targeting high-density lipoprotein cholesterol (HDL-C) reduced cardiovascular events. This secondary analysis suggests that refocusing on HDL subclass, specifically HDL3-C (very-small and denser HDL) may be more relevant in explaining the link between HDL-C and cardiovascular risk.
 
In AIM-HIGH, subjects with cardiovascular disease and low baseline HDL-C concentration were randomized to treatment with simvastatin plus placebo or simvastatin plus extended release niacin 1500 to 2000 mg/day, with ezetimibe added as needed in both groups to maintain on-treatment low-density lipoprotein cholesterol (LDL-C) levels in the range of 40–80 mg/dL. The primary endpoint of the study was a composite of death from coronary disease, nonfatal myocardial infarction, ischaemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization. This secondary analysis evaluated baseline levels of HDL-C, HDL3-C, small dense LDL-C and LDL-triglycerides in 3,094 study subjects on statin therapy before entering the study. The investigators showed that baseline HDL3-C was protective against cardiovascular events (hazard ratio 0.84, p = 0.043). None of the other baseline lipid parameters were associated with risk for cardiovascular events.

Maintaining fitness over the long-term protects against the development of atherogenic dyslipidaemia, according to this report. This study evaluated data from subjects who completed at least three comprehensive medical examinations, including at least one maximal treadmill test, between 1976 and 2006 at the Cooper Clinic in Dallas, Texas. Over an average follow-up of 8.85 years, 193 subjects developed atherogenic dyslipidaemia, defined as low plasma concentration of high-density lipoprotein cholesterol <40 mg/dL, triglycerides ?200 mg/dL, and low-density lipoprotein cholesterol ?160 mg/dL. Individuals who maintained a high level of fitness over this period were 44% less likely to develop atherogenic dyslipidaemia compared with those with reduced fitness, even after adjustment for baseline confounders and changes in other established cardiovascular risk factors (odds ratio 0.56; 95% confidence interval 0.34-0.91). These findings provide another reason why maintaining fitness over time improves cardiovascular health.

In type 2 diabetes patients, the apolipoprotein(apo) CIII antisense agent volanesorsen reduced plasma triglycerides and apoC-III, and also improved insulin sensitivity and glycaemic control. In this phase II double-blind, placebo-controlled study, 15 type 2 diabetes patients with elevated triglycerides (>200 and <500 mg/dl) were randomized to weekly subcutaneous treatment with volanesorsen 300 mg or placebo (2:1) for 13 weeks. Compared with the placebo group, treatment with volanesorsen reduced plasma triglycerides by 69% (p=0.02), apoCIII by 88% (p = 0.02) and raised high-density lipoprotein cholesterol by 42% (p = 0.03). In addition, volvanesorsen treatment led to improvement in whole-body insulin sensitivity by 57% (p < 0.001). This improved insulin sensitivity was associated with reduction in both plasma apoCIII (r = ?0.61, p = 0.03) and triglycerides (r = ?0.68, p = 0.01). There were also improvements in markers of glycaemic control, including glycated albumin, haemoglobin A1c and fructosamine at the end of the study. The adverse event profile in each group was similar and there were no clinically relevant changes in safety parameters including haematology, clinical chemistry or urinalysis values. These findings suggest another agent with promise for the management of type 2 diabetes patients with atherogenic dyslipidaemia.

Data from the prospective Second Manifestations of ARTerial disease (SMART) cohort suggested that higher levels of high-density lipoprotein (HDL) cholesterol at baseline are associated with increased cardiovascular risk in type 2 diabetes patients with controlled low-density lipoprotein (LDL) cholesterol concentration. In total, 1,829 type 2 diabetes patients (mean age 60 years, 70% men, 60% on lipid lowering therapy) were included. Over a median follow-up of 7 years, there were 335 new cardiovascular events (myocardial infarction [MI], ischaemic stroke, vascular death) and 385 patients died. In all patients, the risk of MI decreased by 7% per 0.1 mmol/L increase in HDL cholesterol concentration (adjusted hazard ratio 0.93, 95% confidence interval 0.87–1.00); there was no association with any other endpoint. However, baseline plasma HDL cholesterol concentration was not associated with risk of cardiovascular events (hazard ratio 0.97, 95% confidence interval 0.93–1.01) or all-cause death (hazard ratio 0.99, 95% confidence interval 0.96–1.03). Subgroup analyses did suggest that LDL cholesterol concentration may modify the association between HDL cholesterol and cardiovascular events or all-cause death. Indeed, the risk of cardiovascular events was 10% higher (hazard ratio 1.10, 95% confidence interval 1.07–1.21), and all-cause mortality 14% higher (hazard ratio 1.14, 95% confidence interval 1.07–1.21), in individuals with high baseline HDL cholesterol levels and plasma LDL cholesterol concentration <2.0 mmol/L. There was no association in individuals with higher LDL cholesterol levels. These findings may lend some credence to the proposal that an increase in HDL cholesterol concentration is not always beneficial (as shown by dal-OUTCOMES), possibly attributable to modification of HDL functionality and/or distribution changes within HDL subclasses. Additionally, whereas low HDL cholesterol concentration has been shown to be a cardiovascular risk factor, supported by extensive evidence, raising HDL cholesterol levels with HDL-targeted therapies has not been shown to reduce cardiovascular events. Taken together, these findings raise questions about the relevance of HDL cholesterol to residual cardiovascular risk that persists in high-risk patients despite well controlled LDL cholesterol levels.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study showed significant benefit with fenofibrate on diabetic retinopathy in type 2 diabetes patients treated with simvastatin, reducing disease progression by about one-third over 4 years. The question posed by clinicians was whether this benefit persisted long-term, beyond the clinical trial.
 
As part of the ACCORD Follow-On (ACCORDION) Eye Study (2010–2014), patients were re-evaluated 4 years after the close of the ACCORD trial. The effect of fenofibrate did not persist long-term; progression of diabetic retinopathy was reported for 11.8% of patients allocated fenofibrate versus 10.2% with placebo (adjusted odds ratio 1.13, 95% confidence interval 0.71–1.79, p=0.60). In contrast, the effects of intensive glycaemic control (which did show significant benefit on retinopathy progression in ACCORD-Eye), were even greater than observed during the trial, with 58% reduction in disease progression (5.8% of patients allocated intensive glycemic treatment versus 12.7% with standard treatment showing progression, adjusted odds ratio 0.42, 95% confidence interval 0.28–0.63, p<0.0001). This benefit persisted despite both groups having similar haemoglobin A1c levels. As in the main trial, intensive blood pressure treatment had no benefit (7.5% with intensive blood pressure treatment versus 6.0% on standard treatment showing progression, adjusted odds ratio 1.21, 95% confidence interval 0.61–2.40, p=0.59).
 
As highlighted by the authors, this is the first study to show that previous intensive glycaemic control in patients with type 2 diabetes for at least 10 years and established cardiovascular disease led to a decrease in diabetic retinopathy progression. However, the effects of fenofibrate in reducing diabetic retinopathy progression did not persist beyond the main trial after the drug was discontinuated. This lack of lipid-modification lowering legacy benefit might suggest that previous lipid modification may be less relevant in the long-term for mechanism(s) underlying the pathophysiology of diabetic retinopathy.

Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease, although the underlying mechanism is not clear. Previous reports have suggested an association between hyperlipidaemia and hyperhomocysteinaemia. According to this report from the Very Large Database of Lipids, however, elevated plasma levels of homocysteine were not associated with an atherogenic lipid profile. The study included data from 18,297 U.S. adults with lipid measurements (triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL-C, very low-density lipoprotein and remnant-lipoprotein cholesterol). For subjects in the highest homocysteine quartile, levels of LDL-C, non-HDL-C and HDL-C (p<0.001) were 7-10% lower, and triglyceride-rich lipoproteins were 2-6% higher, in unadjusted analyses. However, these associations were abolished after adjusting for age, sex, HbA1c, insulin, creatinine, and blood urea nitrogen.

Findings from the Swedish National Diabetes Register show the importance of lipid-lowering therapy (LLT) in the primary prevention setting for individuals with type 1 diabetes, reducing the risk of cardiovascular disease by 22–44%.
 
People with type 1 diabetes are at increased risk of cardiovascular events compared with the general population, despite recent advances in care. Recent guidelines have recommended statin therapy for type 1 diabetes individuals aged more than 40 years. However, the data for this recommendation, (based on older individuals, half of whom had cardiovascular disease), do not take account of subsequent changes in diabetes management, and thus may not be generalizable to the primary prevention setting.
 
Investigators used propensity scores for treatment with LLT, which were based on 32 baseline clinical and socioeconomic variables, to estimate the effect of LLT in the overall cohort (n=24,230 with type 1 diabetes). Over the mean follow-up of 6 years, 18,843 individuals received no treatment and 5,387 were treated with LLT (97% statins). Compared with untreated individuals, those receiving LLT had a 40% reduction in cardiovascular mortality (hazard ratio [HR] 0.60, 95% CI 0.50–0.72), 44% reduction in stroke (HR 0.56, 95% CI 0.46–0.70), and 22% reduction in myocardial infarction (HR 0.78, 95% CI 0.66–0.92). This study, the first large observational study to explore the effect of LLT in people with type 1 diabetes without previous CVD, highlights the importance of primary prevention with LLT to reduce cardiovascular risk.

Arterial stiffness is strongly predictive of atherosclerotic cardiovascular disease. In this community-based, longitudinal cohort from China, lower triglyceride levels were significantly associated with decreases in carotid-femoral pulse wave velocity, indicative of improved arterial function. The study measured carotid-femoral pulse wave velocity [PWV] and carotid-radial PWV in 1,447 subjects (mean age, 61.3 years). Over a median follow-up of 4.8 years, they showed that plasma triglycerides were independently associated with carotid-femoral and carotid-radial PWV (both p<0.001). This association was even stronger in older individuals (>65 years). Using multivariate logistic regression analysis, the investigators showed that every 1 standard deviation increase in plasma triglycerides was associated with a 1.296-increased likelihood of the presence of carotid-femoral PWV (odds ratio 1.296; 95 % CI 1.064 - 1.580; p = 0.01). The investigators concluded that lowering plasma triglycerides offers the potential for improvement in arterial stiffness in individuals with atherosclerotic disease.

In this experimental study in rabbits, the HDL mimetic CER-522 improved left ventricular diastolic dysfunction as well as decreasing macrophage accumulation, cardiomyocyte apoptosis, coronary atherosclerosis and remodeling. Experimental left ventricular dysfunction was induced in rabbits fed a cholesterol- and vitamin D2-enriched diet. Subsequently, the rabbits were treated with 10 mg/kg or 30 mg/kg CER-522 infusions 6 times over 2 weeks, or saline infusions (control). Serial echocardiograms and left ventricular histology showed that CER-522 reduced a number of variables indicative of left ventricular diastolic dysfunction, including early filling mitral deceleration time, deceleration rate, and the left ventricular diastolic dysfunction score. Furthermore, CER-522 infusion also reduced macrophage accumulation in the left ventricle, levels of apoptotic cardiomyocytes, as well as atheromatous plaques in the coronary arteries. The results of this study merit further study of CER-522.

This study, involving data from 2636 Icelandic subjects, focused on the ASGR1 gene, which codes for a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. Researchers identified two loss-of-function ASGR1 variants (del12 and p.W158X) that had significant effects on non-HDL-C. When these data were imputed to the Icelandic population, it was shown that individuals who were heterozygous for the del12 mutation (0.8% of the study population) had 15.3 mg/dL (0.40 mmol/L) lower non-HDL-C levels than noncarriers. Furthermore, these heterozygous individuals also had a 34% reduction in risk for coronary artery disease (p=4.0×10?6). Carriers also had lower triglyceride levels, although the effect was weaker than for non-HDL-C. The other loss-of-function variant (p.W158X, found in 1 in 1,850 people) was associated with 24.9 mg/dL decrease in non-HDL-C levels and 35% decrease in coronary risk, although this was not statistically significant (p=0.24). Replication testing in 42,524 case patients and 249,414 controls from five European ancestry populations confirmed the findings. These variants, which disrupt ASGR1 function, therefore represent a link between the sialylation pathway and atherosclerotic disease. In an accompanying editorial,1 Professor Anne Tybjaerg-Hansen (University of Copenhagen, Denmark) suggested that the findings may offer new therapeutic potential, although elucidation of the underlying mechanism(s) is needed. Indeed, given the magnitude of the effects of coronary risk versus lipids compared with other loss-of-function variants (such as PCSK9), this might suggest that the mutation also impacts non-lipid pathways, such as those involving inflammatory mediators. Research is ongoing to identify the target molecule with the aim of developing novel therapies.
 
1. Tybjærg-Hansen A. The sialylation pathway and coronary artery disease. N Engl J Med. 2016 May 18. [Epub ahead of print].

This study suggests that elevated serum fibroblast growth factor 21 (FGF21) levels (>135.5 pg/ml) may be a novel diagnostic biomarker in the initial stages of diabetic retinopathy in individuals with type 2 diabetes.
 
This cross-sectional study included 142 type 2 diabetes patients, with and without diabetic retinopathy. Compared with healthy controls, serum FGF21 levels were elevated in subjects with type 2 diabetes but without retinopathy (mean [SD] 103.50 [75.75] pg/ml versus 99.00 [126.75] pg/mL), and even higher across different stages of diabetic retinopathy (233.00 [109.00] pg/ml for nonproliferative diabetic retinopathy and 215.00 [122.00] pg/ml for proliferative diabetic retinopathy). After adjustment for potential confounders, FGF21 was shown to be the only significant factor associated with diabetic retinopathy in type 2 diabetes patients.

In this study, fine gene mapping from 95 lipid genome wide association studies (GWAS) loci in people with extremely high and low to normal plasma lipid levels led to the identification of one new coding variant associated with elevated triglycerides.
 
GWAS for plasma lipid levels have mapped numerous genomic loci, with each region often containing many protein-coding genes. Targeted re-sequencing of exons is a strategy to pinpoint causal variants and genes. The study used this approach in individuals with extremely high as well as low to normal levels of low-density lipoprotein cholesterol (n = 311), triglycerides (n = 308), and high-density lipoprotein cholesterol (n = 684), and tested whether coding sequence variants, individually or aggregated within a gene, were associated with plasma lipid levels. Findings were replicated by sequencing in independent participants (n = 6,424). Overall, the study identified 6 variants with significant associations with plasma lipids; however, only one of these had a novel association with triglycerides (p.Ser147Asn variant in APOA4, 14.3% frequency).
 
In conclusion, these results provide further insight into the genetic control of lipid traits, specifically elevated triglycerides. Fine mapping GWAS loci may, however, have limitations in studying the cause of these signals.

Findings from this study in patients with coronary artery disease suggest that high-density lipoprotein (HDL) particle size and function may act as markers, or even mediators, of coronary atherosclerosis in humans.
 
The study included 80 patients with non-obstructive (<30% stenosis) coronary artery disease. Assessments included endothelial dysfunction, defined as <50% change in coronary blood flow in response to intra-coronary infusions of acetylcholine during diagnostic coronary angiograph; as well as cholesterol efflux capacity and HDL particle concentration (HDL-P). Whereas cholesterol efflux capacity and HDL-P were both significantly and inversely predictive of endothelial dysfunction (p<0.001 and 0.005, respectively), HDL cholesterol concentration was not informative. Therefore, this report supports the value of other measures beyond HDL cholesterol concentration as markers, or potentially mediators of atherosclerosis in patients with established coronary disease.

The ratio of serum triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) may have potential in estimating the risk of sleep apnoea syndrome, according to this study in non-overweight Japanese men. This cross-sectional study included 1,528 men aged 30-69 years being evaluated for sleep apnoea syndrome, diagnosed as a 3% oxygen desaturation index (ODI) of ?15 events/hour. In total, 241 were diagnosed with sleep apnoea syndrome, independent of conventional risk factors, such as elevated body mass index (BMI). In subjects with a BMI <25 kg/m2, the TG/HDL-C ratio was significantly and positively associated with sleep apnoea syndrome; this was not the case in those with a BMI ?25 kg/m2. The risk of sleep apnoea syndrome was 2-fold higher in individuals with an elevated TG/HDL-C ratio and BMI <25 kg/m2, driven by high triglycerides (multivariable adjusted odds ratio per Log TG-HDL: 2.03, 95 % CI 1.36-3.03). br> 
Taken together, these findings suggest that the TG/HDL-C ratio could have potential in estimating the risk of sleep apnoea syndrome in these individuals, although further study is also merited.

Treatment with evacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, did not reduce cardiovascular events, despite substantially raising high-density lipoprotein cholesterol (HDL-C, increase by 130%) and lowering low-density lipoprotein cholesterol (LDL-C, decrease by 37%).
 
ACCELERATE was a phase 3, multicenter randomized, double-blind trial involving 12,092 patients (mean age 65 years, 23% female, mean body mass index 30.2 kg/m2 and 68% with diabetes) with either an acute coronary syndrome, cerebrovascular atherosclerotic disease, peripheral vascular disease or diabetes with coronary artery disease. Patients were randomized 1:1 to evacetrapib 130 mg daily (n=6,038) or placebo (n=6,054) in addition to standard medical therapy. Almost all (96%) patients were treated with a statin at baseline, although only 46% were treated with high-intensity statin. The total duration of follow-up was 30 months (following termination due to futility). At baseline, mean HDL-C was 45 mg/dl and mean LDL-C was 81 mg/dl.
 
The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), stroke, coronary revascularization and unstable angina. There was no difference in the incidence of the primary outcome over the follow-up period (12.8% for the evacetrapib group vs. 12.7% for placebo, p = 0.85). Similarly, there was no significant effect for any of the individual components of the primary outcome. All-cause mortality was lower in the evacetrapib group but this was not significant (3.8% vs. 4.1% on placebo, p = 0.06).
 
In terms of lipids, mean HDL-C at the end of follow-up was 104 mg/dl vs. 46 mg/dl on placebo (p<0.001); mean LDL-C was 55 mg/dl vs. 84 mg/dl (p < 0.001).
 
There was no difference between the two groups with respect to treatment discontinuation due to adverse events (8.6% in the evacetrapib group vs. 8.7% on placebo, p = 0.86).
 
The reasons for the lack of benefit of evacetrapib in ACCELERATE are so far unclear. The functionality of HDL particles generated by CETP inhibition was also questioned with respect to reverse cholesterol transport and/or other beneficial characteristics. The accumulating evidence suggests that CETP inhibition may not be a good strategy to mitigate residual cardiovascular risk; results are awaited from the ongoing outcomes trial with anacetrapib (REVEAL).

Both low and high HDL cholesterol concentration was associated with risk for development of hypertension in a Japanese working-age male population, according to this report.
  The study included data from 14,215 non-hypertensive male workers (mean age 38±9 years) who were followed up for new-onset hypertension, defined as blood pressure ?140/90 mm Hg or use of antihypertensive medication. Over a median of 4 years, 1,483 subjects developed hypertension. After adjustment for conventional cardiovascular risk factors, including age, body mass index, impaired fasting glucose/diabetes, baseline blood pressure, alcohol intake, smoking, exercise, and parental history of hypertension, the study reported a U-shaped relationship for HDL cholesterol concentration and risk of hypertension, with increased risk confined to the lowest and highest HDL cholesterol quartiles (increase in risk of developing hypertension by 22% and 34%, respectively). In contrast, only elevated total, low-density lipoprotein cholesterol and non-HDL cholesterol were associated with increased risk of developing hypertension in this Japanese cohort.

Isolated low plasma HDL cholesterol concentration was the predominant lipid profile in this analysis of the PERU MIGRANT study, which aimed to investigate the effect of migration on cardiovascular risk profiles and mortality in Peru.
 
This report included data from 988 migrants in Peru, 201 in a rural setting, 598 who moved from rural-to-urban setting and 199 urban subjects. Baseline data (collected in 2007 to 2008) were used for cross-sectional analyses and 5-year follow-up data (2012-2013) were used in the longitudinal analysis. Overall, low HDL cholesterol was prevalent, in 56% of cases, with isolated low HDL cholesterol the predominant phenotype (36% of cases). Multivariable analysis showed that isolated low HDL cholesterol was more prevalent in urban than rural migrants, and in women than men. Elevated body mass index was associated with both isolated and non-isolated low HDL cholesterol concentrations. However, only non-isolated HDL cholesterol was associated with increased cardiovascular mortality, increasing risk by more than 3-fold.

Low HDL cholesterol has already been shown to be an independent risk factor for the development of diabetic kidney disease in the ADVANCE study.1 This study investigated whether this association extended to a wider population including patients with and without diabetes.
 
Researchers used survival models to investigate the association between HDL cholesterol and the risk of incident chronic kidney disease (CKD) and CKD progression, based on a cohort of 1,943,682 male US veterans. Progression of CKD was defined as doubling of serum creatinine, estimated glomerular filtration rate (eGFR) decline of ?30%, or a composite outcome of end-stage renal disease, dialysis, or renal transplantation. The models were adjusted for demographics, comorbid conditions, eGFR, body mass index, lipid parameters, and statin use over a median follow-up of 9 years. Compared with individuals with an HDL concentration of ?40 mg/dl, those with low HDL-C, defined as <30 mg/dl, had a 20% higher risk of incident CKD (odds ratio 1.20, 95% CI 1.18-1.22), and were also at higher risk of CKD progression, as defined by doubling of serum creatinine (odds ratio 1.14, 95% CI 1.12-1.15) GFR decline of ?30% (odds ratio 1.13, 95% CI 1.12-1.14), and the composite renal end point (odds ratio 1.08, 95% CI 1.06-1.11). In summary, the analysis showed that low HDL cholesterol was associated with increased risk of incident CKD and CKD progression, suggesting the need for its incorporation within risk factor screening panel.
 
1. Morton J, Zoungas S, Li Q et al. Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy. Diabetes Care 2012;35:2201–6.

Continuing on the HDL theme, this report from the Veterans Affairs Diabetes Trial (VADT) showed that individuals in the intensive glycaemic arm with higher plasma levels of HDL cholesterol had a lower risk for progression of diabetic retinopathy. VADT was a randomized unblinded clinical trial in patients with type 2 diabetes, comparing tight glycaemic control (HbA1C ~7%) with standard glycaemic control (HbA1c 8-9%). In this report, the incidence and progression of diabetic retinopathy (DR) were assessed in 858 of 1,791 subjects with 7-field stereoscopic fundus photographs at baseline and follow-up 5 years later. At 5 years, the risk of DR progression was reduced by ~40% in individuals in the intensive glycaemic arm with lower levels of total cholesterol (?140 mg/dl, p ? 0.024) or triglycerides (?120 mg/dl, p = 0.004), and higher HDL cholesterol concentration (?40 mg/dl, p< 0.007). After adjustment for covariates, including conventional cardiovascular risk factors, both lower total cholesterol at 5 years, and higher HDL cholesterol during the study were associated with reduction in the risk of DR progression in the intensive glycaemic control arm. High HDL cholesterol plasma concentration was also associated with a better response to intensive glycaemic treatment.

Low plasma concentration of high-density lipoprotein (HDL) cholesterol is recognized as a risk factor for cardiovascular disease, supported by an extensive epidemiologic evidence-base. However, trials investigating the potential of HDL-targeted therapy have so far proved negative. The results of a new report add to the mystifying HDL story. Individuals with a rare genetic variant for scavenger receptor BI (SR-BI), which results in the receptor being unable to take up HDL, not only had higher HDL cholesterol levels but also a higher risk of coronary disease.
 
Using targeted gene sequencing of plasma samples from 328 individuals with high HDL cholesterol levels (mean 106.8 mg/dL), researchers identified a homozygote for a loss-of-function variant in SCARB1, the gene encoding SR-BI (P376L). This P376L variant was shown to impair the function of the SR-BI receptor resulting in reduced HDL cholesterol uptake in in vitro cell systems. Subsequently, in a meta-analysis of 16 population-based genotyping studies including 300,00 individuals, this rare variant was also identified (minor allele frequency 0.0003). Individuals who were heterozygous for this P376L variant had significantly elevated plasma HDL cholesterol concentration, with no impact on levels of low-density lipoprotein cholesterol or triglycerides. Moreover, carriage of the P376L variant was also associated with 79% increased risk for coronary heart disease (p=0.02). HDL biology is complex, with emerging evidence suggesting that HDL function and cholesterol flux may be more important than absolute plasma levels. The twists and turns of the HDL story continue…..

This timely review brings together latest findings from epidemiological and genetic studies which make the case for reconsideration of triglyceride-rich lipoproteins in cardiovascular disease (CVD) management guidelines. There is now accumulating evidence that triglyceride-rich lipoproteins (for which high triglycerides are a marker), are strong and independent predictors of atherosclerotic cardiovascular vascular disease (ASCVD) and that the cholesterol or remnant cholesterol content of these lipoproteins are strong predictors of ASCVD. The relevance of these findings are underscored by the increasing prevalence of hypertriglyceridaemia (and by association, elevated remnant cholesterol), as a result of the ongoing obesity pandemics. For individuals in the general population with nonfasting triglycerides of 6.6 mmol/L (580 mg/dL) versus those with levels of 0.8 mmol/L (70 mg/dL), the risk for myocardial infarction was more than 5-fold higher, ischaemic heart disease or ischaemic stroke more than 3-fold higher, and all-cause death more than 2-fold higher. There is also genetic evidence to suggest that an important part of inflammation in atherosclerosis and ASCVD is due to degradation and uptake of triglyceride-rich lipoproteins and their remnants into macrophage foam cells in the arterial intima. Thus, triglyceride-rich lipoproteins may contribute to both lipid-related risk as well as other components of residual cardiovascular risk.

Treatments that attenuate atheroma progression may offer potential for reduction in cardiovascular risk. This is pertinent when considering results from the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE). SPIKE was a prospective, randomised, open-label, blinded end point study in 282 insulin-treated patients with type 2 diabetes and without a history of overt cardiovascular disease at baseline. Patients were randomly allocated to sitagliptin (n = 142) or control (n = 140). The primary outcomes were changes in mean and maximum common carotid intima-media thickening (CIMT), as measured by echography at the end of a 104-week treatment period. Sitagliptin treatment was associated with significant attenuation of the mean and left maximum CIMT, but not right maximum CIMT versus control (mean [standard error [SE]: ?0.029 [0.013] vs. 0.024 [0.013] mm, p = 0.005; ?0.065 [0.027] vs. 0.022 [0.026] mm p = 0.021; ?0.007 [0.031] vs. 0.027 [0.031] mm, p = 0.45], respectively). However, whether this effect of treatment translates to reduction in cardiovascular outcomes is uncertain. With a lack of major adverse cardiovascular events in Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) (1) and other recent dipeptidyl peptidase 4 inhibitors CV safety trials (such as saxagliptin (SAVOR-TIMI) and alogliptin (EXAMINE)), further study is warranted. 1. Green JB, Bethel A, Armstrong PW et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373:232-42.

Apolipoprotein (apo) B may be an important predictor of coronary risk in young adult life, given its association with the development of coronary artery calcification in later life, according to results from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Data on apoB, cardiovascular risk stratification, and coronary artery calcium score after 25 years from 2,794 adults (recruited at age 18 to 30 years, mean age: 25 ± 3.6 years; 44% male) were evaluated. The presence of coronary artery calcium was defined by a positive, nonzero Agatston score on computed tomography. Discordance analysis, in which biologically linked variables are analysed by groups of concordance or discordance between their relative distributions, was used to avoid predictive capacity in the discordant groups attenuating correlation between the markers of risk in concordant groups. A key finding was that individuals in the middle or high apoB tertile were at higher odds of developing coronary artery calcium at 25 years than those in the lowest apoB tertile, with adjustment for conventional cardiovascular risk factors (odds ratio [OR] 1.53 and 2.28, respectively). The odds of coronary artery calcium at 25 years was highest for individuals with high apoB/high low-density lipoprotein (LDL) cholesterol (OR 1.55) and high apoB/high non–high-density lipoprotein cholesterol (OR 1.45), representing the highest numbers of apoB particles and/or small-dense LDL. As well as being associated with both of these lipid parameters, apoB was also directly related to triglyceride levels (a marker for triglyceride-rich apoB-containing lipoproteins). Taken together, these data suggest that measurement of apoB levels may have value as a predictor of future cardiovascular risk.

Fibroblast growth factor 21 (FGF21), an endocrine factor secreted mainly by the liver in response to peroxisome proliferator-activated receptor-? (PPAR?) activation, exerts favourable effects on glucose and lipid metabolism in animal models and humans. This study proposes a dual mechanism to explain the triglyceride-lowering effects of FGF21, balancing effects in white adipose tissue (WAT, predominantly involved in energy storage and mobilisation) and brown adipose tissue (BAT, involved in non-shivering body thermogenesis). In a murine model, treatment with FGF21 led to reduction in plasma non-esterified fatty acids, hepatic triglyceride content, and very low-density lipoprotein -triglyceride secretion. Metabolic turnover studies provided insights into how FGF21 achieved these changes, by favourable effects on the catabolism of triglyceride-rich lipoproteins in WAT and BAT. In transgenic mice deficient in lipoprotein lipase, these effects were attenuated. Additionally, insulin resistance shifted the FGF21 responses from WAT to BAT. These findings merit further investigation in animal and human studies.

Long-term follow-up of the West of Scotland Coronary Prevention Study (WOSCOPS) showed persistent clinical benefits and reduction in the burden of cardiovascular disease associated with 5 years of statin therapy. The study results reaffirm the benefit of low-density lipoprotein (LDL) cholesterol lowering in a primary prevention setting. However, it is important to note that statin treatment does not eliminate the risk of a cardiovascular event in this population, reinforcing the case for targeted intervention of multiple risk factors. WOSCOPS was one of the early large-scale statin studies, in which 6,595 middle-aged men with an average baseline LDL cholesterol of 4.9 mmol/L (190 mg/Dl) and no existing cardiovascular disease were randomised to treatment with pravastatin 40 mg/day or placebo. Results of the 5-year outcomes study showed a 31% reduction in the relative risk of cardiovascular death or myocardial infarction (MI). As the Scottish national healthcare system captures data relating to the utilisation of medical services, analysis of 20-year outcomes in former study subjects was possible. The only treatment difference between the two original study arms was that the pravastatin group had been on statin therapy for an additional 5 years. After 20 years, patients allocated to pravastatin in the original trial had a 21% reduction in cardiovascular death (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.69-0.90, p=0.0004), which contributed to 13% reduction in all-cause death (HR 0.87, 95% CI 0.80-0.94, p=0.0007). Thus, these individuals gained an average of 5 extra years free of nonfatal MI or cardiovascular death over this time. Additionally, while the trial showed no benefit on heart failure, 20-year follow-up indicated a 35% reduction in the incidence of hospitalisation for heart failure (p=0.002), an important contributor to the clinical and socioeconomic burden of cardiovascular disease. There was no effect of statin on non-cardiovascular death or cancer death. Given the time frame of follow-up, the findings imply improvement in lifetime benefit associated with 5 years of statin treatment in middle-age. However, it is also important to bear in mind an obvious study limitation; i.e. that information on lipid regulating therapy during the last 10 years of follow-up was not available.

Diet, weight loss, and physical activity are fundamental to the management of dyslipidaemia and prevention of cardiovascular disease. This study compared the effects of dietary intervention and intensive exercise training on the atherogenicity of the lipid profile and low-grade inflammation in high risk patients with established coronary artery disease. In total, 70 non-diabetic patients (body mass index 28-40 kg/m2, aged 45-75 years) were randomised to aerobic interval training (85-90% of peak heart rate 3 times/week) or a low energy diet (800-1000 kcal/day) for 8-10 weeks followed by 2-4 weeks' weight maintenance diet. The total duration of each intervention was 12 weeks. Lipoprotein particle size and density profiling were assessed to define the atherogenicity of the lipid profile before and after treatment. Low-grade inflammation was evaluated by tumour necrosis factor alpha (TNF?), C-reactive protein, interleukin 6 and soluble urokinase plasminogen activator receptor levels. Among patients who completed the 12-week study period (26 on aerobic exercise training and 29 on diet), both interventions were shown to significantly reduce total and low-density lipoprotein (LDL) cholesterol. However, the dietary intervention was superior to the exercise intervention for decreasing the atherogenicity of the lipid profile, as reflected by increased LDL (p = 0.003) and high-density lipoprotein (P = 0.026) particle size and a decreased proportion of total lipoprotein constituted by the small, dense LDL subfraction (p = 0.004). The dietary intervention alone also decreased TNF? (p = 0.009). In conclusion, the findings from this small study indicate that this dietary intervention was superior in decreasing the atherogenicity of the lipid profile, with limited effect on low-grade inflammation.

In obese type 2 diabetes patients without pre-existing cardiovascular disease, a structured diabetes education programme (Patient Empowerment Programme [PEP]), is effective in reducing the first occurrence of cardiovascular or microvascular diabetes-related complications. The study enrolled 6, 372 patients allocated to the programme, who were matched one-to-one with controls (non-PEP patients), using a propensity score method with respect to their baseline covariates. Over a median duration of 31.5 months, 350 (PEP/non-PEP: 151/199) patients experienced a first macrovascular or microvascular event and 95 patients (PEP/non-PEP: 34/61) died from any cause. After adjustment for confounding variables, patients allocated to the PEP had lower incidence rates of all-cause mortality [hazard ratio (HR): 0.589, 95 % confidence interval (CI) 0.380-0.915, P = 0.018] and first macrovascular or microvascular disease events (HR: 0.782, 95 % CI 0.632-0.968, P = 0.024) than those who did not take part in the PEP. These findings underline the importance of involving patients in their management to improve outcome in type 2 diabetes.

Cardiovascular risk modification in terms of comprehensive medical therapy (antithrombotic therapy, lipid-lowering therapy, antihypertensive medication) and lifestyle modification (healthy diet, regular exercise, weight loss, smoking cessation) is the cornerstone of cardiovascular disease prevention. Fixed-dose combination treatments, or polypills, have been proposed as a means of optimising adherence and have been shown to reduce cardiovascular risk. Questions remain, however, as to whether the benefit varies according to the level of risk in the patient population. This question was investigated in a post-hoc analysis of a randomised, placebo-controlled trial of a polypill (containing aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in 378 individuals without an indication for any component of the polypill, but with an estimated five-year risk for cardiovascular disease ?7.5%. During follow-up, patients in the polypill group had low-density lipoprotein cholesterol (LDL-C) levels which were lower on average by 0.9 mmol/l (95% confidence interval (CI) 0.8-1.0) than those on placebo. Individuals with elevated LDL-C at baseline (>3.6 mmol/l) derived greater benefit from treatment with the polypill than those with a lower baseline LDL-C (placebo-corrected, -1.1 versus -0.6 mmol/l, respectively). Additionally, individuals with elevated systolic blood pressure at baseline (>135 mm Hg) had a greater absolute blood pressure reduction than those with a lower systolic blood pressure (placebo-corrected, -12 versus -7 mm Hg, respectively). Overall, the mean cardiovascular relative risk reduction associated with polypill treatment was 48% (95% CI 43-52%). Both baseline LDL-C and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill. In conclusion, these findings indicate that patients with only mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill.

This analysis investigated real-world lipid lowering treatment based on the IMS LifeLink PharMetrics Plus commercial claims database. Patients who were initiated on statin ± ezetimibe were classified according to history of cardiovascular events (n=41,934) or coronary heart disease risk equivalent (n=170,344). The primary outcomes were index statin intensity, treatment modifications, possible associated statin/nonstatin intolerance and/or ineffectiveness issues (based on treatment modification), and time-to-treatment modifications. Among all patients, about 1 in 4 (25% to 26%) had possible statin intolerance and/or ineffectiveness issues, and up to 1 in 4 (21% to 24%) permanently discontinued lipid lowering treatment during follow-up. These findings implicate statin tolerability issues as common contributors to residual cardiovascular risk. This is highly relevant when considering the cost of cardiovascular disease, estimated to account for $290 billion of annual health-care expenditure in the USA and Euro 1.25 billion in the European Union.

The first Asian exome-wide association analysis on blood lipid levels has identified three novel lipid-associated loci in the genes, PNPLA3, PKD1L3 and TEAD2. This study genotyped 145,276 single nucleotide polymorphisms (SNPs) from 12,685 individuals from two Chinese cohorts, the University of Hong Kong Theme-based Research Scheme (N=5,233) and Peking University Health Science Center and the University of Michigan Medical School study of Myocardial Infarction (N=7,452). Single-variant and gene-based association analyses were carried out for four blood lipid levels: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol and triglycerides. The analysis identified 19 loci associated with lipids at exome-wide significance (P<2.69 x 10-7), including three Asian-specific coding variants in in CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp. Missense variants at two novel loci (PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser) were shown to influence plasma levels of triglycerides and LDL-C, respectively, and another novel gene, TEAD2, was associated with HDL-C. Most of these novel variants were implicated with coronary artery disease. These findings highlight the need to take account of genetic differences in lipid heritability in different populations which may influence blood lipids, and hence contribute to differences in susceptibility to cardiovascular disease. Such studies may offer insights into novel biological pathways for lipid metabolism, and potentially, novel therapeutic targets.

Negative media publicity about statins has been thought to affect patient compliance with therapy. This Danish study provides support for this proposal and also shows a detrimental impact on risk for cardiovascular events. Data from 674,900 adults aged at least 40 years who started statin treatment between 1995-2010 and were followed until 31 December 2011, were evaluated. As the proportion of people on statins increased (from <1% in 1995 to 11% in 2010), early statin discontinuation trebled (from 6% in 1995 to 18% in 2010). Early statin discontinuation was associated with negative statin-related news stories (odds ratio 1.04, 95% CI 1.02-1.07); in contrast, positive news reports had a favourable effect, reducing discontinuation by 27% (odds ratio 0.73, 95% CI 0.72-0.74). Evidence that early statin discontinuation was also associated with increased risk of myocardial infarction (odds ratio 1.26, 95% CI 1.21-1.30) and death from cardiovascular disease (odds ratio 1.18, 95% CI 1.14-1.23) emphasises the need to take preventive action to optimise statin compliance and cardiovascular risk reduction.

While lowering low-density lipoprotein cholesterol (LDL-C) with a statin is the cornerstone of lipid-modifying intervention to prevent cardiovascular disease, it is well recognised that a substantial residual risk of cardiovascular events persists. This review highlights evidence for other lipid abnormalities, including triglycerides, apolipoproteins and lipoprotein(a) (Lp(a)), as contributors to lipid-related residual risk. The evidence for and relative advantages and disadvantages of different therapeutic approaches targeting non-LDL abnormalities is discussed. The review also highlights a role for ezetimibe and PCSK9 inhibitors for further lowering LDL-C to reduce cardiovascular risk.

Apolipoprotein C-III (apoC-III) plays a key role in regulation of triglyceride metabolism, and is therefore a potential target for therapeutic intervention. In plasma, apoC-III exists in non-sialylated (apoC-III0a without glycosylation and apoC-III0b with glycosylation), monosialylated (apoC-III1) or disialylated (apoC-III2) proteoforms. This study investigated the association of these different apoC-III proteoforms in 204 non-diabetic subjects. The ratios of apoC-III0a, apoC-III0b, and apoC-III1 to apoC-III2 were significantly greater in subjects who were overweight (n = 33) or obese (n = 155), compared with those with healthy weight (n=16). Moreover, fasting triglycerides were significantly correlated (p<0.001) with the ratio of apoC-III0a/apoC-III2, apoC-III0b / apoC-III2 and apoC-III1 / apoC-III2, implying that the association of apoC-III proteoforms with triglycerides appeared to be driven by apoC-III0a, apoC-III0b and apoC-III1 levels but not apoC-III2. In conclusion, the authors propose that proteomic analysis of apoC-III may provide insights into the biology of triglyceride metabolism in obesity.

Previous reports have identified that remnant cholesterol, the cholesterol present in triglyceride-rich lipoproteins, is associated with elevated cardiovascular disease risk. This study adds new evidence showing that remnant cholesterol is a risk marker in young individuals with acute myocardial infarction (AMI). This prospective, multicentre, case-control study included 102 consecutive AMI survivors (?40 years) and 200 controls, matched for age, gender and centre. Overall, individuals with AMI had remnant cholesterol levels that were 1.7-fold higher compared with controls (61.1 ± 36.8 vs 35.8 ± 16.8 mg/dL, p <0.001). Each 1 standard deviation increase in remnant cholesterol was associated with nearly 4-fold increase in AMI risk (odds ratio 3.87; 95% confidence interval 2.26-6.64; P <0.001), independent of other lipid levels. These data reinforce the importance of remnant cholesterol as a marker of coronary risk in this patient population.

Diabetic retinopathy, one of the key reasons for loss of vision, is associated with substantial morbidity, disability and cost. Yet despite extensive research, the exact mechanism(s) responsible have yet to be fully elucidated. A pathogenic role of diabetes-induced peroxisome proliferator-activated receptor alpha (PPAR-alpha) down-regulation in microvascular dysfunction was previously reported (1). This study implicates PPAR-alpha with diabetic retinopathy in a cohort of Chinese type 2 diabetes patients. The study included 812 type 2 diabetes patients (373 men, 439 women, mean age 53.3±14.0 years), of whom 402 had diabetic retinopathy. The authors looked at the association between three single nucleotide polymorphisms previously shown to be associated with PPAR-alpha: rs4253778, rs135539 and rs1800206. Homozygous carriers of the variant rs1800206 had a 22% decreased risk of diabetic retinopathy compared with those with wild-type homozygotes (odds ratio 0.78, 95% confidence interval [CI] 0.66-0.94). There was also evidence of a potential genetic interaction between rs1800206 and the Leu162 allele, associated with the presence of abdominal obesity. Carriers with abdominal obesity had the lowest risk of diabetic retinopathy (odds ratio 0.39, 95% CI 0.30-0.74), after adjustment. In conclusion, this study indicates potential interaction between genetic determinants of PPAR-alpha, abdominal obesity and diabetic retinopathy in this population cohort.
1. Hu Y, Chen Y, Ding L et al. Pathogenic role of diabetes-induced PPAR-alpha down-regulation in microvascular dysfunction. Proc Natl Acad Sci U S A. 2013;110:15401-6.

Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that decreases plasma glucose and has also been shown to improve postprandial triglycerides and triglyceride-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. While in the EXAMINE study (1), cardiovascular event rates were not higher with alogliptin than with placebo in type 2 diabetes patients with recent acute coronary syndrome, experimental studies suggested a beneficial effect on atherosclerosis progression in animal models. These findings provided a rationale for further clinical investigation in SPEAD-A (Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis). SPEAD-A was a prospective, randomized, open-label, blinded-end point study in 341 (mean age 64.4 years, 83% male) patients with type 2 diabetes but without history of cardiovascular disease. Patients were randomly allocated to treatment with alogliptin (n=172) or conventional management (n=169). The primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery, measured by carotid arterial echography, over 24 months. Compared with conventional management, alogliptin was associated with significant attenuation of atherosclerosis progression, as assessed by improvement in mean common IMT (?0.026 mm [standard error, SE 0.009] vs. 0.005 mm [SE 0.009] with conventional management, p = 0.022) and maximum IMT of the right and left carotid arteries ( ?0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], p = 0.025, and ?0.079 mm [SE 0.018] vs. ?0.015 mm [SE 0.018], p= 0.013, respectively). Based on these findings, the authors propose a large-scale prospective trial to evaluate the utility of DPP-4 inhibitors for primary prevention of cardiovascular disease in type 2 diabetes.
1. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369:1327-1335

Results from the ASPIRE-S (Action on Secondary Prevention Interventions and Rehabilitation in Stroke) study highlight the need to improve implementation of guideline-recommended preventive measures in patients with ischaemic stroke. This study included 6 months’ follow-up of 256 patients with ischaemic stroke (mean age 69 years, range 22-95 years). Despite the need for comprehensive preventive strategies, 68% of patients were overweight (BMI >25 kg/m2), and 16% were still smoking. While there was a high prevalence of lipid-lowering therapy (95%) and anti-hypertensive treatment (75%), about one in four patients had low-density-lipoprotein cholesterol levels >2.5 mmol/L, and nearly two-thirds (63%) had a blood pressure >140/90 mmHg. Almost all patients (97%) were receiving anti-platelet and/or anticoagulant therapy. In conclusion, the findings from this prospective study show that despite the widespread prescription of secondary preventive therapy, most patients with a previous ischaemic stroke do not attain current targets for blood pressure and/or cholesterol.

The atherogenic index, the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) is a prognostic marker for cardiovascular risk, especially among patients with evidence of cardiometabolic disease. However, it is not clear whether cut-off values for this index shown by European populations also apply to different ethnic groups. Data from 5,431 subjects (mean age 50.7 ± 11.6 years) enrolled in the Isfahan Cohort Study (ICS), an ongoing, longitudinal, population-based study in urban and rural areas of three districts in central Iran, was used to investigate this issue. A threshold TG/HDL-C ratio of 3.68 was used to screen for cardiovascular risk, with subjects categorised as either “low” or “high” risk at baseline. A slightly higher number of high-risk individuals were identified using European versus ICS cut-off points (63.7% versus 49.5%), although the adjusted hazard ratio for cardiovascular events was slightly higher in high-risk individuals identified by the ICS cut-off (1.58, 95% CI 1.36–1.84 versus 1.44, 95% CI 1.22–1.71 for European cut-off). These data indicate that a TG/HDL-C index of ?3.68 is appropriate for predicting cardiovascular events in this population.

This experimental study suggests that shared genetic connections between dyslipidaemia and dysglycaemia may help to explain why both conditions commonly co-exist. The apolipoprotein E-deficient (Apoe?/?) mouse, cross-bred for BALB and SM, two strains that exhibit distinct differences in high-density lipoprotein (HDL), non-HDL cholesterol, and type 2 diabetes-related traits was used as the model of dyslipidaemia. Quantitative trait locus analysis was used to evaluate potential connections between 144 genetic markers across the genome. The report identified four loci implicated in control of fasting glucose levels, four loci for HDL cholesterol levels, nine loci for non-HDL cholesterol levels, and three loci for triglyceride levels. Importantly, there was evidence of genetic connections between dyslipidaemia (HDL and non-HDL cholesterol) and type 2 diabetes (fasting glucose) as indicated by trait analysis. A significant correlation between fasting glucose and triglyceride levels was also observed. These intriguing findings suggest that dyslipidaemia plays a causal role in the development of type 2 diabetes, but does not, however, prove causality.

In last month’s post it was reported that the clinical development programme with the cholesteryl ester transfer protein (CETP) inhibitor, evacetrapib, had been terminated on the basis of efficacy considerations. With a report confirming that the REVEAL trial with the CETP inhibitor anacetrapib is still ongoing, questions have been raised as to whether there are mechanistic differences between these molecules. However, this month comes news that evacetrapib, either as monotherapy and combined with statins, increased macrophage cholesterol efflux capacity, including ABCA1-specific activity, as well as pre–beta-1 high-density lipoprotein (HDL), compared with placebo. This report analysed data from a phase II trial in 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels based on the National Cholesterol Education Program Adult Treatment Panel III criteria, and triglyceride levels <400 mg/dl. As monotherapy, evacetrapib resulted in a significant, dose-dependent increase in total efflux capacity, by 18% with 30 mg to 34% with the 500 mg dose. There was also a significant increase in ABCA1-specific efflux, although this effect was not dose-dependent. When combined with a statin, evacetrapib also increased cholesterol efflux capacity, although the effect was lesser (by 21% versus statin monotherapy, compared with 31% versus placebo with monotherapy at the same evacetrapib dose). A similar effect was observed for ABCA1-specific efflux activity (15% for evacetrapib plus statin versus 26% for evacetrapib monotherapy, at the 100 mg dose). Pre-beta HDL 1 was also increased by evacetrapib, albeit to a lesser extent in combination with a statin. The authors suggest that these findings imply that this CETP inhibitor has effects on HDL function beyond effects on raising plasma HDL-C levels, although further study is clearly warranted.

In postmenopausal women, frequent bouts of physical activity to interrupt sitting time reduces postprandial triglycerides. Fifteen subjects completed the trial, involving a randomly allocated order of 1) prolonged sitting (for 8 hours), 2) regular walking (either twenty 90-second bouts over 8 hours or one 30 minute bout from 09:00), and 3) prolonged sitting preceded by continuous walking. The incremental area under the curve for plasma triglycerides was 15% and 14% lower after regular walking versus prolonged sitting, or versus prolonged sitting after continuous walking (4.73±2.50 vs. 5.52±2.95 vs. 5.50±2.59 mmol/L, respectively p=0.023). These findings add to evidence for the importance of frequent physical activity to counter deleterious effects of prolonged sedentary behaviour.

This meta-analysis including more than 16,000 patients showed a protective effect with fibrate therapy in the secondary prevention setting, especially for preventing recurrent myocardial infarction (MI). However, the report also makes the case for a definitive outcomes study in patients receiving best evidence-based medicine, including statins. The meta-analysis included 16,112 patients with a history of cardiovascular disease enrolled in 13 randomised controlled trials. Compared with placebo, fibrate treatment was associated with a protective effect for the primary composite outcome of non-fatal stroke, non-fatal MI and vascular death (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.83 to 0.94), with a moderate benefit in preventing MI (RR 0.86, 95% CI 0.80 to 0.93). There was no significant effect on all-cause or vascular death, or stroke. Even with exclusion of data from the clofibrate trials, the benefit of fibrates in preventing MI persisted (RR 0.85, 95% CI 0.76 to 0.94), although there was no effect on the primary outcome (RR 0.90, 95% CI 0.79 to 1.03). These findings support the need for a definitive trial to assess the effects of fibrate treatment in the secondary prevention setting against current standards of care including statins.

The first patient has now been randomized in the Phase III outcomes trial with this agent: BETonMACE. The trial will recruit type 2 diabetes patients at high-risk of coronary artery disease. The primary outcome is time to first occurrence of major adverse cardiovascular events (MACE), defined as a single composite endpoint of cardiovascular death, or non-fatal myocardial infarction or stroke. Patients on high-dose statin therapy (atorvastatin or rosuvastatin) will be randomised to 200 mg/day of apabetalone or placebo. Apabetalone is an orally active small molecule that interacts selectively with the second ligand domain found in bromodomain extra-terminal proteins (BET). This interaction inhibits acetylated lysine, present in histones, from binding to the same site thus altering chromatin structure and in turn activity of selected genes. RVX-208 has been previously shown to increase production of apolipoprotein A-I, the predominant protein in HDL.

Evidence from EURIKA (European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice), showed that despite high-intensity statin treatment, about one in six patients (16.8%) with type 2 diabetes have atherogenic dyslipidaemia (the combination of elevated triglycerides and low high-density lipoprotein cholesterol [HDL-C], as defined by guidelines). While prevalence was lower in non-diabetic patients, still 7% at high global risk (SCORE ?5%) had atherogenic dyslipidaemia. Importantly, about one in three patients with type 2 diabetes (37%) and one in four without type 2 diabetes (22.4%) had elevated triglycerides (as defined by guidelines) despite high-intensity statin treatment. These data clearly highlight the unmet clinical need in these high cardiovascular risk patients.

Two studies highlighted a link between elevated triglycerides, endothelial dysfunction and subclinical atherosclerosis. In this cross-sectional analysis from the FMD-Japan Registry (1) including 4,908 subjects (3,842 men and 1,066 women; mean age 48±12 years), flow-mediated dilatation (FMD), a marker of endothelial function, decreased with increasing triglycerides (from 7.0±3.5% in individuals with triglycerides ?63 mg/dL, 5.8±3.2% in those with triglycerides 132 to 179 mg/dl, and 5.5±3.0% in subjects with triglycerides ?180 mg/dL, p for trend<0.001). This association persisted even after adjustment for age, sex, and cardiovascular risk factors including low plasma concentration of high-density lipoprotein cholesterol. Furthermore, cohort analysis from the ELSA-Brasil Study (2) showed that fasting triglycerides was an independent predictor of subclinical atherosclerosis. This report evaluated data for coronary artery calcium from 2,911 subjects without prior history of cardiovascular disease and who were not receiving lipid-lowering therapy (mean age 50.3±8.5 years, 54% women). After adjustment for cardiovascular risk factors, log transformed triglycerides and the triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) ratio were each significantly associated with coronary artery calcium (p<0.05), although HDL-C was not. Each standard deviation increase in log transformed triglycerides increased the likelihood of coronary artery calcium >0 by 17%, p=0.005. Taken together, these data support the rationale of targeting elevated triglycerides to reduce the risk of atherosclerosis progression and cardiovascular events.
1. Kajikawa M, Higashi Y, Maruhashi T et al. Increased triglyceride levels are associated with endothelial dysfunction: FMD-Japan Registry. Circulation 2015; 132: 10041.
2. Bittencourt MS, Santos RD, Staniak H et al. Fasting triglycerides are independently associated with subclinical atherosclerosis: The ELSA-Brasil Study. Circulation 2015;132:A13139.

ACCORDION, long-term passive follow-up of 4,644 statin-treated patients with type 2 diabetes from the ACCORD (Action to Control Cardiovascular Risk in Diabetes), provides further support for add-on fenofibrate therapy in patients with residual atherogenic dyslipidaemia (the combination of elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol) on simvastatin monotherapy. However, as in the main ACCORD study, there was no benefit in the overall study population. Over a 9-year follow-up period (from the start of ACCORD to the end of ACCORDION), patients originally allocated to fenofibrate + simvastatin had a nonsignificant reduction in the primary endpoint of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death (hazard ratio 0.93, 95% CI 0.83-1.05 95%CI, p=0.25). However, in the subgroup with atherogenic dyslipidaemia at baseline, there was a 37% reduction in this endpoint (hazard ratio 0.73, 95% CI 0.56-0.95) versus no effect in those without this lipid profile (hazard ratio 0.99, 95% CI 0.86-1.13) (interaction p=0.048). These findings reinforce the case for an outcomes trial to test the hypothesis of specifically targeting atherogenic dyslipidaemia in high cardiovascular risk individuals. Importantly, such a trial should also include sufficient numbers of women to fully evaluate the effects of therapy in this patient group.

Lifestyle intervention is the fundamental cornerstone of cardiovascular disease (CVD) prevention. However, ensuring adherence is usually problematic, even in individuals with established CVD. Using a text messaging service may improve adherence, and as a result control of cardiovascular risk factors, including low-density lipoprotein cholesterol (LDL-C), according to this report from the Tobacco, Exercise and Diet Messages (TEXT ME) trial. This was a parallel-group, single-blind, randomised study including 710 patients (mean age 58 years; 82% men; 53% current smokers) with proven coronary heart disease. Patients were randomly allocated to a text messaging service providing advice, motivational reminders, and support to change lifestyle (4 text messages per week for 6 months, n = 352) in addition to usual care, or usual care alone (n=358). At 6 months, levels of LDL-C were significantly lower in the intervention group (by 5 mg/dL, p=0.04). There were also reductions in systolic blood pressure (by 7.6 mmHg, p<0.001), body mass index (by 1.3 kg/m2, p<0.001) and smoking (by 39%, p=0.003), as well as increased physical activity (p=0.003) compared with the control. However, questions remain regarding the duration of these effects, and whether there is any corresponding benefit on clinical outcomes.

Treating high cardiovascular risk patients to guideline-recommended low-density lipoprotein cholesterol (LDL-C) goal attenuated the risk of major cardiovascular events associated with high triglycerides, hypertension and elevated fasting glucose, according to this analysis from the Treating to New Targets (TNT) study. The TNT study included patients with clinical stable CHD who were randomised to double-blind therapy with atorvastatin 10 mg/day (n=5,006) or 80 mg/day (n=4,995) and followed-up for a median of 4.9 years. In patients on atorvastatin 10 mg/day (on-treatment LDL-C 2.6 mmol/L), the presence of each component of the metabolic syndrome significantly increased the risk of major cardiovascular events (high body mass index ?28 kg/m2, p=0.014; elevated triglycerides ?1.7 mmol/L, p=0.006; low HDL-C [1.0 mmol/L in men and <1.3 mmol/L in women], p=0.0006; blood pressure ?130/85 mmHg, p<0.0001; and fasting glucose ?5.6 mmol/L, p<0.0001). However, further lowering of LDL-C with atorvastatin 80 mg/day (on-treatment LDL-C 2.0 mmol/L) attenuated the predictive power of elevated triglycerides and fasting glucose, and to a lesser extent, hypertension. It is pertinent that a majority of patients in the TNT study had these characteristics: over 75% were hypertensive, 60% had elevated triglycerides and about 50% of patients had elevated fasting glucose or high body mass index. Although the impact of elevated triglycerides was reduced, the presence of this component was still associated with a 9% major cardiovascular event rate over the follow-up period.

Common carotid artery intima-media thickness (CCA-IMT), an established marker for atherosclerosis, was associated with fasting triglycerides in ischaemic stroke patients; however, there was no association with nonfasting triglycerides. In total, 158 ischaemic stroke patients (34% female; mean age 63 years) who were enrolled in the Berlin "Cream and Sugar" study, were included. A combined oral glucose and triglyceride tolerance test was performed 3-7 days after the incident ischaemic stroke, and patients were classified on the basis of time to peak triglycerides post-fat challenge. Multiple regression analysis, adjusting for modifiable risk factors, showed that older age, more severe strokes, and higher levels of fasting triglycerides were significantly and independently associated with higher mean CCA-IMT.

The triglyceride (TG): high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) is an index of atherogenic dyslipidaemia, as well as a surrogate for insulin resistance. A new report also shows that the TG/HDL-C ratio is strongly associated with increased risk of incident fatty liver disease. This observational cohort study included 4,518 healthy Japanese subjects (2,637 men and 1,881 women) who underwent yearly health-check-ups. Fatty liver was diagnosed using ultrasonography. Over a 10-year period, 38.8% men and 17.2% of women developed fatty liver. The odds ratio for the association of TG/HDL-C with incident fatty liver was 1.59 (95% confidence interval [CI] 1.42-1.79, p<0.0001) in men and 2.50 (95% CI 1.80-3.51, p <0.0001) in women. The optimal cut-point was a TG/HDL-C >0.88 in men and >0.64 in women. Given that the TG/HDL-C ratio is readily measured in routine clinical practice, identification of individuals at risk of incident fatty liver disease and implementation of lifestyle intervention can have important implications for public health.

Previous studies implicate PCSK9 (proprotein convertase subtilisin/kexin type 9) in triglyceride metabolism. Findings from a mechanistic in vitro study suggest that PCSK9-mediated CD36 degradation may limit fatty acid uptake and triglyceride accumulation in tissues, such as the liver. CD36, a member of the class B scavenger receptor family of cell surface proteins, has a key role in fatty acid transport and metabolism, and may also be involved in glucose intolerance and atherosclerosis. In this report, overexpression or recombinant PCSK9 induced CD36 degradation, and reduced uptake of the palmitate analogue Bodipy FL C16 in 3T3-L1 adipocytes and oxidized low-density lipoprotein in hepatic HepG2 cells. Small interference RNA knockdown of endogenous PCSK9 in hepatic cells increased CD36 protein more than 3-fold. Similar increases were observed in the liver and visceral adipose tissue of PCSK9 deficient mice, and were correlated with increased uptake of fatty acid and accumulation of triglycerides. Taken together, these findings implicate a role for PCSK9 beyond low-density lipoprotein cholesterol, specifically in triglyceride metabolism.

ACCELERATE, the Phase III outcomes trial with the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, has been terminated on the recommendation of the Independent Data Monitoring Committee due to insufficient efficacy. This decision was based on data from periodic data reviews, which suggested there was a low probability that the study would achieve its primary endpoint. The study is not being stopped for safety findings. Lilly will discontinue development of evacetrapib for the treatment of high-risk atherosclerotic cardiovascular disease and will now conclude other studies in the programme. Source: https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130
 
This leaves the REVEAL trial with the CETP inhibitor anacetrapib as the sole ongoing outcomes trial in the field of CETP inhibition. For further information: http://www.ctsu.ox.ac.uk/reveal/

This report suggests a link between low plasma concentration of high-density lipoprotein cholesterol (HDL-C) and inflammatory biomarker levels in patients with acute coronary syndrome (ACS). This cross-sectional study included 6,134 patients with ACS, with very low (<30 mg/dL), low (30–39.9 mg/dL), or normal HDL-C (?40 mg/dL) plasma concentration. Overall, 18.5% of patients had very low HDL-C levels; these patients also had higher levels of high sensitivity-C-reactive protein (hs-CRP) compared with those with low or normal HDL-C levels (median 17.8 [interquartile range 7.2–54.5] versus 12.6 [5.6–33.9] versus 12.0 [5.4–36.9] mg/L, respectively, p <0.001). In addition, patients with the lowest HDL-C plasma concentration also had the lowest albumin levels (median 3.6 [3.3–4.0] versus 3.8 [3.5–4.0] versus 3.8 [3.5–4.1] g/dL, respectively, p <0.001). Multivariate analysis showed that both low albumin (?3.5 g/dL) and elevated hs-CRP (?10 mg/L) were independent predictors of very low HDL-C plasma levels in patients with ACS.

Accumulation of circulating small size chylomicron particles may partly explain the increased cardiovascular risk of individuals with hypertriglyceridaemia, according to this study. The concentration of apolipoprotein (apo) B48, a measure of chylomicron particle number, in different density lipoprotein fractions was compared between normocholesterolaemic subjects with hypertriglyceridaemia (?1.7 mmol/L, n=12) and those without (n=12), matched for age and gender. The distribution of chylomicron particles was assessed by determining the fasting concentration of apoB48 in serum lipoprotein fractions with Svedberg flotation rates of (Sf) >400, Sf 20-400 and Sf <20. ApoB48 concentration in subjects with hypertriglyceridaemia was almost twice that observed in controls (8.7 ± 1.0 ?g/mL vs 5.0 ± 0.6 ?g/mL, p=0.016), with >80% of the increase residing in the small, dense lipoprotein fraction (Sf<20 fraction). Significantly greater concentrations of apoB48 were also observed in the less dense fractions (p<0.001). These findings indicate that increased atherogenic risk in normocholesterolemic, moderately hypertriglyceridaemic subjects is due to greater apoB48 concentration in the small, dense lipoprotein fraction.

Elevated lipoprotein(a) (Lp[a]), a potential contributor to residual cardiovascular risk, is also associated with aortic stenosis. This study sought to provide insights into how Lp(a) mediates progression of aortic stenosis. The study measured oxidised phospholipids, key mediators of calcification in valvular cells, on apolipoprotein B100 (apoB100), as well as Lp(a) in 220 patients with mild-to-moderate aortic stenosis. The primary endpoint was the progression rate of aortic stenosis, measured by the annualized increase in peak aortic jet velocity in m/s/year by Doppler echocardiography. The secondary endpoint was the need for aortic valve replacement and cardiac death. During a mean 3.5 years of follow-up, patients in the top tertiles of Lp(a) and oxidised phospholipid-apoB100 showed more rapid progression of aortic stenosis than those in the lowest tertile (p=0.005 and p=0.01, respectively). After multivariable adjustment, elevated Lp(a) or oxidised phospholipid-apoB100 levels remained independent predictors of faster aortic stenosis progression. In conclusion, these findings support the hypothesis that Lp(a) mediates progression of aortic stenosis via its association with oxidised phospholipids. Randomized trials of treatments with the potential for lowering Lp(a) and oxidised apoB100 in aortic stenosis are merited.

While pro-protein convertase subtilisin-kexin 9 (PCSK9) inhibition is effective in lowering low-density lipoprotein cholesterol levels, the potential impact of this treatment on the metabolism of triglyceride-rich lipoproteins (TRL) is attracting increasing attention. This timely review summarises current evidence supporting a link between PCSK9 and TRL. This includes evidence of a correlation between plasma PCSK9 and triglycerides (TG) levels, as well as between plasma PCSK9 and markers of carbohydrate metabolism, which is closely related to TG metabolism. In addition, TG-lowering treatments such as fibrates have been shown to lower plasma PCSK9 levels. There is also evidence of effects of PCSK9 on postprandial lipaemia, adipose tissue biology, apolipoprotein B production in the liver and intestine, as well as on receptors other than low-density lipoprotein receptor (LDLR) that are involved in TRL metabolism. Finally, subgroup analyses have shown TG-lowering effects with-PCSK9 monoclonal antibody therapy which warrant further evaluation. These emerging data highlight the need for further investigation of the underlying mechanisms of these effects.

A Mediterranean diet supplemented with extra virgin olive oil may protect against the development of diabetic retinopathy, according to this report from the PREvencion con DIeta MEDiterranea (PREDIMED) study group. The PREDIMED Investigators conducted a post hoc analysis of 3,614 type 2 diabetes subjects (mean age 67 years, 47% men, 61% with dyslipidaemia) who were free of microvascular complications at entry. Subjects were randomly allocated to Mediterranean diet supplemented with extra virgin olive oil or nuts, or a low-fat control diet. Over a median follow-up of 6.0 years, 74 subjects developed retinopathy (22 in the Mediterranean diet + olive oil group, 20 in the Mediterraenean diet + nuts group and 32 in the control group) and 168 developed nephropathy (64, 51 and 53, respectively). Compared with the control diet, subjects allocated either Mediterranean diet regimen had reduction in the risk of developing retinopathy, by 44% (hazard ratio 0.56, 95% CI, 0.32–0.97) for the group also receiving olive oil, and by 37% (hazard ratio 0.63 (0.35–1.11, not statistically significant) for the group also receiving nuts. Furthermore, the protective effect of the Mediterranean diet plus olive oil was even greater in subjects who were highly adherent to the diet (66% relative reduction, hazard ratio 0.34, 95% CI, 0.13–0.89, p=0.001 for trend) compared with subjects with the lowest adherence. There were no differences between groups observed for new-onset nephropathy. In conclusion, this post hoc analysis of the PREDIMED study suggests that dietary intervention based on a Mediterranean diet supplemented with extra virgin olive oil protects against diabetic retinopathy but not diabetic nephropathy in elderly subjects with type 2 diabetes.

Patients with type 2 diabetes and an evening chronotype (so-called ‘night owls’) have a higher prevalence of atherogenic dyslipidaemia and poorer glycaemic control, but a markedly lower prevalence of cerebrovascular disease. In this study, 454 patients with type 2 diabetes (mean age 66 years; mean diabetes duration 16 years), were categorised by chronotype based on self-reported mid-sleep time (i.e. the midpoint between sleep onset and wake time) on weekends. Patients with an evening chronotype had significantly worse metabolic control than morning chronotypes, as characterised by HbA1c (mean [SD] 59[10] vs. 57[10] mmol/mol, p 0.0388), and an increased prevalence of atherogenic dyslipidaemia (56% vs. 42%, p 0.0028). The ratio of log[TG/HDL-C] was also higher in evening compared with morning chronotypes (mean [SD] 0.50[0.34] vs. 0.43[0.34], p 0.0335). However, the prevalence of transient ischaemic attack/stroke was higher in morning than evening chronotypes (11% vs. 3%, p 0.0066). There were no significant differences between the two groups with respect to other characteristics.

Data from the European Study on Cardiovascular Risk Prevention and Management in Daily Practice (EURIKA, NCT00882336) highlighted the prevalence of atherogenic dyslipidaemia (elevated triglycerides [TG] with/without low high-density lipoprotein cholesterol [HDL-C]), especially in diabetic patients on a statin. EURIKA was a cross-sectional study conducted in 12 European countries which recruited 7,641 patients aged ? 50 years (48% male, mean age 63.2 years), without clinical cardiovascular disease (CVD) but with at least one CVD risk factor. Elevated TG was defined as ?200 mg/dL (2.26 mmol/L) and low HDL-C was defined as <40 mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women. In the overall population, the prevalence of elevated TG, low HDL-C and both were 20.8%, 22.1% and 9.9%, respectively. Less than 60% of diabetes patients were receiving lipid-modifying therapy. In patients with diabetes who were on a statin, 27.9% had elevated TG, 29.8% had low HDL-C, and 14.6% had both. These data highlight the unmet clinical need for improved management of atherogenic dyslipidaemia in primary prevention patients, especially those with diabetes.

The link between lipid levels and diabetic macular oedema (DME) warrants further investigation, according to this systematic review and meta-analysis. The authors identified 21 studies reporting on the relationship between blood lipid levels and DME (5 cross-sectional, 5 cohort, 7 case-control, and 4 randomised controlled studies). Meta-analysis of case-control studies showed that mean total serum cholesterol (p<0.001), low-density lipoprotein cholesterol (p<0.05), and serum triglycerides (p<0.05) were significantly higher in patients with DME than in those without DME. However, meta-analysis of prospective randomised controlled trials did not show significant increased risk of worsening of hard exudates and severity of DME in patients treated with lipid-modifying agents compared with placebo. Given the significant public health relevance, further investigation of these discrepancies is warranted.

Coronary artery disease (CAD) is an inflammatory state which has been shown to adversely affect the biological function of high-density lipoproteins (HDL). This study investigated the interaction between HDL cholesterol (HDL-C) and C-reactive protein (CRP) in CAD patients undergoing first percutaneous coronary intervention (PCI). Of 3,507 consecutive patients undergoing PCI, 1,682 patients (48%) had been treated with statin at this time. This group were stratified by HDL-C levels (cutoffs of 40 (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women, respectively) and a CRP cutoff of 2 mg/dL into four groups: 1) high HDL-C/low CRP, 2) high HDL-C/high CRP, 3) low HDL-C/low CRP, and 4) low HDL-C/high CRP. Over a median follow-up of 1,985 days, 197 (11.7%) patients died due to cardiac death (n=58), carcinoma (n=61), stroke (n=10) and other causes (n=69). Multivariate Cox hazard regression analyses showed that the group with low HDL-C and high CRP had a significantly higher rate of all-cause death even after adjustment for other covariates (hazard ratio 2.38, 1.59-3.61, p<0.0001). The authors highlight the combination of low HDL-C and elevated CRP as predictive of worse long-term outcome after PCI in statin-treated CAD patients.

In this meta-analysis of more than 12,200 patients in 25 randomised controlled trials, the PCSK9 inhibitors evolocumab and alirocumab were shown to be well tolerated, lowering low-density lipoprotein (LDL) cholesterol by 50-55%. Evolocumab has now been approved for use in Europe; alirocumab is approved by the US Food and Drug Administration (FDA) and has also received a favourable response from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicine Agency (EMA). Alirocumab was associated with an increased rate of injection-site reactions (relative risk [RR] 1.48, 95 % CI: 1.05 to 2.09, p = 0.02); and evolocumab was associated with reduced rates of abnormal liver function (RR 0.43, 95 % CI: 0.20 to 0.93, p = 0.03) compared with placebo. Both evolocumab and alirocumab significantly reduced LDL cholesterol (by 54.6%, 95% CI 58.7 to 50.5% for evolocumab, 52.6%, 95% CI: -58.2 to -47.0% for alirocumab) versus placebo, and increased high-density lipoprotein cholesterol (by 6-8%) These findings reaffirm the efficacy and safety profiles of these novel therapies previously observed in individual studies.

According to this report from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE-IT TIMI) 22 group, the adipokine resistin is a marker of residual cardiovascular risk in patients hospitalised with a recurrent acute coronary syndrome. This nested case-control cohort of statin-treated patients in the PROVE-IT TIMI 22 study measured plasma levels of resistin and leptin in 176 cases with coronary death, myocardial infarction, or unstable angina pectoris during follow-up, matched 1:1 to 176 controls. In logistic regression analysis adjusted for additional risk factors including high-sensitivity C-reactive protein and history of diabetes, on-statin resistin levels were associated with recurrent coronary events (tertile 3 vs 1 adjusted odds ratio 2.08; 95% confidence interval 1.04 to 4.19). There was, however, no association between circulating leptin levels and recurrent coronary events. These findings suggest potential for other biomarkers, beyond lipids, in residual vascular risk.

Part 2 of the National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia are due to published later this year. These recommendations will focus on special patient populations, including Hispanics, South Asians, African Americans, older patients, and children and adolescents. In addition, there will be specific recommendations for residual risk, as well as unique issues in women's health.

Cholesterol efflux is a marker of high-density lipoprotein (HDL) function. In this study, the potent and selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, LY518674, was shown to increase cholesterol efflux capacity in metabolic syndrome patients. Subjects with metabolic syndrome were randomised to either LY518674 100 ug daily (n = 13) or placebo (n = 15) for 8 weeks. Cholesterol efflux capacity was measured in an ex vivo assay using apolipoprotein-B depleted plasma. After 8 weeks, LY518674 resulted in a 15.7% increase from baseline in efflux capacity compared with placebo (p=0.01). The change in apolipoprotein A-I production rate was strongly associated with the change in cholesterol efflux capacity (p= 0.01). These findings reinforce the relevance of PPAR alpha stimulation to HDL functionality.

This study sought to investigate the underlying rationale for the accelerated atherosclerosis that is characteristic of type 2 diabetes. The authors hypothesised that the interstitial fluid (IF)-to-serum gradient ratio for apolipoprotein (apo)B-containing atherogenic lipoproteins may be greater in type 2 diabetes than in healthy controls, reflecting increased leakage of lipoproteins across the vascular wall. However, evaluation of lipoprotein profiles in serum and IF from 35 patients with type 2 diabetes and 35 healthy controls showed that this was not the case. Instead, the IF-to-serum gradients for very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) cholesterol, and apoB were all reduced in patients with type 2 diabetes compared to healthy controls. The authors suggest that increased uptake of atherogenic lipoproteins from the IF may lead to an increased load of cholesterol to peripheral tissues, which in turn would contribute to the markedly higher propensity to develop atherosclerosis in type 2 diabetes.

Whether PCSK9 inhibitors (the most advanced awaiting regulatory approval), have any effect on glucose homeostasis has long been debated, following conflicting data in mouse models. However, results from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study show no increased risk of incident type 2 diabetes in individuals carrying the PCKS9 p.R46L loss-of-function variant. This analysis included data from 4,630 French subjects in the DESIR study and 1,342 French subjects with type 2 diabetes. Not surprisingly, carriage of p.R46L was associated with lower total cholesterol (-0.394 mmol/l), low-density lipoprotein cholesterol (-0.393 mmol/l) and apolipoprotein B concentrations (-0.099 g/l). However, there was no association between carriage of p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin and glycated haemoglobin), and risk of incident type 2 diabetes. These findings provide reassurance regarding the safety of PCSK9 inhibitors as regards glucose homeostasis.

This report from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) shows that cardiac autonomic neuropathy (CAN) can be detected very early in newly diagnosed type 2 diabetes, emphasising the importance of early testing for cardiovascular autonomic function. The study included data from a cohort of 557 patients with newly diagnosed type 2 diabetes (mean age 58.3 years, glycated haemoglobin 6.9%). Early and confirmed neuropathy were assessed using a standardised methodology. Early CAN was detected in 15.3% of patients (15.9% in men and 14.5% in women); confirmed CAN was present in 1.8% of all patients. Clinicians should therefore be aware of the possibility of autonomic dysfunction soon after diagnosis in type 2 diabetes, and test and treat accordingly.

ANCHOR study evaluated icosapent ethyl, a high-purity prescription form of eicosapentaenoic acid ethyl ester, in statin-treated patients at high risk for cardiovascular disease with persistently high triglycerides (?200 and <500 mg/dL) and well controlled low-density lipoprotein cholesterol levels. This exploratory analysis evaluated the effect of treatment on lipoprotein particle concentration and size, as assessed using nuclear magnetic resonance spectroscopy. Data from 216 patients in the icosapent ethyl 4 g/day group and from 211 patients on placebo were analysed. Compared with placebo, treatment with icosapent ethyl significantly reduced key atherogenic lipoprotein particle concentrations, including very-low-density lipoprotein particles (by 12.2%, p=0.0002), small low-density lipoprotein particles (by 13.5%, p<0.0001) and total high-density lipoprotein (HDL) particles (by 7.4%, p<0.0001), and also increased LDL particle size. To determine whether these potentially beneficial effects translate into reduction in cardiovascular events, the results of the REDUCE-IT study (Reduction of Cardiovascular Events with EPA-Intervention Trial) are awaited.

In this large prospective observational study, elevated triglycerides were independently associated with an increased risk for cardiovascular disease. The study included 76,434 participants who had undergone a regular health check between January 2007 and June 2011. Higher triglycerides were associated with ?50% increase in risk for major cardiovascular disease events (odds ratio: 1.52, 95% CI: 1.27-1.82) and overall cardiovascular disease events (odds ratio 1.49, 95% CI: 1.37-1.63). These findings remained significant after adjustment for multiple risk factors including HDL-cholesterol. These findings add to the evidence-base supporting elevated triglycerides as a cardiovascular risk factor.

Attenuation of endothelial function may underlie the renoprotective effects of fenofibrate, according to results in an animal model of diabetic nephropathy. Diabetic rats were treated with fenofibrate (100 mg/kg/day) for 12 weeks. At the end of treatment, there was improvement in renal function, as shown by reduction in urinary albumin excretion and serum levels of creatinine and urea, as well as an increase in creatinine clearance compared with controls. Mechanistically, fenofibrate led to increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B1 (LKB1), indicative of improved endothelial function. These findings merit further investigation of the underlying effects of fenofibrate on renal function.

Findings from this cross-sectional, family-based observational cohort study suggest a role for adiponectin in the underlying pathogenesis of diabetic retinopathy. The study included 507 Latino subjects with type 2 diabetes, with diabetes for at least 10 years or more and/or with diabetic retinopathy. Serum adiponectin was measured and insulin sensitivity was estimated using homeostasis model assessment (HOMA). Diabetic retinopathy was assessed by digital fundus photography and graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Scale. Fasting adiponectin concentrations were elevated in patients with diabetic retinopathy compared with those without (12.9±0.5 ug/ml vs. 10.5±0.5 ug/ml, p=0.0004). This effect remained significant after multiple covariate adjustment (age, gender, body mass index, HbA1c, diabetes duration, statin use, blood pressure, and renal function, p=0.013 - 0.018). Adiponectin was also positively correlated with the severity of diabetic retinopathy in patients with non-proliferative disease (p<0.0003). Further research is indicated to investigate whether adiponectin is a marker or biological mediator of diabetic retinopathy.

Extensive epidemiologic data support low high-density lipoprotein cholesterol (HDL-C) as a risk factor for cardiovascular disease. However, to date clinical trials evaluating HDL-targeted therapy have been largely negative, and in the case of niacin (nicotinic acid), associated with harm. Given these discrepancies, together with growing realisation that the HDL particle population is heterogeneous in terms of size, structure, composition and functionality, there has been a view that the functional activity of HDL particles may be more relevant than HDL-C level. This report from the University of Pennsylvania helps to clarify this. This nested case-control sample from the prospective EPIC-Norfolk study showed that cholesterol efflux capacity, a potentially atheroprotective function of HDL, was significantly and inversely associated with incident coronary heart disease events, independent of several established cardiovascular risk factors and even after adjusting for HDL-C or apolipoprotein A-I concentrations. However, the researchers advise caution in the interpretation of causality, until Mendelian randomisation studies have been conducted to investigate this potential association.

New analyses from the Global Burden of Disease Study 2013 report that aging and population growth are primarily responsible for increasing global cardiovascular death rates, despite an overall decrease in age-specific death rates in most regions. In 2013, more than 17 million people from 188 countries died from cardiovascular disease.
 
This report shows that over the period 1990-2013, worldwide there was a 41% increase in cardiovascular disease mortality. This was driven both by a 55% increase in mortality due to the aging of populations, together with a 25% increase due to population growth. Only in Central and Western Europe did gains in cardiovascular health offset these demographic sufficiently to cause a decline in the number of cardiovascular deaths.
These data highlight the need for health system planning to understand the absolute burden of disease, also taking account of the effect of population aging.

Recent studies have highlighted the relevance of this parameter, the ratio of triglycerides/high-density lipoprotein cholesterol (TG/HDL-C), to risk prediction.
 
The TG/HDL-C ratio is an indirect measure of insulin resistance/hyperinsulinemia and an independent predictor of cardiovascular risk. Moreover, in patients with chronic kidney disease (CKD), the TG/HDL-C ratio was also a predictor of poor cardiovascular outcome. In a longitudinal, observational, retrospective study in 197 patients (CKD Stages 1 to 5), there were 11 cardiovascular (CV) deaths and 43 nonfatal CV events over a mean follow-up period of 30 months.1 The TG/HDL-C ratio was a significant independent determinant of CV outcomes (hazard ratio 1.36, 95% CI 1.11-1.67, p = 0.003). Furthermore, the TG/HDL-C ratio was also an independent determinant of flow-mediated vasodilatation of the brachial artery (assessed by high-resolution ultrasonography), a marker of endothelial dysfunction (p = 0.02). Based on these findings, the authors argue for consideration of the TG/HDL-C ratio as a novel predictor of CVD risk in subjects with CKD.
 
Furthermore, there is also evidence that the TG/HDL-C ratio may be a better discriminator of cardiometabolic risk than non-HDL-C in obese children. In a retrospective, cross-sectional study in 5,505 children (aged 5-18 years), 78% were shown to be obese.2 When categorised according to the 75th percentile of non-HDL-C (?130 mg/dl) or TG/HDL-C ratio (?2.2), the odds ratios for insulin resistance, high blood pressure, metabolic syndrome, presence of liver steatosis, increase in carotid intima-media thickness and left ventricular hypertrophy were higher in children with a high TG/HDL-C ratio compared with children with high levels of non-HDL-C.

Recent studies have highlighted the relevance of this parameter, the ratio of triglycerides/high-density lipoprotein cholesterol (TG/HDL-C), to risk prediction.
 
The TG/HDL-C ratio is an indirect measure of insulin resistance/hyperinsulinemia and an independent predictor of cardiovascular risk. Moreover, in patients with chronic kidney disease (CKD), the TG/HDL-C ratio was also a predictor of poor cardiovascular outcome. In a longitudinal, observational, retrospective study in 197 patients (CKD Stages 1 to 5), there were 11 cardiovascular (CV) deaths and 43 nonfatal CV events over a mean follow-up period of 30 months.1 The TG/HDL-C ratio was a significant independent determinant of CV outcomes (hazard ratio 1.36, 95% CI 1.11-1.67, p = 0.003). Furthermore, the TG/HDL-C ratio was also an independent determinant of flow-mediated vasodilatation of the brachial artery (assessed by high-resolution ultrasonography), a marker of endothelial dysfunction (p = 0.02). Based on these findings, the authors argue for consideration of the TG/HDL-C ratio as a novel predictor of CVD risk in subjects with CKD.
 
Furthermore, there is also evidence that the TG/HDL-C ratio may be a better discriminator of cardiometabolic risk than non-HDL-C in obese children. In a retrospective, cross-sectional study in 5,505 children (aged 5-18 years), 78% were shown to be obese.2 When categorised according to the 75th percentile of non-HDL-C (?130 mg/dl) or TG/HDL-C ratio (?2.2), the odds ratios for insulin resistance, high blood pressure, metabolic syndrome, presence of liver steatosis, increase in carotid intima-media thickness and left ventricular hypertrophy were higher in children with a high TG/HDL-C ratio compared with children with high levels of non-HDL-C.
 
Sonmez A, Yilmaz MI, Saglam M et al. The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease. Lipids in Health and Disease 2015;14:29.

HDL-C may be implicated as a novel predictor of lower-extremity amputation risk in diabetes patients with foot ulcers, according to this observational study in 163 Japanese patients with diabetic foot ulcers. The primary endpoint was a composite of the worst of the following outcomes for each individual; (1) minor amputation (below the ankle), (2) major amputation (above the ankle), and (3) wound-related death.
 
Over a median follow-up period of 5.1 months, this endpoint was observed in 67 patients (41%): 43 had minor amputations, 16 had major amputations, and 8 had wound-related deaths. Univariate Cox proportional hazard model analysis showed that a lower HDL-C concentration was associated with increased incident primary outcome (hazard ratio 0.16, 95% CI 0.08-0.32, p < 0.001). Multivariate Cox proportional hazard model analysis (hazard ratio 0.30, 95% CI 0.14-0.63, p = 0.002). and categorical variable analysis (HDL-C ?1.03 mmol/L or <1.03 mmol/L) also identified low HDL-C as a predictor of incident lower-extremity amputation.

A new systematic review and meta-analysis provides further insight suggestive of clinical benefits with monoclonal antibody therapy targeting PCSK9 (proprotein convertase subtilisin/kexin type 9). This analysis included data from 10,159 patients included in 24 Phase II and III randomised controlled trials.
 
Not surprisingly, treatment with PCSK9 antibody therapy reduced low-density lipoprotein cholesterol to a significantly greater extent than in patients who did not receive this treatment (by 47%, p <0.001). Additionally, PCSK9 inhibitor treatment was associated with reduction in all-cause mortality by 55% (odds ratio 0.45, 95% CI 0.23 to 0.86, p = 0.015); and cardiovascular mortality by 50% (odds ratio 0.50, 05% CI 0.23 to 1.10, p = 0.084). Treatment was well tolerated with no increase in serious adverse events.
 
While acknowledging that the analysis was based on limited endpoints and study-level rather than patient-level data, the findings do suggest promise with this mode of lipid-modifying therapy for reducing residual cardiovascular risk.

A new review discusses the potential of specific therapeutic strategies that directly target hypertriglyceridaemia to reduce vascular risk. A growing evidence-base, including cohort studies and meta-analyses, supports an association between increases in fasting and nonfasting triglycerides levels and cardiovascular risk. Furthermore, genomic and biomarker studies show that the metabolism of triglyceride-rich lipoproteins plays an important role in atherosclerosis. These data support resurgence in the use of omega-3 fatty acids for therapeutic lowering of triglycerides levels, including in patients with moderately elevated levels. Specifically, the review discusses data for icosapent, containing only eicasopentaenoic acid (EPA). Definitive evidence is awaited from the ongoing outcomes study, REDUCE-IT.

Evidence from the Da Qing study highlights diabetes as a major cause of cardiovascular disease, predominantly stroke, in China. This report included data from 630 people with newly-diagnosed diabetes (NDD) and 519 with normal glucose tolerance (NGT) who were included in the study in 1986. Over a 23 year follow-up period, 338 (57%) of those with NDD and 100 (20%) with NGT died. CVD was the cause of death in nearly half of those with diabetes (48% in men and 50% in women), the majority due to stroke (52% in men and 42% in women). Furthermore, the age-standardised incidence of all-cause mortality was 3-fold higher in subjects with NDD compared with those with NGT (incidence per 1,000 person-years: 36.9, 95% CI 31.5-42.3 versus 13.3, 95% 10.2-16.5 in men; and 27.1, 95% CI 22.9-31.4 vs. 9.2, 95% CI 7.8-10.6 in women, both p < 0.0001). These data highlight an urgent need for action to address escalating rates of diabetes and cardiovascular disease in China.

While the presence of subclinical disease measures has been directly associated with the development of cardiovascular disease in whites, there are less data for African Americans. This analysis from the Jackson Heart Study showed a moderately high prevalence of subclinical disease in this group, which in turn translated to higher cardiovascular risk, especially with concomitant metabolic syndrome and diabetes.
 
The analysis included 4,416 subjects (mean age 54 years; 64% women) who attended the first examination of the Jackson Heart Study. In total, 1,155 (26%) subjects had subclinical disease, defined as the presence of peripheral arterial disease, left ventricular hypertrophy (LVH), microalbuminuria, high coronary artery calcium (CAC) score, and/or low left ventricular ejection fraction. Cross-sectional multivariable-adjusted logistic regression analysis showed that subjects with metabolic syndrome or diabetes were at high risk of subclinical disease compared with those without these conditions (odds ratios 1.55 [95% CI 1.30–1.85] and 2.86 [95% CI 2.32–3.53], respectively). Furthermore, having either condition significantly increased the hazard of incident cardiovascular disease, independent of the presence of subclinical disease (P < 0.001).

There has been support for the concept that the presence of microvascular complications is predictive of an increased risk of cardiovascular events. This study tested this concept in patients with type 2 diabetes and diabetic retinopathy (DR) compared with those without DR. A total of 312 people with diabetes (mean age 57 years, 51% male) were included in the study, of whom 153 (49%) had DR. All participants underwent carotid ultrasound imaging to assess carotid intima-media thickness and the presence of carotid plaques. A higher percentage of patients with DR had carotid plaques than those without DR (68% vs 52%, p=0.0045). Patients with DR also had a higher prevalence of ?2 carotid plaques (44.4% vs 21.4%, p<0.0001). However there were no differences in the cIMT measured at different carotid regions between the two groups. Using multivariate logistic regression (with adjustment for major risk factors for atherosclerosis), DR was independently associated with mean-internal cIMT (p = 0.0176), the presence of carotid plaques (p = 0.0366) and carotid plaque burden (?2 plaques; p < 0.0001).
 
DR in patients with type 2 diabetes is associated with a higher atherosclerotic burden in the carotid arteries than seen in patients with type 2 diabetes and no DR. As patients with increased atherosclerotic burden have a higher risk of cardiovascular events, the authors recommended that patients with type 2 diabetes and DR should be considered for carotid ultrasound imaging to ensure a more individualised and careful cardiovascular assessment.

A new study from China highlights differences in the awareness, treatment and control of hypertension and dyslipidaemia in previously-diagnosed and newly-diagnosed subjects with diabetes. In total, 98,658 adults aged at least 18 years were identified from the China Noncommunicable Disease Surveillance 2010 study. Glycaemia was defined according to the 2010 American Diabetes Association criteria; hypertension was diagnosed according to the 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; and dyslipidaemia was diagnosed according to the 2004 National Cholesterol Education Program Adult Treatment Panel III. The prevalence of dyslipidaemia increased from 47% in subjects with normal glucose levels to 63% in subjects with newly-diagnosed diabetes and 70% in those with previously-diagnosed diabetes. Compared with subjects with newly-diagnosed diabetes, those with previously diagnosed diabetes were more likely to aware of dyslipidaemia (34% versus 13%), and were receiving pharmacotherapy (19% versus 5%). Among subjects with previously diagnosed diabetes, low-density lipoprotein cholesterol levels were controlled in 87%; however, management of triglycerides and high-density lipoprotein levels lagged behind (50% and 27% had controlled levels). These findings show that detection and control of dyslipidaemia remains far from optimal in Chinese adults.

Increasingly, evidence supports elevated remnant cholesterol, for which serum triglycerides are a marker, with residual cardiovascular disease risk in patients with well controlled levels of low-density lipoprotein cholesterol (LDL-C). New data suggest that remnant cholesterol may contribute to formation of coronary plaque.
 
In this study, 40 Japanese men with stable angina (mean 71 years, mean baseline LDL-C 107 mg/dL or 2.8 mmol/L) underwent intravascular ultrasound and coronary angiography to evaluate the severity of coronary artery disease, and plaque morphology and composition. Blood samples were taken to measure serum levels of adiponectin, omentin-1 and serum remnant cholesterol. The cross-sectional area at the most stenotic site of the plaque of target lesions correlated strongly with body mass index (r5=0.53, p<0.001) and negatively with serum adiponectin levels (r5=-0.34, p=0.03). Serum remnant cholesterol was the strongest positive factor for necrotic tissue and a negative determinant for fibrotic tissue in the plaques. Furthermore, the remnant cholesterol/triglyceride ratio was significantly correlated with the proportion of lipid in plaques, whereas serum LDL-C or high-density lipoprotein cholesterol levels were not. In conclusion, this study supports the concept that increased serum remnant-like cholesterol levels may contribute to the development of coronary plaques in patients with stable angina with well controlled LDL-C levels on statin therapy. Measurement of remnant cholesterol may aid evaluation of residual cardiovascular risk in this setting.

Elevated triglycerides are a marker of elevated remnant cholesterol and a component of atherogenic dyslipidaemia. Atherogenic dyslipidaemia is a key driver of atherosclerosis especially in individuals with cardiometabolic disease. It has been proposed that variation at the APOA5 gene locus, encoding apoAV, a key regulator of triglyceride levels, modulates lipoprotein subclass distributions toward a more atherogenic pattern in dyslipidaemic patients.
 
In this study of 422 treatment-naïve subjects, two APOA5 variants, rs662799 (-1131T>C) and rs3135506 (S19W), were genotyped. Circulating lipoproteins were determined by nuclear magnetic resonance, and intima-media thickness (IMT) was evaluated using B-mode ultrasonography. Carriers of the rs662799 and rs3135506 variants had a proatherogenic lipid profile based on remnant (very low-density lipoprotein [VLDL] and intermediate density lipoprotein [IDL] subclasses), resulting in an increase in large VLDL (+133%, p < 0.001) and small LDL (+34%, p = 0.014). This atherogenic subclass distribution was significantly associated with increased carotid IMT, especially in patients with increased body mass index (?25 kg/m2). These findings add to the evidence supporting a link between remnant cholesterol, atherogenic lipoprotein profile and IMT-defined subclinical atherosclerosis.

In a multi-ethnic Asian population, diabetic retinopathy was associated with prevalent and incident end-stage renal disease (ESRD). Data from 5,763 subjects (aged at least40 years) from the Singapore Malay Eye Study and the Singapore Prospective Study) were evaluated. Retinopathy was graded using the modified Airlie House classification system. Retinal vascular parameters were measured using computer-assisted programs to quantify the retinal vessel widths (arteriolar and venular caliber) and retinal vascular network (fractal dimension). Data on ESRD was obtained by record linkage with the ESRD cases registered by National Registry of Diseases Office, Singapore. Retinopathy was associated with prevalent ESRD (odds ratio [OR], 3.21, 95% confidence interval [CI]: 1.28–8.05) and incident ESRD (hazard ratio [HR], 2.51, 95%CI:1.14–5.54). This association was largely seen in subjects with diabetes and not in those without diabetes. However, other microvascular changes in the retina were not associated with ESRD.

Atherogenic dyslipidaemia, the combination of elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) is an important driver of cardiovascular risk in type 2 diabetes. This meta-analysis of 15 studies, with a total sample size of 4,010, showed a positive association between the Atherogenic Index, defined as log(TG/HDL-C) and type 2 diabetes. Indeed, the standardised mean difference (SMD) for the AIP was 1.78 (95% confidence interval (CI): 1.04-2.52), which was higher than for other parameters, including triglycerides (0.93, 95% CI: 0.78-1.09) and low-density lipoprotein cholesterol (LDL-C) ( 0.44, 95% CI: 0.11-0.77). Taken together, these results suggest AIP may be more closely associated with the risk of type 2 diabetes than other lipid parameters.

A new report from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, implicates fibroblast growth factor 21 (FGF21) levels in cardiovascular risk in patients with type 2 diabetes. FGF21 has already been shown to be elevated in obesity, dyslipidaemia, insulin resistance and type 2 diabetes. The investigators evaluated baseline plasma FGF21 levels in 9,697 individuals with type 2 diabetes in the FIELD study. The primary outcome was total cardiovascular disease (CVD) events. In analyses adjusted for confounding factors, higher baseline FGF21 levels were associated with higher risk for total CVD events (hazard ratio [HR] and 95% confidence interval [CI] 1.28, 1.10, to 1.50). Moreover, addition of FGF21 levels to a model including established CVD risk factors for predicting total CVD events led to significant improvement in discrimination and net reclassification of CVD risk. Taken together, these data add to emerging evidence for FGF21 as a contributor to cardiovascular risk in type 2 diabetes patients.

Latest findings from EUROASPIRE survey, a cross-sectional study of secondary prevention patients from 24 countries in Europe shows that achievement of guideline-recommended lipid goals is still far from optimal. This latest report from EURASPIRE include 7,998 patients (24.4% females) aged <80 years with coronary disease, who had coronary artery bypass graft, percutaneous coronary intervention or an acute coronary syndrome. Of the 74% of patients with dyslipidaemia, only 17% of women and 22% of men achieved the recommended low-density lipoprotein cholesterol goal of <1.8 mmol/L (70 mg/dL). This was despite 86.6% of patients receiving lipid-lowering therapy, principally statins. Moreover, there was also room for improvement with management of blood pressure, glycaemia, stopping smoking and lifestyle intervention. Nearly 50% of patients smoking at the time of the event were still smoking, 60% reported no or little physical activity, 38% of patients were obese (body mass index ?30 kg/m2), 43% had blood pressure ?140/90 mmHg and 27% had diabetes. Despite prescription of cardioprotective medication in >75% patients (anti-platelets 94%; beta-blockers 83%; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75%; and statins 86%), most coronary patients did not achieve guideline standards for secondary prevention. Clearly, much remains to be done in terms of achieving healthier lifestyles, better risk factor control and adherence with cardioprotective medication in these patients.

This review in Atherosclerosis brings together new evidence that conclusively shows that the different components of diabetic dyslipidaemia are not isolated abnormalities but closely linked metabolically. Of note, the underlying disturbances are hepatic overproduction and delayed clearance of triglyceride-rich lipoproteins. Recent findings clearly show that triglyceride-rich lipoproteins and their remnants are atherogenic. Thus, understanding of the pathophysiology of dyslipoproteinaemia in humans reinforces the importance of targeting triglyceride rich lipoproteins for the prevention and treatment of dyslipidaemia.

PCSK9 plays a key role in cholesterol homeostasis by regulating the availability of low-density lipoprotein (LDL) receptors and in turn catabolism of LDL, thus influencing circulating levels of plasma LDL cholesterol. Moreover, there is also evidence that PCSK9 influences the metabolism of other lipoproteins including very low-density lipoprotein (VLDL), with high levels of PCSK9 shown to down-regulate VLDL receptor expression.¹ This study investigated the relationship between PCSK9 and the lipoprotein profile using nuclear magnetic resonance (NMR) in 267 patients with diabetes and metabolic syndrome who were not receiving any lipid-lowering therapy. Levels of plasma PCSK9 levels were significantly and positively correlated with circulating levels of triglycerides (r=0.136, p=0.033), total cholesterol (r=0.219, p<0.001), and apolipoprotein B (r=0.226, p=0.006) and with an atherogenic lipoprotein profile. There was a positive association between circulating PCSK9 levels and large VLDL particles (r=0.210, p=0.001), and their remnants, specifically, proatherogenic circulating remnant lipoprotein cholesterol levels (r=0.171, p=0.006). In conclusion, these data highlight that PCSK9 is not only associated with LDL homeostasis, but also atherogenic lipoproteins such as VLDL, and remnant lipoprotein levels.
1. Roubtsova A, Munkonda MN, Awan Z et al. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler Thromb Vasc Biol 2011;31:785-91.

This study reports data with a novel apoC-II mimetic peptide in an experimental mouse model (apolipoprotein E-knockout mice). This peptide promoted cholesterol efflux from ATP-binding cassette transporter ABCA1-transfected BHK cells, and activated lipolysis by lipoprotein lipase in vitro. Intravenous administration (30 mg/kg) to apolipoprotein E-knockout mice significantly reduced plasma cholesterol (by 38%) and triglycerides (by 85%), at 4 hours. The authors concluded that this novel peptide may offer future therapeutic potential for the management of elevated triglycerides.

The cost and impact on daily life of diabetic retinopathy (DR) and diabetic macular oedema (DME) were highlighted by this US retrospective cohort study, using claims data (2001-2012) from the Human Capital Management Services Group Research Reference Database on annual direct/indirect health benefit costs and absences for employees aged ? 18 years, total data (n=466,251). Employees were divided into two groups, drivers (n=39,702) or nondrivers (n=426,549). Among nondrivers with diabetes, the presence of DME or DR significantly increased sick leave and short-term disability costs. Thus, this study using real-world data highlights the need for renewed emphasis on early detection and management of diabetes-related eye disease in working-age adults. Beyond mandatory management of blood glucose and blood pressure, data from two major prospective studies support a role for fenofibrate in the management of early DR. As recommended by the R3i, incorporation of fenofibrate into management algorithms may help to reduce costs and improve quality of life among patients with diabetes.(1)
 
1. Hermans MP, Fruchart JC, Davignon J et al. Residual microvascular risk in type 2 diabetes in 2014: Is it time for a re-think? A perspective from the Residual Risk Reduction Initiative (R3i). Journal of Diabetes & Metabolism 2014, 5:413.

Recent data from the U.S. show reduced life expectancy and increased lifetime healthcare expenditure in obese individuals with diabetes compared with those of normal weight. These data highlight the urgent need to tackle the escalating burden of cardiometabolic disease in the US and beyond. The analysis included data from the National Health Interview Survey (NHIS, 1997-2000), the Medical Expenditure Panel Survey (1997-2000), and the NHIS Linked Mortality Public-use Files, with mortality followed-up to 2006. Markov modelling with risk and cost estimates was used to compute life years and total lifetime healthcare expenditures by age, race, sex, and body mass index (BMI) classifications for patients with or without diabetes. The presence of diabetes not only decreased life expectancy by 3.3 to 18.7 years, but also increased lifetime healthcare expenditures by $8,946 to $159,380, depending on age-race-sex-BMI classification groups. In U.S. adults aged 50 years, white females with diabetes and BMI >40 kg/m2 had 17.9 remaining life years and lifetime health expenditures of $185,609. By comparison, females with diabetes and normal weight had 22.2 remaining life years and lifetime health expenditures of $183,704. These data reinforce evidence on the costs of obesity, in terms of decreased life expectancy and increased lifetime healthcare expenditure.

A previous review by the Residual Risk Reduction Initiative highlighted a link between microvascular and macrovascular disease in type 2 diabetes.(1) This new study adds to the evidence, suggesting that retinal microvascular endothelial dysfunction is a marker for underlying coronary artery disease (CAD) in non-diabetic subjects.
 
The study investigated 197 subjects, 119 without CAD but at least 2 cardiovascular risk factors (non-CAD controls) and 78 with stable CAD, using retinal arteriolar and venular dilatation to flicker light, a nitric oxide dependent phenomenon, as a marker of retinal microvascular endothelial dysfunction. Fingertip pulse volume amplitude to calculate reactive hyperaemia index (RHI) and brachial artery flow-mediated dilatation (FMD) were measures of peripheral microvascular and conduit vessel endothelial function, respectively. There was attenuation of mean retinal arteriolar dilatation in subjects with CAD (1.51±1.51% vs 2.37±1.95% in non-CAD controls; p = 0.001). Even after adjustment for age, gender, cardiovascular risk factors and medication use, retinal arteriolar dilatation remained independently associated with CAD (odds ratio 1.60, 95% CI 1.14, 2.25; p = 0.007). In conclusion, this study provides further support of a link between microvascular and macrovascular disease.
 
1. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 2011;218:13-8.

A new report provides evidence of an interaction between cholesteryl ester transfer protein (CETP) genotype and diet on changes in blood lipids (high-density lipoprotein cholesterol [HDL-C] and triglycerides, i.e. atherogenic dyslipidaemia).
 
This study evaluated whether the common CETP rs3764261 genotype influenced lipid changes in response to weight-loss diets, specifically the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) and Dietary Intervention Randomized Controlled Trial (DIRECT) studies. In the POUNDS LOST study in 732 overweight/obese adults, those carrying the CETP-rs3764261 CC genotype and on a high-fat diet had larger increases in HDL-C (10.1% vs 4.5%, p=0.001) and decreases in triglycerides (24.0% vs 14.7%, p=0.007) than individuals on a low-fat diet at 6 months. These gene-diet interactions affecting changes in HDL-C and triglycerides were replicated in the DIRECT study. The authors concluded that individuals with the CETP rs3764261 CC genotype might derive greater benefit in targeting atherogenic dyslipidaemia with a low-carbohydrate/high-fat weight-loss diet instead of a low-fat diet.

Recent reviews highlight the case for triglycerides, more specifically triglyceride-rich lipoproteins (TRLs), in the development of cardiovascular risk.
 
Tenenbaum et al argue for re-consideration of the role of TRLs in cardiovascular disease, taking into account epidemiological, genetic and mechanistic data. This review also discusses mechanisms whereby TRLs stimulate atherogenesis, including excessive free fatty acid (FFA) release, production of proinflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. As discussed by Khetarpal and Rader,2 genetic studies have provided convincing evidence that plasma levels of TRLs are causally related to the development of coronary artery disease (CAD), specifically implicating the key triglyceride-regulating enzyme lipoprotein lipase (LPL), in CAD risk. Beyond LPL, there is also strong evidence implicating the genes APOC3 and APOA5, encoding apolipoproteins (apo) C-III and apoA-V, respectively; data indicate that apoC-III promotes and apoA-V protects against CAD.
 
While the mainstay of management of hypertriglyceridaemia is lifestyle, genetic data also provide a rationale for the development of novel targeted therapies, such as an antisense APOC3 oligonucleotide, which offer the potential for reducing residual cardiovascular risk beyond that achieved with current therapy.
 
1. Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk. New insights from human genetics. Arterioscler Thromb Vasc Biol 2015 [Epub ahead of print].
2. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2014 [Epub ahead of print]

A new review highlights the importance of targeting atherogenic dyslipidaemia, the key feature linking metabolic syndrome and type 2 diabetes, which is insufficiently addressed by statin therapy. In particular, the review highlights the need for urgent action in regions characterised by a high prevalence of atherogenic dyslipidaemia, notably south Asia and the Middle East. Consistent with recommendations of the Residual Risk Reduction Initiative,(1) the authors advocate a role for fibrates and omega-3 polyunsaturated fatty acids that target atherogenic dyslipidaemia and elevated triglycerides, respectively, and thus offer the potential to reduce residual cardiovascular risk associated with this dyslipidaemia.
 
1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.

HIV patients undergoing antiretroviral therapy are at increased risk of developing atherogenic dyslipidaemia, and thus predisposed to cardiovascular disease. This cross-sectional, observational outpatient study investigated whether variability in the genes influencing the metabolism of triglycerides, APOA5, APOC3, LPL, CETP, HL, MTP, APOE, LRP5 and VLDLR, may predispose to the development of atherogenic dyslipidaemia. The study enrolled 468 antiretroviral-treated HIV-infected patients, 173 with normal lipids and 148 with atherogenic dyslipidaemia, defined as triglycerides >1.7 mmol/L and high-density lipoprotein cholesterol [HDL-C] < 1.02 in men or 1.28 mmol/L in women. Genetic analyses showed that specific polymorphisms in LPL (rs328), CETP (rs708272) and HL (rs1800588) were more frequent in subjects with normal lipid levels than in those with atherogenic dyslipidaemia, with at least one of these polymorphisms detected in 90% of patients (versus 75% in patients with atherogenic dyslipidaemia, p=0.003). Indeed, in patients with the combination of these protective alleles, there was a trend towards higher HDL-C levels (mean 1.13 versus 1.24 mmol/L), lower triglycerides (2.23 versus 1.89 mmol/L) and lower remnant lipoprotein concentration (16.4 versus 13.0 mmol/L). Further study is needed to investigate genetic variability in susceptibility to atherogenic dyslipidaemia as a factor predisposing to protection against cardiovascular disease in HIV patients.

While observational studies support a low plasma concentration of high-density lipoprotein cholesterol (HDL-C) as a strong CV risk factor, it may not be the optimal surrogate for cardiovascular risk. Indeed, in recent major prospective clinical studies, such as dal-OUTCOMES,(1) targeting HDL-C did not result in reduction in cardiovascular disease outcomes. Given that HDL particles have been associated with multiple atheroprotective functions, it is likely that HDL-C level, a static measure, is inappropriate as a biomarker of HDL function and dynamics. Instead, there is growing support for measures of HDL functionality as improved biomarkers for cardiovascular risk. Attention has focused on cholesterol efflux from macrophages to HDL, a key step in reverse cholesterol transport, as one of the most important functions of HDL. Previous studies have shown an inverse association between cholesterol efflux capacity and prevalent coronary artery disease, which is independent of HDL-C level.(2)
The current study investigated the association between cholesterol efflux capacity and incident cardiovascular disease events in 2,924 subjects (median age 42 years, 43% male, 49% black and with median low-density lipoprotein cholesterol 104 mg/dL [2.7 mmol/L]) from the Dallas Heart Study free from clinical cardiovascular disease at baseline. Overall, 46% of women had HDL-C <50 mg/dL (1.3 mmol/L) and 35% of men had HDL-C <40 mg/dL (1.05 mmol/L). The primary end point was atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation or death from cardiovascular causes. Over a median follow-up of 9.4 years, 132 subjects had a primary atherosclerotic cardiovascular disease event. There was a graded inverse association between HDL cholesterol efflux capacity and the primary end point, which persisted after adjustment for multiple traditional cardiovascular risk factors. Comparing the highest versus lowest quartiles, there was a 67% reduction in cardiovascular risk (hazard ratio, 0.33; 95% CI, 0.19 to 0.55). Thus, this study adds to emerging data for the value of HDL cholesterol efflux capacity as a biomarker for cardiovascular risk. However, this measure is a research tool with further validation needed before this can be translated to routine clinical practice.
 
1. Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
2. Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.

Decision tree analysis identified elevated triglycerides as the main risk factor for carotid atherosclerosis in middle-aged women.
Decision tree analysis is commonly used to identify a strategy most likely to reach a goal, and thus may be relevant in assessing the relative importance of different risk factors for carotid atherosclerosis, an intermediate clinical endpoint used as surrogate for cardiovascular disease. This study included 5,822 subjects aged 20-80 years, who underwent physical examination and routine laboratory testing (blood pressure, fasting plasma glucose, total cholesterol, triglycerides, high density lipoprotein-cholesterol and low density lipoprotein-cholesterol). Carotid intima-media thickness (CIMT) was measured by carotid ultrasonography. CIMT was defined as carotid atherosclerosis when CIMT was ?0.9 mm. Overall, the incidence of carotid atherosclerosis was 12.2% (14.1% in men and 9.2% in women). The most important modifiable risk factors in men aged 20-40 years was total cholesterol (>6.31 mmol/L), whereas in those aged 41–59 years, fasting plasma glucose (>5.79 mmol/L) was more important. In contrast, in women, fasting plasma glucose (>5.52 mmol/L) was key in younger subjects (20–40 years), but triglycerides (>1.51 mmol/L) most relevant in those 41–59 years of age. These findings suggest that cardiovascular prevention strategies should target modifiable risk factors according to their relevance in men and women.

In a large study from China, critical components of the metabolic syndrome, including low plasma concentration of high-density lipoprotein cholesterol (HDL-C), were risk factors for reduced glomerular filtration rate (GFR). This cross-sectional study included 75,468 urban workers (21,497 with the metabolic syndrome) who underwent annual health examinations between March 2010 and September 2012. The group with metabolic syndrome had a higher mean age (52.3 versus 47.4 years) and a greater percentage of men (66% versus 52%) compared with those without metabolic syndrome. The presence of the metabolic syndrome was associated with reduced GFR (odds ratio [OR] 1.43, 95% confidence interval [CI] 1.13-1.83). In multivariate analyses, elevated blood pressure (OR 1.34, 95% CI 1.00-1.78), low HDL-C (OR 1.88, 95% CI 1.44-2.43), and elevated fasting blood glucose (OR 1.42, 95% CI 1.09-1.85) were each independently associated with the metabolic syndrome. Low HDL-C was associated with a 19.7% population-attributable risk for reduced GFR. The study adds to other findings, such as those from the ADVANCE study, showing a link between HDL-C and decreased renal function.(1,2)
 
1. Zoppini G, Targher G, Chonchol M et al. Higher HDL cholesterol levels are associated with lower incidence of chronic kidney disease in patients with type 2 diabetes. Nutr Metab Cardiovasc Dis 2009;19:580-6.
2. Morton J1, Zoungas S, Li Q et al. Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy: results of the ADVANCE study. Diabetes Care 2012;35:2201-6.

The increased risk of ischaemic heart disease in obesity is mediated partly by elevated levels of nonfasting remnant cholesterol, according to this Danish study.
The study used a Mendelian randomisation approach, a type of ‘natural randomised trial’, to delineate which variables prevalent with obesity are likely to be mediators of the risk of ischaemic heart disease associated with obesity. Data from ? 90,000 subjects from the Copenhagen General Population Study (n=69,535), the Copenhagen City Heart Study (n=10,099), and the Copenhagen Ischemic Heart Disease Study (n=5,050) were analysed. The potential association of lipoproteins, blood pressure, glucose, and/or C-reactive protein with ischaemic heart disease was initially examined in observational analyses, and thereafter in genetic analyses based on the presence of variants known to be associated with body mass index, and seven intermediate variables: nonfasting remnant cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL-C), systolic and diastolic blood pressure, glucose and C-reactive protein. The genetic data were not subject to confounding and reverse causation as were the observational data. Elevated levels of nonfasting remnant cholesterol and LDL-C, elevated blood pressure, and possibly elevated nonfasting glucose levels, were implicated as causal mediators of the increased risk of ischaemic heart disease due to obesity, whereas HDL-C and C reactive protein were not. In genetically determined obesity, LDL cholesterol, systolic blood pressure and remnant cholesterol contributed 8%, 7% and 7%, respectively, of the excess risk of ischaemic heart disease, whereas in observational data, the corresponding excess risks were 21%, 11%, and 20%, respectively. These data provide a rationale for prospective studies testing whether lowering of elevated remnant cholesterol, closely associated with elevated triglycerides, may reduce ischaemic heart disease risk.

One in 6 patients treated in lipid and vascular risk units has atherogenic dyslipidaemia, according to a report from EDICONDIS-ULISEA. This observational, retrospective study included patients aged ?18 years who were referred for dyslipidaemia and vascular risk to 43 lipid clinics in Spain. In total, 295 (17.9%) of 1,649 patients with a lipid profile at first visit had atherogenic dyslipidaemia. However, only a minority (44 or 16.1%) of these patients with atherogenic dyslipidaemia were successfully managed at subsequent follow-up. The authors concluded that management of atherogenic dyslipidaemia, characterised by elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), clearly needs to improve in Spain.

The CEPHEUS (Centralized Pan-Middle East Survey) evaluated the treatment of hypercholesterolemia in patients aged ?18 years of age in six Middle Eastern countries (November 2009 -July 2010). Lipid goals were those recommended by the joint Consensus Statement of the American Diabetes Association and American College of Cardiology. The study included 5,275 patients (mean age 56?±?13 years, 58% male and 69% at very high cardiovascular risk). In very high-risk patients, there was suboptimal management of LDL-C (only 25% achieved recommended targets), non-HDL-C (36%) and apolipoprotein B (38%); in patients with triglycerides ?2.2?mmol/L, LDL-C and apolipoprotein B goal attainment was even lower (16% and 15%, respectively). Thus, despite being on lipid-modifying therapy, patients at very high cardiovascular risk remain inadequately managed across this region.

Accumulating evidence indicates a role for retinal inflammation in the pathogenesis of diabetic retinopathy. Chronic inflammation in the diabetic retina leads to leukocyte activation, via the action of specific chemokines, adhesion to the vascular endothelium and extravasation into the retinal tissues. One of the most potent chemotactic factors for monocytes is CCL2, also known as monocyte chemoattractant protein (MCP-1). In this experimental study, expression of CCL2 was significantly up-regulated in the retinas of the streptozotocin-treated rats (a well established model of diabetes), as well as in human retinal endothelial cells treated with high glucose and glucose flux. Subsequent studies in Cx3cr1-GFP mice showed that intraocular injection of CCL2 increased retinal monocyte/macrophage infiltration; when these mice were made diabetic and CCL2 injected, there was increased infiltration of monocytes/macrophages in retinal tissues, as well as activation of retinal microglia. Cell culture impedance sensing studies showed that while purified CCL2 was unable to modify the integrity of the human retinal endothelial cell barrier, monocyte conditioned medium led to significant reduction in cell resistance, implying that CCL2 may take part in early immune cell recruitment leading to subsequent changes in the blood-retinal-barrier. Taken together, these findings suggest that chemokine CCL2 plays an indirect role in mediating the increase in retinal vascular permeability brought about by hyperglycaemia, and thus may represent a potential therapeutic target for reducing the residual risk of this complication in diabetic patients.

Compared with statin monotherapy, the combination of statin plus niacin was associated with less progression of carotid intima-media thickness (CIMT) when given long-term in patients with coronary artery disease. Patients who completed the Familial Atherosclerosis Treatment Study (FATS) either received usual care with statin therapy alone (n=26) or were enrolled in the 20-year FATS-Observational Study (n=43) and received lovastatin (40 mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11 years, followed by simvastatin (10-80 mg/day) or lovastatin (40-80 mg/day) plus niacin (2-4 g/day). At follow-up (mean 17.8 years with combination therapy and 19.0 years with usual care), combination therapy was associated with improved lipid control, as shown by greater decreases in total cholesterol (by 42% versus 31% with usual care, p=0.008), low-density lipoprotein cholesterol (by 57% versus 38%, p<0.001), as well as a greater increase in high-density lipoprotein cholesterol (by 38% versus 15%, p = 0.02). These lipid changes were also associated with significantly less CIMT progression (0.902 ± 0.164 versus 1.056 ±- 0.169 mm, p <0.001). These findings support the value of statin combination therapy in providing more comprehensive lipid control and reduced atherosclerosis progression in patients with established coronary artery disease.

This study from Italy highlights the need to improve the management of elevated triglycerides in patients with type 2 diabetes. The study included 1,917 patients with type 2 diabetes (mean age 58 years, 59% male), attending the hospital-based outpatient clinic. Over a mean follow-up period of 10 years, there were 95 deaths. Cox proportional hazard analysis showed a direct significant association between triglycerides levels during follow-up and all-cause mortality, independent of confounding factors such as low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, HbA1c, blood pressure, body mass index, fasting glucose, and antihypertensive and glucose-lowering treatment (III vs I tertile: HR:1.87;95% confidence intervals: 1.12-3.12, p=0.016). The authors concluded that more attention should be given to managing elevated triglycerides as part of the cardiovascular risk profile in type 2 diabetes patients.

The PREDI-MED study previously showed the benefit of a Mediterranean diet in reducing cardiovascular disease (CVD) events in high-risk patients without pre-existing CVD.1 New findings from this group indicate that long-term adherence to a Mediterranean diet may also reverse the metabolic syndrome, specifically reducing obesity and hyperglycaemia. Subjects in the PREDI-MED trial were randomly assigned either a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts, or advice on following a low-fat diet (the control group). In total, 5,801 subjects were followed over a mean of 4.8 years. In 3,392 subjects who had metabolic syndrome at baseline, 958 (28%) no longer had this phenotype at follow-up. Notably, subjects on a Mediterranean diet supplemented with either olive oil or nuts were more likely to undergo reversion (by 35% [15-58%] or by 28% [8-51%], respectively compared with control, p < 0.001 for each comparison). Subjects on either Mediterranean diet shown significant decreases in central obesity (p<0.05); those allocated to olive oil supplementation also showed a significant decrease in glycaemia (p = 0.02). In 1,919 subjects who did not have metabolic syndrome at entry to the study, there was no difference in the risk of developing metabolic syndrome between the three groups. In conclusion, a Mediterranean diet supplemented with either extra virgin olive oil or nuts is more likely to lead to reversion of the condition, suggesting potential benefit as part of lifestyle intervention in the management individuals with central obesity. 1. Estruch R, Ros E, Salas-Salvadó J et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.

In contrast to the recent ACC/AHA guideline for management of cholesterol,1,2 the NLA recommendations emphasise the importance of cholesterol goals in clinical practice, not only for clinicians to use in monitoring the efficacy of treatment, but also for patients to understand and work toward. These recommendations favour the use of non-HDL cholesterol, which includes all potentially atherogenic lipoproteins, i.e. low-density lipoprotein, intermediate density lipoproteins, very low-density lipoproteins (VLDL) and VLDL remnants, chylomicron remnants, and lipoprotein (a), as the preferable marker for risk for cardiovascular disease and to monitor therapy. The NLA also provides recommendations for the management of elevated triglycerides, closely associated with metabolic syndrome, obesity and diabetes, and an important contributor to residual cardiovascular risk. The use of fibrates, niacin or omega-3 fatty acids can be considered if triglyceride goals are not reached with statins alone.
br> 1. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934. 2. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S1-45.

In ODYSSEY COMBO II, the addition of the PCSK9 monoclonal antibody therapy, alirocumab, to maximally tolerated statin therapy resulted in superior control of low-density lipoprotein cholesterol (LDL-C) compared with oral ezetimibe in high cardiovascular risk patients with inadequately controlled LDL-C levels. This double-blind, multicentre study enrolled 720 patients (LDL-C =1.81 mmol/L [=70 mg/dL] in patients with established cardiovascular disease (CVD), or =2.59 mmol/L (=100 mg/dL) if no history of CVD but with other risk factors). Patients were randomised 2:1 to either alirocumab 75 mg subcutaneously every 2 weeks (increasing to 150 mg every 2 weeks at Week 12 if LDL-C was =1.81 mmol/L at Week 8) or ezetimibe 10 mg daily. The primary endpoint (% change in LDL-C from baseline to Week 24, intent-to-treat analysis), showed that treatment with alirocumab was significantly superior to ezetimibe (51% versus 21%, p<0.0001). This "treat to target" approach with alirocumab resulted in >75% of alirocumab-treated patients achieving guideline-recommended LDL-C goals (<1.81 mmol/L or<70 mg/dL) at 24 weeks. Consistent LDL-C reductions were maintained over 52 weeks (mean percent LDL-C reduction 50% versus 18% with ezetimibe, absolute LDL-C reduction 2.2 versus 1.4 mmol/L). Treatment with alirocumab was well tolerated with no adverse signal, compared with ezetimibe. In conclusion, the addition of the PCSK9 monoclonal antibody alirocumab significantly improved attainment of LDL-C goal in high CV risk patients.

ISIS-APOCIIIRx selectively inhibits hepatic synthesis of apolipoprotein (apo)C-III, which has a key role in regulating plasma triglyceride (TG) levels. The current study investigated the effect of treatment with ISIS-APOCIIIRx, either as a single agent or in combination with fibrates, on fasting lipids and lipoproteins in patients with hypertriglyceridaemia (HTG) and 1) with type 2 diabetes on = 1g/day stable metformin and not on TG-lowering medication; 2) not on TG-lowering medication or (3) on stable fibrate therapy. Treatment with ISIS-APOCIIIRx resulted in consistent and significant dose-dependent decreases in apoC-III and TG, as well as increases in high-density lipoprotein cholesterol (HDL-C), with no significant change in non-HDL-C, when given alone or in combination with a fibrate (see Table). These data support further evaluation of ISIS-APOCIIIRx, either alone or in combination with a fibrate, in the management of HTG.

Mean (SD) Percent change from baseline to 13 weeks, after treatment with ISIS-APOCIIIRx

Parameter	HTG with diabetes ISIS-APOCIIIRx + metformin (n=7)	ISIS-APOCIIIRx (n=11)	ISIS-APOCIIIRx + fibrate (n=10)
ApoCIII	-88 (6.0)*	-80 (9.3)***	-71 (13.0)**
Triglycerides	-72 (8.3)*	-71 (14.1)***	-64 (8.9)**
HDL-C	+40 (19.8)*	+46 (24.0)***	+52 (23.7)***

*p=0.05, **p=0.01, ***p=0.001

This experimental animal model showed that the potent and selective peroxisome proliferator-activated receptor alpha (PPARa) agonist, K-877, attenuates fasting and postprandial hypertriglyceridaemia by enhancing lipoprotein lipase (LPL) activity and reducing weight gain. The study used male C57BL/6J mice, which were fed either a western diet (WD), WD containing K-877 (0.0005%) or WD containing fenofibrate (0.05%) for 4 weeks (n=10/group). Compared with the WD group, fasting triglycerides were significantly lower with K-877 (81.0±21.5 versus 32.0±8.7 mg/dL) or fenofibrate (81.0±21.5 versus 29.7±8.8 mg/); p<0.01 for each treatment group versus WD. Additionally, LPL activity was significantly increased in mice treated with K-877 or fenofibrate suggesting that both prevent the accumulation of remnant lipoproteins by increasing LPL activity. Treatment with K-877 or fenofibrate was also associated with less weight gain although dietary intake was similar. These findings from this experimental model indicate that treatment with K-877 improves postprandial hypertriglyceridaemia, and provide a rationale for investigation in humans.

This study highlights the importance of managing atherogenic dyslipidaemia, elevated triglycerides (TG) and low plasma concentration of high-density lipoprotein cholesterol (HDL-C), to reduce atherosclerosis progression in patients with diabetes. A total of 109 patients (mean age 68±9 years, 31% female, 89% on statins) were included. Atheroma burden was assessed using intravascular ultrasound (IVUS), performed at baseline and a median of 1.3 years (474 days) later. The primary endpoints were normalised total atheroma volume (TAV) and percent atheroma volume (PAV), calculated in the target segment in each patient. Patients with inadequate control of both HDL-C (<40 mg/dL or 1.03 mmol/L) and TG (>150 mg/dL or 1.7 mmol/L) showed greatest coronary artery progression, as defined by both the change in TAV (7.7±21.9 mm3 versus -3.8±19.3 mm3 in patients with controlled levels p=0.006) and by the change in PAV (1.2±4.9% versus 0.5±3.4%, p=0.034). These findings emphasise the importance of atherogenic dyslipidaemia as a contributor to residual risk of coronary atherosclerosis in statin-treated patients with diabetes.

The Residual Risk Reduction Initiative has already drawn attention to unmet clinical needs in the management of secondary prevention patients. For example, in the Prospective Urban Rural Epidemiology (PURE) study, only 15% of patients were taking statins 5 years after a myocardial infarction (MI), and use was substantially lower in low to middle income countries.1 These data highlight the need for education and re-thinking of strategies to improve management in these high-risk patients. Subsequently, the use of a once-daily fixed-dose combination - or polypill - including key medications to reduce cardiovascular risk has shown promise in studies of patients with established cardiovascular disease.2 However, to date there has been no direct evaluation of the impact of this polypill strategy on treatment adherence. Consequently, the FOCUS (Fixed Dose Combination Drug for Secondary Cardiovascular Prevention) project aimed to better understand adherence to medication in the post-MI setting.

The study involved two phases:
Phase 1, a comprehensive analysis of factors that determine the appropriate use of preventive interventions including 2,118 patients in 5 countries (Argentina, Brazil, Italy, Paraguay, and Spain);
and Phase 2, a randomised, controlled clinical trial (695 patients from those previously included in Phase I) testing the effect of a fixed combination of aspirin 100 mg, simvastatin 40 mg and ramipril 2.5, 5 or 10 mg, versus treatment with the individual agents, on adherence and control of cardiovascular risk factors.

In Phase I, overall adherence was 45.5% (=20 on the self-reported Morisky-Green questionnaire); younger age, depression, being on a complex medication regimen, poorer health, insurance coverage, and a lower level of social support were all associated with reduced risk of treatment adherence across all five countries. In Phase 2, patients in the polypill group had significantly improved adherence compared with the group receiving the medications separately; after 9 months, adherence (assessed by a score of =20 on the self-reported Morisky-Green questionnaire and high pill count [80-110%]) was 51% vs 41% (p=0.019; intention-to-treat population). There was no difference in mean low-density lipoprotein cholesterol levels at follow-up (89.9 vs 91.7 mg/dL). The authors concluded that the use of a polypill significantly improves treatment adherence compared with concomitant use of three individual therapies. Longer-term trials are required to evaluate whether this improved adherence translates to improved clinical benefit.

1. Yusuf S, Islam S, Chow CK et al. Prospective Urban Rural Epidemiology Study I. Use of secondary prevention drugs for cardiovascular disease in the community in high income, middle-income, and low-income countries (the pure study): A prospective epidemiological survey. Lancet 2011;378:1231-43.
2. Thom S, Poulter N, Field J et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: The umpire randomized clinical trial. JAMA 2013;310:918-29.

This study evaluated the association between fasting and postprandial serum triglycerides (TG) as risk modifiers in patients with coronary artery disease (CAD) treated with a statin. In total, the cohort included 514 patients (median age 68 years, 83% male) with angiographically confirmed, clinically stable CAD, 95% of whom were on a statin (median LDL-cholesterol 105 mg/dL). Both fasting and postprandial TG predicted cardiovascular events:
• Fasting TG (>150 mg/dL versus <106 mg/Dl): Hazard ratio 1.79, 95%-CI 1.31-2.45, p=0.0001
• Nonfasting TG AUC >1120 mg/dL vs. <750 mg/dL: Hazard ratio 1.78, 95%-CI 1.29-2.45, p=0.0003.
Risk prediction by TG was independent of traditional risk factors, medication, glucose metabolism, LDL- and HDL-cholesterol. The authors concluded that postprandial TG does not improve risk prediction over fasting TG in statin-treated patients with CAD.

Adding a measure of visceral adipose tissue (VAT) to body mass index (BMI) provides a better predictor of cardiovascular risk, according to this study. A total of 369 consecutive patients without a history of cardiovascular disease were enrolled. VAT was assessed using 64-slice computed tomography angiography (CTA), with the percent VAT calculated as VAT/(VAT + subcutaneous adipose tissue) × 100, and its median value was 39.4%. Patients were divided into four groups based on BMI (<25 and 25=) and %VAT (<39.4 and 39.4=). Cardiovascular risk factors were hypertension, hyperglycaemia, and dyslipidaemia. Over the median follow-up of 2020 days, there were 32 cardiovascular events. Cox proportional hazards analysis showed that the risk of a cardiovascular event was higher in patients with both elevated BMI and VAT, after adjustment for confounding factors (see Table). On the basis of these findings, assessing both VAT and BMI may provide added value in cardiovascular risk assessment.
Hazard ratio (% CI) for major adverse cardiovascular events, after adjustment for cardiovascular risk factors

Category		HR (95% CI)	p-value
BMI =25 kg/m2 and higher %VAT	Vs. BMI<25 kg/m2 with lower %VAT	4.38, 1.58–12.18	0.005
	Vs. BMI<25 kg/m2 with higher %VAT	2.74, 1.18–6.35	0.02
	Vs. BMI=25 kg/m2 with lower %VAT	4.68, 0.98-22.51	0.05

There is ongoing debate relating to the effects of incretin-based therapies on cardiovascular risk parameters, including lipids. This meta-analysis of 28 trials (10,171 patients with diabetes) showed that incretin-based therapies significantly reduced triglycerides (-0.29 mmol/L, 95% CI -0.48 to -0.11; p=0.002) and raised high density lipoprotein cholesterol (0.03 mmol/L, 95% Cl 0.0003-0.06; p=0.05, respectively), compared with other diabetes treatments. On the basis of these findings, not only do incretin-based therapies lower blood glucose in patients with type 2 diabetes, but there are also significant positive effects on the lipid profile.

As previously reported, treatment with niacin/laropiprant in the HPS2-THRIVE trial did not improve clinical outcome in adults with cardiovascular disease and well-controlled low-density lipoprotein cholesterol (LDL-C, 63 mg/dL or 1.63 mg/dL) .1 What is especially worrying is that treatment with niacin/laropiprant was also associated with serious harm. As well as the anticipated skin-related adverse effects (p=0.003), there was also a significant increase in gastrointestinal, musculoskeletal, and bleeding complications, loss of glycaemic control in patients with diabetes at baseline, new-onset diabetes, and unexpectedly infectious adverse events (all p<0.001). Moreover, there was also a 9% (95% confidence interval [CI] 1-21%) increase in the risk of death which was of borderline statistical significance (p = 0.08), with similar nonsignificant increases in both vascular and nonvascular mortality. Added to this, a new safety analysis from AIM-HIGH shows an excess of skin-related, gastrointestinal and glycaemic complications, as well as a higher rate of serious bleeding with niacin use. Taken together, these safety issues and lack of clinical benefit, question the role of niacin (where still available) in clinical use. Although the authors of HPS2-THRIVE suggest that niacin might still be relevant some patients, they also emphasise the need to take into consideration the risks of treatment, especially given these safety findings.
1. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34):1279-91.

In statin-treated patients with a previous cerebrovascular event, the presence of atherogenic dyslipidaemia was associated with a higher residual cardiovascular risk compared with those without this lipid profile. These findings were based on a post hoc analysis from PERFORM (Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack, n=19,100) and SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels; n=4,731). Atherogenic dyslipidaemia was defined as low high-density lipoprotein cholesterol (=40 mg/dL or 1.03 mmol/L) and high triglycerides (=150 mg/dL or 1.7 mmol/L) 3 months after randomization. The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). Overall, 10% of subjects in PERFORM (n=1,057) and 9% in SPARCL (n=259) had atherogenic dyslipidaemia after 3 months on statin therapy. In PERFORM, this lipid phenotype was more likely to be associated with Asian ethnicity. During a median follow-up of 2.3 years in PERFORM, 1,123 subjects had major cardiovascular events. The risk of a major cardiovascular event was higher in patients with atherogenic dyslipidaemia at baseline than in those without (hazard ratio [HR], 1.36, 95% CI 1.14–1.63, p<0.001). The presence of atherogenic dyslipidaemia was also associated with an increased risk of incident stroke (HR 1.27, 95% CI 1.04–1.56, p=0.02). In SPARCL, 485 patients had a major cardiovascular event after a median follow-up of 4.9 years. As for the PERFORM data, the risk of this event was higher in patients with atherogenic dyslipidaemia (HR 1.40, 95% CI 1.06–1.85, p<0.017). This association was attenuated but remained significant after multivariable adjustment in PERFORM (HR 1.23; 95% CI, 1.03–1.48, p=0.02)). The authors conclude that atherogenic dyslipidaemia confers a higher residual cardiovascular risk (by ~25% after multivariate adjustment) in patients with pre-existing cerebrovascular disease (stroke or transient ischaemic attack) receiving statin therapy. These data highlight an unmet therapeutic need to address this residual risk.

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the recycling of low-density lipoprotein (LDL) receptors and hence plasma levels of LDL cholesterol. In this study of patients with coronary artery disease (CAD), serum triglycerides were correlated with PCSK9 and modified risk prediction by PCSK9. The study enrolled 504 patients with clinically stable CAD documented by coronary angiography (mean age 68 years, 83% male, 95% treated with a statin). The primary outcome was a composite of cardiovascular death and unplanned cardiovascular hospitalization. When the data were analysed according to tertiles of baseline PCSK9 plasma levels, patients in the highest tertile (>622 ng/ml) were at increased risk for the primary outcome compared with those in the lowest tertile (<471 ng/ml); hazard ratio 1.55, 95%-CI 1.11–2.16, p = 0.009). Higher PCSK9 levels were also associated with higher triglycerides (p<0.0001), whereas there was no difference based on tertile analysis of total cholesterol, LDL cholesterol and HDL cholesterol plasma levels. Adjustment for fasting triglycerides attenuated the association of PCSK9 levels with cardiovascular events. These data strongly suggest that higher triglycerides, a component of atherogenic dyslipidaemia, contribute to PCSK9-associated CV risk.

South Asians are known to be at greater risk of developing premature atherosclerotic cardiovascular disease (ASCVD) than other ethnicities. It is thought that a greater prevalence of cardiovascular risk factors earlier in life, including a proatherogenic lipoprotein profile (elevated apolipoprotein B-containing triglyceride-rich lipoproteins, and low high-density lipoprotein cholesterol [HDL-C]), may be a contributing factor. This study evaluated whether the cholesteryl ester transfer protein (CETP), involved in mediating the hetero-exchange of cholesteryl esters and triglycerides between lipoproteins, may be implicated in the pathogenesis of atherogenic dyslipoproteinaemia. CETP activity was measured in healthy individuals of South Asian (N=244) and European Caucasian (N=238) descent, enrolled in the Study of Health Assessment and Risk in Ethnic groups (SHARE). Serum and lipoprotein lipids and apolipoproteins were measured and lipoprotein particle number and size were determined using nuclear magnetic resonance spectroscopy. Atherogenic dyslipoproteinaemia was more severe in South Asian than European subjects. After adjustment for age, sex, body mass index and waist circumference, CETP activity was 30% higher in South Asians than Europeans (p<0.0001). CETP activity was directly associated with serum triglycerides, apoB and LDL particle number, and inversely associated with HDL-C and LDL size. The authors concluded that CETP activity was strongly associated with all of the key elements of atherogenic dyslipidaemia, notably elevated triglycerides, low HDL-C and changes in LDL particle number and size. These findings therefore implicate elevated CETP activity as a contributing factor to the increased atherogenic risk in South Asians.

This report from the Cohort Norway project provides further support for a causal role of elevated triglycerides in coronary heart disease, even among individuals with favourable plasma levels of high-density lipoprotein cholesterol (HDL-C). Data from 140,790 Norwegians without coronary heart disease at baseline (1994–2003) and with follow-up data (December 2009) were evaluated. The mean age at baseline was 47.4 years (standard deviation [SD] 14.3) for men and 46.3 years (SD 14.1) for women. A total of 3,219 (4.8%) men and 1,434 (1.9%) women had a myocardial infarction (MI) during follow-up (mean 11.5 years). In age-adjusted analyses, the incidence of MI increased from 21.9 to 58.4 per 10,000 person-years in men and from 7.3 to 32.9 in women from the lowest to the highest triglycerides decile. There was evidence of significant sex interaction for triglycerides impact. When the highest (=2.88 mmol/l) and lowest (<0.7 mmol/l) triglycerides deciles were compared, there was a 4.7-fold excess risk in women compared with 2.8-fold excess risk in men. Even in subjects with a favourable HDL-C level (>1.0 mmol/l for men and >1.3 mmol/l for women), the risk of MI increased with increasing triglycerides quartiles (trend analysis, p<0.001). The authors concluded that high triglycerides levels, despite favourable HDL-C levels, may identify a subset of individuals at risk for CHD.

Researchers evaluated the prevalence of atherogenic dyslipidaemia (triglycerides =150 mg/dl or 1.7 mmol/L and high-density lipoprotein cholesterol [HDL-C] <40 mg/dl or 1.03 mmol/L in men and <50 mg/dL or 1.29 mmol/L in women) in the ICARIA (Ibermutuamur CArdiovascular RIsk Assessment) study. A total of 70,609 subjects (72% male, mean age 39.2 ± 10 years) were included in this observational cross-sectional study. Overall, 5.7% (95% CI 4.7-6.9) of the study population had atherogenic dyslipidaemia. After adjustment for obesity and alcohol intake, the presence of atherogenic dyslipidaemia was significantly associated with cardiovascular risk (hazard ratio 1.27, 95% CI 1.12-1.45, p=0.0003). The authors concluded that screening for atherogenic dyslipidaemia may improve cardiovascular risk stratification over the current SCORE model.

In the recently reported FIRST trial, the combination of fenofibric acid plus atorvastatin did not further decrease progression of atherosclerosis, compared with atorvastatin alone, in high-risk patients with mixed dyslipidaemia. The rationale for the FIRST trial has been previously reported on the R3i website. Briefly, this multicentre, double-blind, placebo-controlled study included patients with mixed dyslipidaemia (fasting triglycerides =150 mg/dL or 1.7 mmol/L; high-density lipoprotein cholesterol =45 mg/dL or 1.2 mmol/L [men] or =55 mg/dL or 1.4 mmol/L [women]; low-density lipoprotein cholesterol =100 mg/dL or 2.6 mmol/L once and averaging =105 mg/dL or 2.7 mmol/L) and a history of coronary heart disease or risk equivalent. Patients on background atorvastatin (continued on starting dose or titrated to 40 mg) were randomised to fenofibric acid 135 mg/day or placebo. The primary end point, the rate of change from baseline to week 104 of the mean posterior-wall carotid intima-media thickness, measured by ultrasound, was similar in each group (-0.006 mm/y with fenofibric acid plus atorvastatin versus 0.000 mm/y with atorvastatin alone; p=0.22). The study will be discussed in a future Landmark Trial analysis.

Findings from the landmark Da Qing Diabetes Prevention Study show that sustained lifestyle intervention can reduce cardiovascular and all-cause mortality and diabetes in Chinese people with impaired glucose tolerance. This study included 577 adults with impaired glucose tolerance who were enrolled by 33 clinics in Da Qing, China in 1986. Subjects were randomised (1:1:1:1) to a control group (n=138) or lifestyle intervention groups (diet, exercise, or both, n=439). The intervention lasted for 6 years and patients were followed-up after 23 years. The primary outcomes were all-cause mortality, cardiovascular disease mortality and diabetes incidence; 542 (94%) subjects had complete data for mortality. Over the 23-year follow-up period, 174 participants died (121 in the intervention groups versus 53 in the control group). Compared with the control group, the cumulative incidence of cardiovascular disease mortality and all-cause mortality was lower in the intervention group (11.9% versus 19.6%, hazard ratio 0.59, 95% CI 0.36–0.96; p=0.033 for cardiovascular mortality and 28.1% versus 38.4%, hazard ratio 0.71, 95% CI 0.51–0.99; p=0.049 for all-cause mortality). There was significantly greater effect in women than men; lifestyle intervention was associated with 72% reduction in cardiovascular mortality in women (versus 9% in men), and 54% reduction in all-cause mortality (versus 3% in men). These differences may relate to higher smoking rates in men. The incidence of diabetes was also significantly lower in the intervention group (72.6% versus 89.9%, hazard ratio 0.55, 95% CI 0.40–0.76; p=0.001); this effect was similar in both men and women. These findings based on hard outcomes data provide further justification for the importance of sustained lifestyle intervention to control the consequences of impaired glucose tolerance and diabetes, and have important implications for public health policy about diabetes prevention.

This study investigated the role of intestinal triglyceride-rich lipoprotein overproduction in atherogenic dyslipidaemia in obese subjects. Duodenal samples from 20 obese subjects undergoing bariatric surgery were matched for age, sex, and body mass index irrespective of insulin sensitivity (homeostasis model assessment of insulin resistance). Intestinal insulin signalling was defective in insulin-resistant subjects, as shown by reduced protein kinase B phosphorylation and increased p38 mitogen-activated protein kinase phosphorylation, possibly as a result of high oxidative stress and inflammation. In addition, the study showed an increase in de novo lipogenesis and apolipoprotein B-48 biogenesis coincident with triglyceride-rich lipoprotein overproduction in insulin-resistant subjects. These subjects also showed high expression levels of liver and intestinal fatty acid-binding proteins and microsomal transfer protein. The authors concluded that dysregulation of intestinal insulin signalling, possibly induced by oxidative stress and inflammation, may represent a key mechanism which contributes to atherogenic dyslipidaemia in patients with metabolic syndrome.

Findings from the San Antonio Family Heart Study (SAFHS) highlight the additive value of the plasma lipidomic profile in metabolic syndrome. This study used a novel statistical approach to quantify the value of the plasma lipidome in explaining metabolic syndrome variability in Mexican American families recruited in the SAFHS, involving two steps: principal components analysis of the high resolution plasma lipidomics data, and construction of a subject-subject lipidomic similarity matrix. The analysis was based on data for 1,206 subjects (from 42 families, mean age 40 years, 60% female), with a high prevalence of type 2 diabetes (~15%), central obesity (~48%) and elevated triglycerides (~41%). The plasma lipidome contributed to 22% variability in insulin sensitivity (HOMA-IR) and 16% – 22% variability in glucose, insulin and waist circumference independent of obesity and measures of lipidaemic status. These findings argue for consideration of the biological pathways involved in lipid/lipoprotein metabolism, in addition to specific lipid/lipoprotein classes, and highlight a potential role for evaluating differences in the plasma lipidome as biomarkers for increased susceptibility to the metabolic syndrome. Indeed, a recent study has shown that the lipidomic approach has allowed for identification of distinct ceramide molecular species strongly associated with fatal outcome of coronary artery disease patients independently of traditional risk factors.1
1. Tarasov K, Ekroos K, Suoniemi M et al. Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency. J Clin Endocrinol Metab 2014;99:E45-E52.

Analyses from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, suggest that tooth loss and gingivitis may be potential risk markers for cardiovascular disease. The STABILITY trial investigated the potential of darapladib, a selective oral inhibitor of lipoprotein-associated phospholipase A2, for prevention of major cardiovascular events in 15,828 patients with stable coronary heart disease. At baseline, all subjects had a physical examination and blood testing, and completed a lifestyle questionnaire, which included information on dental health. Specifically, the questionnaire collected data on the remaining number of teeth (none, 1–14, 15–20, 21–25, or 26–32 (all)) and frequency of gum bleeding (never/rarely, sometimes, often or always). There was a high overall prevalence of tooth loss; 16% of subjects reported having no teeth, and 41% reported having fewer than 15 remaining teeth. Furthermore, 26% of subjects reported gum bleeding when brushing teeth. Analyses showed that increasing prevalence of tooth loss was significantly associated with higher fasting glucose levels, low-density lipoprotein (LDL) cholesterol levels, systolic blood pressure and waist circumference. Similarly, a higher prevalence of gum bleeding was significantly associated with higher LDL cholesterol levels and systolic blood pressure. In conclusion, the authors suggest that dental health may be a marker of cardiovascular disease risk, although acknowledging that demographic, genetic and socioeconomic disparities may be confounding factors to this association.

An increased prevalence of low plasma concentration of high-density lipoprotein cholesterol (HDL-C) in Turkey is already well recognised. This report highlights the high prevalence of atherogenic dyslipidaemia, especially among the 46-to-65-year-old age group. The study included 4,309 people (aged 20 to 83 years) from both urban and rural regions according to a stratified sampling method. Overall, 36.2% had high low-density lipoprotein cholesterol (LDL-C), 41.5% had low HDL-C, and 35.7% had elevated triglycerides; at least one lipid abnormality was identified in the majority of subjects (79% of men and 80% of women). Moreover, the presence of these lipid abnormalities increased with age, and was highest in the 46-to-65-year-old age group. These findings highlight an unmet need for increased awareness of the high prevalence of dyslipidaemia, including elevated triglycerides and low HDL-C, in this population.

Based on a North European population (=55 years), statin therapy would be recommended for almost all male patients and two-thirds of female patients according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of cholesterol. These estimations exceed predictions for the 2011 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines. Predictions were based on 4,854 subjects in the Rotterdam Study (mean age 65.5 years, 55% women); at baseline, 14% of male and 13% of female subjects were on a statin. For the 2013 ACC/AHA guidelines, there was a shift in the proportion of the study cohort from ‘treatment considered’ to ‘treatment recommended’ categorisations; for men, the relative percentages were 96.4% versus 3.3%, and for women, 65.8% and 14.2%. In contrast, for the 2011 ESC/EAS guidelines, treatment was recommended for 66.1% of men (versus considered in 31.6%) and 39.1% of women (versus considered in 51.4%), based on 10-year risk estimations. Thus, by lowering the cut-off for treatment, the 2013 ACC/AHA guidelines have substantially overestimated the proportion of individuals at high levels of actual cardiovascular disease risk. As well as highlighting the potential risk of statin overprescription, these findings also implicate the need for education and intervention aimed at prevention of risk factor aggregation so as to reduce future cardiovascular disease rates.

A previous report by the Residual Risk Reduction Initiative (R3i) highlighted microvascular disease as a predictor of cardiovascular disease (CVD) risk.1 The hyperaemia index, assessed by peripheral artery tonometry, is a measure of microvascular dysfunction, with low levels indicative of impaired reactive hyperaemia. The current study investigated whether this variable (logarithmic transformed data) could be used to stratify for residual coronary risk. The study included 213 coronary artery disease patients on statin therapy (mean age 66.7 years, 74% male, mean LDL cholesterol 70 mg/dL). Over a median follow-up of 2.7 years, coronary events occurred in 4 (4.0%) patients with hyperaemia index = 0.5) versus 18 (15.8%) patients with an index < 0.54 (p = 0.006). Cox regression analysis showed that the hyperaemia index was an independent predictor for coronary events even after adjustment for traditional risk factors, as well as estimated glomerular filtration rate (Hazard ratio 0.79, 95% confidence interval 0.66-0.95, p=0.012). In conclusion, the authors suggest that approaches aimed at improving microvascular dysfunction may offer potential to reduce residual risk in patients with coronary heart disease.
1. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 2011;218:13-8.

DYSIS-Middle East, part of the main DYSIS (Dyslipidemia International Study) trial, enrolled 2,182 patients (=45 years) on statin treatment (=3 months) in the United Arab Emirates, Saudi Arabia, Lebanon and Jordan. Most (83%) were classified as being at very high risk of cardiovascular events. Despite statin treatment, only 62% of patients attained guideline-recommended targets for low-density lipoprotein (LDL) cholesterol, and 56% and 49% attained desirable levels for high-density lipoprotein (HDL) cholesterol and triglycerides, respectively. This study highlights the high prevalence of lipid abnormalities among statin-treated patients in this region. Notably, atherogenic dyslipidaemia, i.e. elevated triglycerides with or without low HDL cholesterol, was present in about 50% of patients, indicating the need for improved clinical management.

Both high triglycerides (TG) and a low plasma concentration of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk for coronary heart disease (CHD). The ratio of TG/HDL-C is also predictive of residual risk for CHD and poorer metabolic control in people with type 2 diabetes. This survival analysis (n=39,447 men) evaluated the potential of the TG/HDL-C ratio (cut-point 3.5), as a predictor for CHD, cardiovascular disease (CVD) and all-cause mortality. The total follow-up was 581,194 person-years. The TG/HDL-C ratio predicted CHD, CVD, and all-cause mortality after adjustment for established risk factors and non-HDL-C. These data reaffirm the role of atherogenic dyslipidaemia as a marker of residual coronary risk.

As shown by the REALIST-Micro STUDY,1 elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are robustly associated with diabetic kidney disease in patients with type 2 diabetes and controlled low-density lipoprotein cholesterol (LDL-C) levels.1 This cross-sectional study (n=216,007 Japanese adults, 88,516 men 127,491 women) used TG/HDL-C quartile analysis to assess the association with chronic kidney disease (CKD). The TG/HDL-C quartiles were <1.26, 1.26-1.98, 1.99-3.18 and >3.18 in men; <0.96, 0.96-1.44, 1.45-2.22, and >2.22 in women). Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 (low eGFR) and/or proteinuria (defined as urinary protein =1+ on dipstick testing)]. In both men and women, the prevalence of CKD, low eGFR, and proteinuria increased significantly with increasing quartiles of TG/HDL-C (p for trend <0.001). Compared with those in the lowest quartile, subjects in the highest quartile of TG/HDL-C had a significantly greater risk of CKD (adjusted odds ratio: 1.57, 95% confidence interval 1.49-1.65 in men; and 1.41, 1.34-1.48 in women). The increase in risk of CKD with TG/HDL-C was evident irrespective of the presence or absence of hypertension, diabetes and obesity. In conclusion, this analysis of more than 200,000 Japanese men and women reaffirms the link between triglycerides and HDL-C and risk for CKD.
1. Sacks FM, Hermans MP, Fioretto P et al. Association between plasma triglycerides and HDL-cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes: A global case-control study in 13 countries. Circulation 2013 Dec 18. [Epub ahead of print].

There is growing evidence (see also Landmark Study) implicating increased triglycerides (TG), a marker for cholesterol in remnant lipoproteins, as a risk factor for cardiovascular disease (CVD). Whether lifelong low levels of TG (due to a genetic aetiology) are associated with reduced mortality is not known. In this study, a Mendelian randomisation approach was used to test this hypothesis based on data from the Copenhagen City Heart Study. The study analysed observational data (n = 13,957) and data based on the presence of genetic variants of lipoprotein lipase leading to low nonfasting TG and remnant cholesterol (n = 10,208). Observational analyses reaffirmed the association between nonfasting TG and all-cause mortality. In analyses based on genetic data, each 1 mmol/L (89 mg/dL) decrease in nonfasting TG was associated with 50% (95% CI 18-70%) reduction in risk for all-cause mortality. The corresponding observational analysis showed a 13% (95% CI 11-15%) reduction in risk. In conclusion, this study shows that low concentrations of nonfasting plasma TG due to the presence of genetic variants in lipoprotein lipase are associated with reduced all-cause mortality. The authors suggest this lower risk might be mediated by reduced amount of cholesterol contained in remnant lipoproteins.

The International Steering Committee of the Residual Risk Reduction Initiative (R3i), comprising 40 leading specialists from North and South America, Europe, the Middle East, Asia and Japan, has today highlighted priorities for action against atherogenic dyslipidaemia, an important contributor to lipid-related residual cardiovascular risk. The R3i defines atherogenic dyslipidaemia as the imbalance between triglyceride-rich apolipoprotein B-containing-lipoproteins, for which triglycerides are a marker, and apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL).

The R3i has identified three key priorities:

• To improve recognition of atherogenic dyslipidaemia in high risk patients, including those with diabetes
• To target atherogenic dyslipidaemia, using non-HDL cholesterol (total cholesterol – HDL cholesterol) for treatment decisions
• To improve management of atherogenic dyslipidaemia, and adherence to guideline-recommended therapies. The addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe to statin therapy are all approaches to reduce non-HDL cholesterol.

The R3i recognises that there is a need for new treatment options that can more effectively target atherogenic dyslipidaemia, and reviews future possibilities in this paper. This paper will have important implications for the routine management of patients who remain at high residual cardiovascular risk despite well controlled low-density lipoprotein (LDL) cholesterol levels.

The full paper is available to read at Cardiovascular Diabetology. The paper will be discussed on the website in a following post.

In this phase 2 proof-of-concept study, ECT-1002 lowered low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) and improved high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia, without deterioration in glycaemic control. ETC-1002 is a small molecule which in nonclinical studies has been shown to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In this single-centre, double-blind, placebo-controlled trial, 60 patients with type 2 diabetes and elevated LDL-C (mean 128 mg/dL or 3.3 mmol/L) were randomly allocated to treatment with ETC-1002 (80 mg once daily for 2 weeks followed by 120 mg once daily for 2 weeks) or placebo for 4 weeks. At the end of the study, ETC-1002 was associated with significant reduction (versus placebo) in LDL-C (by 43%), non-HDL-C (by 32%) and total cholesterol (by 25%) (all p<0.0001), although there was no significant effect on HDL-C (-1.2%). High-sensitivity C-reactive protein was reduced by a median of 41% (versus reduction by 11% on placebo, p=0.0011). ECT-1002 appeared to be well tolerated with no adverse safety signal. In conclusion, ETC-1002 may offer a potential novel therapeutic approach in this high risk patient population.

This study adds to evidence linking hepatic steatosis with atherogenic dyslipidaemia and resultant increased cardiovascular risk. In total, 6,333 asymptomatic subjects without clinical cardiovascular disease in Brazil were included over the period 2008 to 2010. Hepatic steatosis was diagnosed by ultrasound. Atherogenic dyslipidaemia was defined using 2 definitions: i) criteria for metabolic syndrome or ii) insulin resistance (triglyceride/high-density-lipoprotein (HDL) cholesterol ratio of =2.5 in women and =3.5 in men). Hepatic steatosis was detected in 36% of the sample (mean age 43.5 years, 79% men, average body mass index 26.3 kg/m2). While plasma levels of low-density-lipoprotein (LDL) cholesterol were similar in subjects with and without hepatic steatosis, HDL cholesterol was lower and triglycerides were higher in subjects with steatosis. After multivariate adjustment, hepatic steatosis was significantly and independently associated with atherogenic dyslipidaemia for both definitions: i) odds ratio 2.47, 95% confidence interval [CI] 2.03 to 3.02, and for ii) odds ratio 2.50, 95% confidence interval 2.13 to 2.91). The association between hepatic steatosis and atherogenic dyslipidaemia was independent of obesity, physical activity, hyperglycaemia, and systemic inflammation. This study suggests potential for atherogenic dyslipidaemia as a target of interest for therapeutic intervention in non-alcoholic fatty liver disease/steatosis.

The European Atherosclerosis Society (EAS) Consensus Panel has called for a streamlined definition of hypertriglyceridaemia. Recent insights into the genetics of hypertriglyceridaemia indicate that phenotypic heterogeneity reflects the cumulative burden of both common small-effect genetic variants, as well as rare heterozygous large-effect variants of genes which are directly or indirectly associated with plasma triglycerides. Taking this into consideration, the EAS Consensus Panel calls for a simplified redefinition, with hypertriglyceridaemia categorised as either mild to moderate (triglycerides 2-10 mmol/L or 175-885 mg/dL), or severe (>10 mmol/L or >885 mg/dL). A multigenic or polygenic basis accounts for mild to moderate hypertriglyceridaemia, whereas severe hypertriglyceridaemia is likely to have a monogenic basis. This redefinition should help to simplify the diagnosis and management of hypertriglyceridaemia in routine practice.

This study investigated whether altered renal triglycerides and cholesterol metabolism underlies lipid accumulation in human diabetic nephropathy (DN). Kidney biopsies of patients with diagnosed DN (n=34) and normal controls (n=12) were investigated. Heavy lipid deposition observed in kidneys of DN patients was associated with down-regulation of fatty acid ß-oxidation pathways, including peroxisome proliferator-activated receptora (PPAR-a), carnitine palmitoyltransferase I (CPT1), acyl-CoA oxidase (ACO) and liver-type fatty acid binding protein (L-FABP), as well as renal lipoprotein lipase. There was also upregulation of genes for cholesterol uptake receptors, including low-density lipoprotein (LDL) receptor, oxidized LDL receptors and acetylated-LDL receptor, as well as downregulation of genes influencing cholesterol efflux (ATP-binding cassette transporters (ABCA1, ABGC1) and apolipoprotein E). Evidence of a highly significant correlation between estimated glomerular filtration rate, inflammation and lipid metabolism genes, suggests that abnormal lipid metabolism may be implicated in the pathogenesis of DN, which may offer potential for pharmacotherapeutic intervention.

In this report from the ProActive Study, increased sedentary time was independently associated with increased cardiometabolic risk and triacylglycerol in adults at high risk of developing type 2 diabetes. Physical activity (accelerometer measures), adiposity measures and television viewing as a proxi measure of sedentarity (self-reported survey) were assessed at baseline and after a mean of 6.27 (±0.46) years in 171 adults (mean age 42.5 ±6.3 years; 46% men) with a parental history of diabetes. Greater increases in sedentary time were associated with larger increases in clustered cardiometabolic risk (CCMR: 0.08 [95% CI 0.01, 0.15]; CCMR without adiposity component: 0.08 [0.01, 0.16]) and triacylglycerol (0.15 [0.01, 0.29]), independent of baseline sedentary and moderate-to-vigorous physical activity duration, change in moderate-to-vigorous physical activity time and other confounders. However, the association with change in high-density lipoprotein cholesterol did not achieve statistical significance. Change in waist circumference and body mass index did not appear to mediate the association between CCMR without adiposity component and triacylglycerol. Television viewing was not independently associated with any of the cardiometabolic outcomes. These data highlight the potential benefits reducing sedentary time to potentially reduce cardiometabolic risk.

There are emerging data that atherogenic dyslipidaemia associated with intermittent hypoxia may contribute to the increased cardiovascular risk associated with obstructive sleep apnoea (OSA). The current study investigated potential links between the effects of apolipoprotein E (APOE) genotype and sleep apnoea severity on atherogenic dyslipidaemia in patients with OSA. In total, 519 subjects were screened, and OSA was identified by polysomnography in 391 subjects. Across all APOE genotype groups, increased severity of OSA was associated with significant increases in serum triglycerides (p<0.05, fully adjusted analyses). APOE genotype and the oxygen desaturation index were both independent predictors of serum triglycerides (p=0.009 and p<0.001, respectively). These findings suggest that OSA has adverse effects on atherogenic dyslipidaemia beyond effects related to APOE genotype.

In the general population, the offspring of very elderly individuals have a lower prevalence of major cardiometabolic conditions. This is not solely explained by reduced exposure to conventional risk factors. Consequently, whether parental lifespan may be an additional factor influencing cardiometabolic risk in the offspring was investigated in this cross-sectional study in patients with type 2 diabetes. Of 558 patients screened, 405 (mean age 69 years, 32% female) satisfied the criteria for longevity for at least one parent, i.e. aged =80 years at the time of parental death(s), or age at the time of the study if still alive. Individuals whose parents had a shorter lifespan had more severe insulin resistance and hyperinsulinaemia phenotype; earlier occurrence of diabetes; poorer glycaemic control; and a higher prevalence (by 53%) and greater severity (by 13% of the atherogenic index (log[triglycerides]/high-density lipoprotein cholesterol). Given that offspring of parents with a shorter lifespan did not differ from those with a long lifespan in terms of body mass index, waist circumference, adiposity and visceral fat, suggests that innate and genetic influences may possibly at least partly explain these findings.

The prevalence of aortic valve stenosis (AVS) increases with advancing age. Currently, more than 3% of the very elderly population (>75 years) are affected, although it is likely that this will increase with changing population demographics. Epidemiological data suggest an association between low high-density lipoprotein (HDL) cholesterol concentration and progression of aortic valvular calcium and AVS severity. However, in the light of controversy over the relevance of measurement of HDL cholesterol concentration to cardiovascular risk, it has been proposed that impaired HDL functionality may underlie the risk for AVS. The current report tested this by 1) determining whether genetic variants that are associated with HDL cholesterol concentration are associated with the risk of AVS in a case–control study; and 2) investigating cholesterol efflux capacity, a measure of HDL functionality, and HDL-related parameters in a cohort of this study. In the case-control study, 1,435 single nucleotide polymorphisms in genes associated with HDL cholesterol levels (in or around GALNT2, LPL, ABCA1, APOA5, SCARB1, LIPC, CETP, LCAT, LIPG, APOC4, and PLTP) were genotyped in 382 patients with echocardiographic-confirmed AVS (aortic jet velocity =2.5 m/sec) and 401 controls. None of these variants was predictive of AVS. In a subsample of this cohort (86 patients with AVS and 86 matched controls), measures of cholesterol efflux capacity in apolipoprotein B–depleted serum samples did not differ between cases and controls. Given that HDL cholesterol levels and measures of cholesterol efflux and HDL size were all lower in patients with coronary artery disease than controls, independent of the presence or absence of AVS, suggests a true negative association between parameters of HDL functionality or metabolism and AVS risk, although corroborative studies are needed.

This timely review overviews the evidence for remnant cholesterol as a causal risk factor for ischaemic heart disease (IHD), and discusses present and future pharmacotherapeutic approaches. Most recently, in a Mendelian randomisation study of genetic variants associated with elevated remnant cholesterol level, each 1 mmol/L (39 mg/dL) increase in levels of nonfasting remnant cholesterol associated with a 2.8-fold increased risk of IHD, independently of high-density lipoprotein cholesterol levels (this study was discussed on the R3i website earlier this year).1 Furthermore, genetic studies show that elevated levels of remnant cholesterol are causally associated with both low-grade inflammation and IHD (see Landmark Trial). Definitive outcomes evidence from large randomised trials is, however, still awaited.

There are emerging data to support nonfasting (postprandial) triglyceride concentrations, a marker for triglyceride-rich lipoproteins (TRLs) and their remnants, as a clinically significant risk factor for cardiovascular disease. The syndecan-1 heparan sulfate proteoglycan (HSPG) pathway is important for clearance of remnant TRLs in mouse models of type 2 diabetes, with uptake of remnant lipoproteins suppressed by accelerated degradation of HSPG due to hepatic induction of a heparan sulfate 6-O endosulfatase (SULF2). However, its relevance in man is uncertain. The current study investigated whether polymorphisms in genes responsible for HSPG assembly and disassembly contribute to atherogenic dyslipoproteinaemia in humans. After a 12-hour fast, 68 healthy subjects (31 men, mean age 46 years) underwent an oral fat load test (57 g fat, 63 g carbohydrates, and 40 g protein, total 934 calories). Blood samples were taken before and 3, 4, 6, and 8 hours after the test meal for analysis of chylomicrons and very low density lipoproteins (VLDL) 1 and 2. Single nucleotide polymorphisms in genes for syndecan-1 and enzymes involved in the synthesis or degradation of HSPG were genotyped in the study subjects. The study showed that genetic variation in rs2281279 in SULF2 associates with postprandial clearance of remnant TRLs and triglyceride levels, and with hepatic SULF2 mRNA levels, in healthy subjects. This study therefore supports the contention that clinically relevant postprandial hyperlipidaemia due to reduced hepatic clearance of remnant TRLs may result from genetic polymorphisms that affect hepatic HSPG, and suggests a novel target for improving atherogenic dyslipoproteinaemia.

Accumulating evidence implicates atherogenic dyslipidaemia, the combination of elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) levels, as an important contributor to lipid-related residual cardiovascular risk. This review discusses current and emerging options for the management of this dyslipidaemia. Following the recent European Medicines Agency suspension of niacin, fibrates (especially fenofibrate) represent the preferred option for add-on therapy to treat elevated triglycerides and low HDL-C. Novel agents, such as monoclonal antibodies against PCSK9, offer opportunities for achieving substantial incremental reductions in low-density lipoprotein cholesterol in excess of 60% in high-risk patients on statin therapy Outcomes trials with the more advanced of these antibody therapies are currently in progress.

Along with rising numbers of patients with metabolic syndrome, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased in line with the obesity epidemic. Currently, there are no established treatments for NAFLD, although ongoing research is targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications. Among potential targets identified to date are farnesoid X receptor (FXR); members of the peroxisome proliferator activated receptor (PPAR) sub-family receptors, currently the target of several drugs under evaluation for the treatment of NAFLD; Pex11, which plays a role in regulating peroxisomal function, and p53, implicated in NAFLD largely through its role in regulating fatty acid oxidation. Most of the potential targets identified to date are at an early stage of clinical investigation, which much work required to elucidate the mechanisms contributing to NAFLD.

Retinol binding protein 4 (RBP4) is an adipokine secreted mainly by the liver and adipocytes, which is linked to obesity and its comorbidities, and thus may potentially contribute to the development of insulin resistance. This study investigated the possible role of RBP4 in lipid metabolism in obese patients with varying degrees of insulin resistance. In total, 299 middle-aged morbid obese patients (body mass index 40 kg/m2) were enrolled, and categorised as euglycaemic (n=84), or with metabolic syndrome (n=164) or type 2 diabetes (n=51). RBP4 levels were significantly higher in patients with metabolic syndrome or type 2 diabetes than in euglycaemic subjects (42.9±14.6 or 42.3±17.0 versus 37.4±11.7 µg/ml, respectively). For all subjects, RBP4 correlated with triglycerides (p<0.001) but not with HOMA-IR. There was a significant increase in serum RBP4 levels in patients with high triglycerides (=150 mg/dL or 1.7 mmol/L) independent of insulin resistance. In a subgroup analysis (n=80), RBP4 was also associated with the percentage of small dense high-density lipoprotein, independent of insulin resistance. In summary, the study showed that systemic RBP4 levels could play a role in lipid and lipoprotein metabolism in morbid obesity, increasing triglyceride levels and contributing to the formation of small triglyceride-rich HDL.

This review of the mode of action of fenofibrate in diabetic retinopathy is timely following the recent Australian approval of fenofibrate to slow progression of early stage diabetic retinopathy (DR) in patients with type 2 diabetes.(1) This approval was based on data from two recent large, well-designed clinical trials - Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes-Eye (ACCORD-Eye) - which demonstrated large reductions in the progression of DR in patients with type 2 diabetes. In both trials, the greatest benefit on DR regression was observed in those patients with early-stage DR at baseline. Multiple mechanisms appear to underpin the benefit of fenofibrate on DR, including pathways influencing lipid and lipoprotein control, inflammation, angiogenesis and cell apoptosis. Cell experiments have demonstrated improved survival of retinal endothelial and pigment epithelial cells in conjunction with reduced stress signalling under diabetic conditions. Further, in rodent models of diabetes and retinal neovascularisation, fenofibrate improved retinal outcomes. Taken together, these findings provide impetus to establish the benefits of fenofibrate in other major forms of diabetes with high prevalence and incidence of retinopathy, foremost of all in including type 1 diabetes.
1. TGA okays Lipidil for diabetic retinopathy. Available at http://www.medicalobserver.com.au/news/tga-okays-lipidil-for-diabetic-retinopathy

The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study included 1,104 patients with hypercholesterolaemia previously enrolled in four phase II trials (parent trials). Patients were randomised (2:1) to treatment with open-label subcutaneous evolocumab 420 mg every 4 weeks with the standard of care (n=736) or standard of care alone (n=368). The duration of treatment was 52 weeks. Patients who received evolocumab for the first time in OSLER had substantial reduction in low-density lipoprotein cholesterol (LDL-C) levels compared with baseline in the parent trials (mean 52.3%). Patients who received evolocumab in the parent trial and then continued on evolocumab had durable LDL-C responses (reduction by 50.4% at the end of the parent trial and 52.1% at 52 weeks in OSLER). Additionally, patients who started or continued on evolocumab had significant reductions from baseline in the parent trial for triglycerides (by 8.3% and 9.0%, respectively) and lipoprotein(a) (by 32.8% and 29.9%, respectively). Both of these groups had elevation in high-density lipoprotein cholesterol levels at 52 weeks versus baseline in the parent trial (by 8.5% and 9.1%, respectively). In contrast, for patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Rates of adverse events and elevations in creatine kinase and aminotransferases were not appreciably greater in patients who achieved low LDL-C plasma levels on evolocumab. These are promising data from the largest and longest efficacy and safety evaluation of an anti-PCSK9 antibody to date.

Latest data from EUROASPIRE III show that while management of dyslipidaemia in patients with coronary heart disease (CHD) in Europe has improved over the last decade, many patients are still inadequately treated. This report summarizes data from 8,467 CHD patients enrolled by centres in 22 European countries. Despite increasing use of lipid-lowering therapy over the course of the survey, from 32.3% of patients in 1994-1995 to 88.8% of patients in 2006-2007, a high proportion of dyslipidaemic patients still have lipid abnormalities. Notably, 34.7% of patients had elevated fasting triglycerides (= 1.7 mmol/L or 150 mg/dL) and 36.7% had low plasma levels of high-density lipoprotein (< 1.0 mmol/L or 39 mg/dL for men, and <1.2 mmol/L or 46 mg/dL for women). The authors conclude that there is still much to be done to improve the management of dyslipidaemia in Europe.

Apolipoprotein C-III (apoC-III) is both an independent risk factor and a key regulatory factor influencing plasma triglycerides concentrations, a marker for levels of triglyceride-rich lipoproteins. In addition, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. This report describes the results of treatment with a novel antisense oligonucleotide inhibitor of apo-CIII. In animal studies, inhibition of apoC-III was well tolerated and was not associated with increased liver triglycerides deposition or hepatotoxicity. In a phase I clinical study in healthy subjects, administration of this human apoC-III antisense oligonucleotide (50, 100, 200, and 400 mg dose groups) resulted in dose-dependent median reductions in plasma apoC-III (by 19.7%, 17.3%, 70.5%, and >77.5%, respectively), with concomitant lowering of triglycerides levels (19.5%, 25.0%, 43.1%, and 43.8%). There was no evidence of adverse safety signals. Further study is ongoing.

Data from the Western Norway B-Vitamin Intervention Trial in 2,378 patients with coronary artery disease (mean age 62 years, 80% male) show that a high dietary intake of n-3 long-chain polyunsaturated fatty acids (mean daily intake 1.12 g, adjusted for energy intake), was associated with a reduced risk of acute myocardial infarction (AMI) in patients with diabetes, independent of glycaemic control. Dietary intake was assessed using a food frequency questionnaire which had been validated previously by using plasma phospholipid fatty acids as a reference. Over a mean follow-up of 4.8 years, 208 subjects (8.7%) experienced a fatal or non-fatal AMI. The incidence of AMI was about 2-fold higher in diabetic patients (n=317) compared with non-diabetic patients (n=1,012) or those with pre-diabetes (n=1,049): 13.6% versus 7.6% or 8.4%, respectively. In diabetic patients, a high intake of n-3 long-chain polyunsaturated fatty acids was associated with reduced risk of AMI (hazard ratio 0.38, 95%CI 0.18, 0.80), whereas there was an increased risk in patients without diabetes (hazard ratio 1.45, 95%CI 0.84, 2.53). The authors concluded that patients with diabetes and coronary artery disease may benefit from a high intake of n-3 long-chain polyunsaturated fatty acids, whereas caution is advised in patients with normal glucose tolerance.

Insulin resistance is characterised by elevated levels of triglyceride-rich lipoproteins (TRLs), of both hepatic and intestinal origin. However, the mechanism(s) underlying the accumulation of intestinal apolipoprotein (apo) B-48-containing TRLs in insulin resistance are uncertain. This study investigated the relationships between apoB-48-containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipoprotein metabolism in insulin resistance. The study included 14 obese men with insulin resistance (plasma triglycerides >1.5 mmol/L or 133 mg/dL) and 10 insulin-sensitive men matched for waist circumference and with triglycerides <1.5 mmol/L. Compared with insulin-sensitive subjects, TRL apoB-48 pool size and production rate were significantly higher (by 102%, p<0.0001 and 87%, p=0.01, respectively) in subjects with insulin resistance. There was also evidence that key genes involved in intestinal lipid and lipoprotein metabolism (sterol-regulatory-element-binding protein-2, hepatocyte nuclear factor 4a, and microsomal triglyceride transfer protein) were down-regulated in subjects with insulin resistance. Whether intestinal gene down regulation is related to relative hyperinsulinism and/or adaptive responses to chronic exposure to high levels of circulating free fatty acids and insulin merits further study.

There is extensive evidence from population studies that there is an inverse relationship between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) risk irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising plasma levels of HDL-C through lifestyle modification and pharmacologic intervention would reduce the risk of CVD, supported by studies in animal models, as well as post hoc analyses from randomized controlled trials. However, recent studies that were designed to test the "HDL hypothesis" have failed to show benefit, leading many to question whether HDL-C is a legitimate therapeutic target. This Consensus Statement from an expert panel convened by the National Lipid Association reviewed the current state of knowledge of HDL particle structure, composition, and function; and identified pertinent questions relating to the role of HDL in either preventing or contributing to atherosclerotic disease. The Panel concluded that while low HDL-C identifies patients at elevated risk, HDL-C is not a therapeutic target at the present time. Risk-stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non-HDL-C) should remain the primary and secondary targets of lipid-altering therapy in patients at risk, as described by established guidelines.

Current international guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) as a secondary target, especially in individuals with atherogenic dyslipidaemia, characterised by elevated triglyceride-rich remnant lipoproteins, and often associated with insulin-resistant conditions. These triglyceride-rich lipoproteins include very-low density lipoproteins and their remnants, intermediate-density lipoproteins, and chylomicron remnant particles whose combined contribution to atherogenic risk is accounted for by measurement of non-HDL-C rather than low-density lipoprotein cholesterol (LDL-C). Recommended non-HDL-C cut points are 30 mg/dL higher than those for LDL-C. This study evaluated whether there is patient-level discordance between non-HDL-C and LDL-C percentiles at different LDL-C and triglyceride levels. Population percentiles for non-HDL-C and Friedewald-estimated LDL-C values were assigned for 1,310,440 US adults (mean age 59 years, 52% female) with triglycerides <400 mg/dL (4.5 mmol/L). LDL-C cutpoints of 70, 100, 130, 160, and 190 mg/dL (1.8, 2.6, 3.4, 4.1 and 4.9 mmol/L) were at the same population percentiles as non-HDL-C values of 93, 125, 157, 190, and 223 mg/dL (2.4, 3.2, 4.1, 4.9 and 5.8 mmol/L), respectively. The study highlighted a high level of patient-level disconcordance between non-HDL-C and LDL-C percentiles, especially among patients with low LDL-C and hypertriglyceridemia. The use of non-HDL C reclassified a significant proportion of patients in a higher risk category compared with LDL-C, especially at LDL-C levels in the treatment range for high-risk patients with triglycerides =150 mg/dL. Of patients with LDL-C < 70 mg/dL (1.8 mmol/L), 15% were discordant with a non-HDL-C = 100 mg/dL (2.6 mmol/L, guideline-based cut point) and 25% had a non-HDL-C = 93 mg/dL (2.4 mmol/L, percentile-based cutpoint); if patients also had moderately elevated fasting triglycerides in the range 150-199 mg/dL (1.7-2.3 mmol/L), discordance rates were higher, at 22% and 50%, respectively. These findings have implications for residual risk assessment and management.

Inflammation plays a key role in the development and progression of atherosclerosis. In a pre-specified post hoc analysis of the SATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) study, on-treatment C-reactive protein (CRP) levels were associated with residual risk for major adverse cardiovascular events (MACE) among patients with well controlled LDL-C levels (mean 65.9 mg/dL or 2.7 mmol/L) on potent statin therapy (Hazard ratio 1.28, 95% CI 1.04, 1.56, p=0.02). In addition, there was an incremental association between on-treatment CRP levels and time to first MACE. Multivariable analysis showed that for subjects for whom CRP levels did not increase on statin treatment, there was greater atheroma regression (percent atheroma volume, p=0.01). In contrast, there was no association between on-treatment LDL-C levels and MACE (HR 1.09, 95% CI 0.88, 1.35, p=0.45). These data highlight systemic subclinical inflammation as an important prognostic biomarker and potentially a driver of residual cardiovascular risk in patients with coronary artery disease treated with aggressive statin therapy.

Further analysis of AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) study implicate lipoprotein(a) [Lp(a)] as a contributor to residual cardiovascular risk. Both baseline and on-study Lp(a) were predictive of cardiovascular events in the simvastatin+placebo (baseline hazard ratio [HR]= 1.24, p=0.002 and on-study HR=1.21, p=0.017) and the simvastatin+niacin treatment groups (baseline HR=1.25, p=0.001 and on-study HR=1.18 p=0.028). However, baseline apolipoprotein (apo) B100 (apoB) and the ratio of apoB/apoA-I were only predictive of cardiovascular events in the simvastatin+placebo group (HR=1.17, p=0.018 and HR=1.19, p=0.016). These data suggest a role for Lp(a) as a modifiable contributor to residual cardiovascular risk in patients in the AIM-HIGH study.

Recent findings from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study indicate the limitations of low plasma HDL-C as a risk marker in patients with coronary artery disease (CAD). The authors analysed data from 3,141 subjects (70% male, mean age 62.6 years, mean baseline HDL-C concentration 38.9 mg/dL [1.01 mmol/L]). In this cohort, 699 subjects did not have coronary artery disease (CAD), 1,515 had stable CAD and 927 had unstable CAD. Over a median follow-up period of 9.9 years (interquartile range 8.7-10.7 years), there were 590 deaths due to cardiovascular disease. Overall, there was a significant inverse association between plasma HDL-C concentration and cardiovascular mortality (p=0.009), consistent with previous findings. However, when the data were re-analysed according to the presence of CAD at baseline, this association was weakened in patients with stable or unstable CAD. The authors confirmed their findings in a meta-analysis of the LURIC, AtheroGene and ESTHER cohorts (n=12,292).

The International Atherosclerosis Society (IAS) has updated recommendations for the management of high cholesterol and dyslipidaemia with the aim of reducing the risk for atherosclerotic cardiovascular disease. While recognising that low-density lipoprotein cholesterol (LDL-C) is the major target of lipid-modifying therapy, the IAS also highlights the importance of very low-density lipoprotein cholesterol (VLDL-C), especially in individuals with hypertriglycaeridemia. Non-high density lipoprotein cholesterol (non-HDL-C), the sum of LDL-C and VLDL-C which includes cholesterol in all atherogenic lipoproteins, is an alternative to LDL-C as a target of therapy. Non-HDL-C is also more reflective of atherogenicity in persons with elevated triglycerides. Consequently, the IAS favours adoption of non-HDL-C as the major target of lipid-lowering therapy.

Lifestyle interventions underpin diabetes management. In particular, weight loss improves insulin resistance and glycaemic control, which may reduce the need for anti-diabetic therapy in some patients. The current retrospective cohort study suggests that the baseline triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio may be useful in predicting success in reducing anti-diabetic medication use via weight loss. Case records of 121 overweight and obese subjects attending two outpatient weight management centres were analysed. The weight loss intervention consisted of a calorie-restricted diet (~1000 Kcal/day deficit), a behaviour modification plan, and a plan for increasing physical activity. Patients were followed for a mean of 12.5 ± 3.5 months. At the end of follow-up, mean weight loss was 15.4 ± 5.5 kg and mean reduction in HbA1c was 0.5 ± 0.2%. Overall, 81 (67%) patients in the study cohort achieved at least one dose reduction of any anti-diabetic medication. A baseline TG/HDL-C ratio = 3 was shown to be a predictor of successful dose reductions of anti-diabetic medications (81% sensitivity and 83% specificity, 90% positive predictive value), with acceptable reproducibility. The investigators concluded that the TG/HDL-C ratio may be useful as a predictive tool for reducing antidiabetic medication with weight loss and merits further study.

Robust evidence supports the association between low plasma concentration of high-density lipoprotein (HDL)-cholesterol and increased coronary risk, and provides a firm basis for inclusion of HDL cholesterol in risk assessment scores (PROCAM and SCORE). However, recent clinical-trials investigating agents that target HDL cholesterol, including the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib and dalcetrapib, and niacin, failed to show significant reduction in cardiovascular events in high risk patients with coronary-disease. This state-of-the-art review discusses experimental and translational evidence for several potential anti-atherogenic effects of HDL, including preventive effects on LDL oxidation and its adverse endothelial effects, as well as stimulation of endothelial cell production of nitric-oxide, anti-inflammatory, anti-apoptotic, anti-thrombotic effects, and endothelial-repair processes. These vasoprotective effects of HDL are not only highly heterogenous but appear to be altered in patients with coronary disease, leading to the concept that HDL may become ‘dysfunctional’ in different pathophysiological states. The authors highlight the need for greater understanding of the mechanisms of action of HDL and how these are altered in different disease states. Targeting HDL-mediated anti-atherogenic mechanisms, rather than HDL cholesterol levels, may be a more valid approach. However, this requires appropriate validation in both general and at-risk populations before application becomes a possibility.

The ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaque is thought to underlie the inverse correlation between HDL cholesterol and cardiovascular risk. Infusion of CSL112, a reconstituted apolipoprotein AI formulation, into rabbits caused a strong and immediate increase in the ABCA1-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent cholesterol esterification. In human plasma, CSL112 increased cholesterol efflux from macrophages to a greater extent than native HDL, predominantly via the ABCA1 transporter. Addition of CSL112 to plasma increased the level of very small HDL, a favourable substrate for ABCA1. As preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal, CSL112 may represent a promising candidate for the management of acute coronary syndrome, in addition to current standards of care.

Human immunodeficiency virus (HIV) is associated with increased aortic stiffness and metabolic syndrome phenotype in Caucasian patients. This study also shows an increased burden and severity of metabolic syndrome and arterial stiffness in treatment-naïve HIV patients in Cameroon. The study compared age-matched healthy subjects (controls, n=96) and untreated HIV-positive patients (HIV+, n=108). Variables evaluated included lipids, pulse wave velocity, aortic augmentation index and brachial blood pressure. The prevalence and severity of metabolic syndrome was based on the American Heart Association/National Heart, Lung, and Blood Institute score =3.5 of the following: impaired fasting glucose or diabetes; hypertension; enlarged waist; elevated fasting triglycerides (TGs); decreased high-density lipoprotein cholesterol (HDL-C). Fasting TGs, the atherogenic dyslipidemia ratio [log(TGs)/HDL-C] and the prevalence of metabolic syndrome (47% versus 21%) were all higher in HIV+ patients than controls (p<0.05). Compared with controls, age- and sex-adjusted pulse wave velocity was higher (p = 0.02) and the aortic augmentation index was significantly lower (p = 0.01) in HIV+ patients. Thus, consistent with findings in Caucasians, this study shows an increase in metabolic syndrome, an early marker of atherosclerosis in African HIV patients.

Recent findings from the Jackson Heart Study shed new light onto the development of metabolic syndrome in African Americans. In a cohort of the study (n=3,019, mean age, 54 years; 64% women) the association between a biomarker panel (including high-sensitivity C-reactive protein [CRP], leptin, B-natriuretic peptide [BNP], cortisol, aldosterone, endothelin and homocysteine) to the development of metabolic syndrome was investigated. In total, 278 (22.9%) of 1,215 participants without metabolic syndrome at baseline developed the syndrome at follow-up. Development of metabolic syndrome was significantly associated with serum aldosterone (p = 0.004), CRP (p = 0.03), and BNP (p for trend = 0.005). Aldosterone was positively associated with change in all metabolic syndrome risk components, except low high-density lipoprotein (HDL) cholesterol and waist circumference. CRP was directly associated with systolic blood pressure and waist circumference and inversely associated with HDL cholesterol. However, for BNP, there was a U-shape relationship with systolic blood pressure and triglycerides. The authors concluded that this association for BNP and metabolic syndrome components warrants further study.

New guidelines for the diagnosis and prevention of cardiovascular disease were recently published on-line. While identifying low-density lipoprotein cholesterol (LDL-C) as the main priority for lipid management, the guidelines also highlight the relevance of a low plasma concentration of high-density lipoprotein cholesterol (HDL-C) and/or elevated triglycerides – atherogenic dyslipidemia - to cardiovascular risk. Treatment targets for HDL-C are =40 mg/dL and for triglycerides are <150 mg/dL.

Evidence from the Health Professionals Follow-up Study links lower adiponectin levels with increased risk of symptomatic lower extremity peripheral artery disease (PAD). This was a prospective, nested case-control study among 18,225 male participants who were free of diagnosed cardiovascular disease at the time of blood sampling (1993-1995). Over the 14-year follow-up period, 143 men developed PAD. Controls were selected in a 3:1 ratio and matched on age, smoking status, fasting status, and date of blood sampling (n=429). At baseline, median (interquartile range) adiponectin concentrations were lower among cases compared with controls (4.1 [3.2-5.5] versus 5.4 [3.8-7.5] µg/mL; p<0.001). After controlling for baseline cardiovascular risk factors, a log-linear inverse association with PAD risk was observed across the range of adiponectin concentrations. For each 1 SD increase in natural log-transformed adiponectin there was a 42% lower risk of PAD (relative risk, 0.58; 95% confidence interval, 0.45-0.74) after adjustment for cardiovascular risk factors. Adjustment for high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C reactive protein, and cystatin C attenuated this risk (relative risk, 0.68; 95% confidence interval, 0.51-0.92), although further adjustment for haemoglobin A1c, triglycerides, and gamma-glutamyltransferase had little impact (relative risk, 0.68; 95% confidence interval, 0.50-0.92). These findings build on other evidence linking low adiponectin levels with increased cardiovascular risk.

Obstructive sleep apnoea (OSA) is an underdiagnosed condition characterised by recurrent episodes of obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia during sleep. This review highlights evidence that OSA exacerbates cardiometabolic risk attributed to obesity and the metabolic syndrome, supported by experimental and clinical evidence. In patients with metabolic syndrome, OSA is independently associated with increased glucose and triglycerides levels, as well as markers of inflammation, arterial stiffness and atherosclerosis. In addition, recent studies showed a marked increase in atherogenic dyslipidemia indices (including HDL-C; apoA-I and log(TG)/HDL-C ratio] together with inflammation, worsening beta-cell function, poorer glycemic control and coronary artery disease risk in individuals with type 2 diabetes and OSA versus those without OSA.1,2
Thus, emerging evidence implicates OSA with an increase in residual vascular risk for microvascular and macrovascular events in type 2 diabetes. Thus, treating OSA is an additional intervention to be considered for reducing residual risk in obese patients.
 
References
1. Hermans MP, Ahn SA, Rousseau MF. Micro- and macrovascular risk and complications in T2DM males with obstructive sleep apnoea. J Clin Metab Diab 2011;2:64-70.
2. Hermans MP, Ahn SA, Mahadeb YP, Rousseau MF. Sleep apnoea syndrome and 10-year cardiovascular risk in females with type 2 diabetes: relationship with insulin secretion and insulin resistance. Diabetes Metab Res Rev 2013;29:227-34.

This review highlights the central role of peroxisome proliferator-activated receptor (PPAR) agonists in the management of residual vascular risk, especially in people with cardiometabolic disease such as type 2 diabetes. However, the available PPARa-agonists have limited efficacy due to dose-related adverse effects. This review makes the case for a new generation of highly potent and selective PPARa-modulators (SPPARMa) that separate the benefits of the PPARa-agonists from their unwanted side effects. The highly-potent, specific PPARa-agonist (K-877) has emerged as the first SPPARMa. Compared with fenofibrate, K-877 has more potent PPARa-activating efficacy in vitro, improved efficacy in lowering triglycerides and raising high-density lipoprotein cholesterol, and a reduced risk of adverse effects. The review concludes that K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual cardiovascular risk associated with metabolic syndrome and type 2 diabetes.

In this report, structural modeling was used to test a hypothesized model of causal pathways related with prediabetes among older adults in the U.S. The analysis was based on data from 2,230 adults (=50 years) without diabetes included in the morning fasting sample of the 2001–2006 National Health and Nutrition Examination Surveys. Demographic data included age, income, marital status, race/ethnicity, and education. Behavioural data included physical activity (metabolic equivalent hours per week for vigorous, moderate, muscle-strengthening, walking/biking, and house/yard work), and poor diet (refined grains, red meat, added sugars, solid fats, and high-fat dairy). Modeling was used to examine the interrelationships among these variables with family history of diabetes, high blood pressure, body mass index, large waist (waist circumference: women, =35 inches; men, =40 inches), triglycerides =200 mg/dL, and total- and high-density lipoprotein (HDL) (=60 mg/dL) cholesterol. Large waist circumference had the strongest direct effect on prediabetes. Physical activity had direct effects on cardiometabolic risk factors including HDL-cholesterol, triglycerides, and high blood pressure.

Patients with end-stage renal disease (ESRD) are at increased risk of atherosclerosis and cardiovascular morbidity and mortality. The atherogenicity associated with ESRD is driven by inflammation, oxidative stress, and dyslipidemia. Notably, low plasma levels of high-density lipoprotein cholesterol (HDL-C) and HDL dysfunction are the hallmarks of ESRD-related dyslipidemia. Clinical and laboratory studies show that ESRD is associated with significantly reduced apolipoprotein A-I and HDL-C levels, as well as changes in HDL composition. While ESRD is generally associated with reduced HDL functionality (affecting antioxidant and anti-inflammatory properties), in a small proportion of patients HDL may be dysfunctional (pro-oxidant and proinflammatory effects). These findings reinforce the view that standard measurement of plasma HDL-C level is not a dependable indicator of cardiovascular disease burden in ESRD. Moreover, the authors highlight the need for routine markers of HDL function to accurately identify patients with ESRD at risk for cardiovascular disease.

Escalation in childhood obesity has led to an increase in the prevalence of combined dyslipidemia, characterized by elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C), with normal or mildly-elevated levels of low-density lipoprotein cholesterol (LDL-C). Despite recent National Heart, Lung and Blood Institute (NHLBI) guidelines for the management of primary dyslipidemias in pediatric patients, there is still no general consensus regarding pharmacologic treatment of obesity-related lipid abnormalities in children. Diet and lifestyle modification remain the first line therapy. However, given the challenges of instituting and maintaining lifestyle modification in pediatric patients, it is likely that drug therapy may be also required in many children. Of treatment options currently available, the fibric acid derivatives have a cholesterol lowering profile that is most likely to be effective in obese children with the atherogenic dyslipidemic phenotype of high triglycerides/low HDL-C. However, additional information regarding the short and long-term safety and lipid-lowering vs. reducing hard CV endpoint efficacy of fibrate therapy in children with obesity-related lipid disorders is needed before wider use of these agents can be recommended.

The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. This study evaluated the role of apolipoproteins (apo) E and AV in the clearance of TRL in experimental models. ApoE was shown to be a major determinant of TRL clearance, as indicated by TRL enrichment in apoE deficient mice, decreased binding of apoE-deficient TRLs to HSPGs on human hepatoma cells in vitro, and decreased clearance of apoE-deficient [3H]TRLs in vivo. ApoAV emerged as a candidate based on 6-fold enrichment of apoAV in TRLs accumulating in Ndst1f/fAlbCre+ mice, decreased binding of TRLs to proteoglycans after depletion of apoAV or addition of anti-apoAV monoclonal antibody, and decreased heparan sulfate-dependent binding of apoAV-deficient particles to hepatocytes. Furthermore, disruption of hepatic heparan sulfate-mediated clearance increased atherosclerosis. The authors concluded that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.

This report from the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial evaluated whether physical activity (varying in intensity and frequency) influenced vascular outcomes in 11,140 patients. Physical activity was categorized as none, mild, moderate or vigorous, and the frequency of activity was categorised by the number of sessions in a week. In total 46% of patients reported moderate to vigorous physical activity for >15 minutes at least once in the previous week. The study end points were major cardiovascular events, microvascular complications and all-cause mortality. Over a median of 5 years of follow up, 1,031 patients died, 1,147 experienced a major cardiovascular event and 1,136 a microvascular event. Compared with patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a reduced risk of cardiovascular events (hazard ratio [HR] 0.78, 95% CI 0.69-0.88, p<0.0001), microvascular events (HR 0.85, 95% CI 0.76-0.96, p0.010) and all-cause mortality (HR 0.83, 95% CI 0.73-0.94, p0.0044). The authors concluded that moderate to vigorous leisure-time physical activity is associated with reduced vascular morbidity and mortality in patients with type 2 diabetes.

There is a general perception that atherosclerosis is related to modern lifestyle and was therefore not present in ancient populations. However, data from a study reported in The Lancet refutes this and raises the possibility of a more basic predisposition to the disease. Whole-body computed tomography scans of 137 mummies from four different regions or populations of various socioeconomic strata and spanning more than 4,000 years - ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America, and the Unangan of the Aleutian Islands - were imaged. Atherosclerosis was considered definite if a calcified plaque was seen in the wall of an artery, and probable if calcifications were seen along the expected anatomical course of an artery. Probable or definite atherosclerosis was noted in 47 (34%) of 137 mummies and in all four geographical populations. Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one or two beds in 34 (25%) mummies, in three or four beds in 11 (8%), and in all five vascular beds in two (1%). Age at the time of death was positively correlated with atherosclerosis (mean 43 [SD 10] years for mummies with atherosclerosis vs. 32 [15] years for those without; p<0·0001) and with the number of arterial beds involved (mean age was 32 [SD 15] years for mummies with no atherosclerosis, 42 [10] years for those with atherosclerosis in one or two beds, and 44 [8] years for those with atherosclerosis in three to five beds; p<0·0001). The authors concluded that their findings indicate that atherosclerosis is an inherent component of human ageing and not characteristic of any specific socioeconomic status, diet or lifestyle.

A new analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has reports a significant inverse relationship between baseline bilirubin levels and incident total lower-limb amputation, suggesting that a higher bilirubin level may be associated with protection against amputation. Bilirubin is known to exhibit antioxidant and anti-inflammatory properties. Indeed, previous studies have shown that higher bilirubin levels were associated with reduced prevalence of peripheral arterial disease. This pre-specified analysis investigated the relationship between baseline plasma total bilirubin levels and amputation events in the FIELD study population (n=9,795). Lower-limb amputation was adjudicated blinded to treatment allocation. The analysis showed a significant inverse association between plasma bilirubin concentrations and lower-limb amputation. Patients with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 µmol/l decrease in bilirubin concentration, 95% CI 1.07 to 1.79, p=0.013). This association was still evident after adjustment for demographic variables, smoking status, y-glutamyltransferase level, HbA1c, study treatment allocation and previous cardiovascular disease (including peripheral arterial disease), amputation or diabetic skin ulcer, as well as microvascular complications (neuropathy, nephropathy and diabetic retinopathy). In summary, these findings implicate total bilirubin as a protective factor/marker for amputation in type 2 diabetes.

Peroxisome proliferator-activated receptor (PPAR) agonists have been shown to have favourable effects on plasma lipoprotein levels, inflammation, and insulin resistance, all of which influence the risk of cardiovascular disease. The mechanisms underlying these effects include PPAR-alpha activation in the enterocyte influencing high-density lipoprotein (HDL) and chylomicron formation; direct effects by PPAR-y agonists on adipocytes and regulatory T cells within visceral adipose; and inhibition by PPAR-d agonists of foam cell formation induced by excessive levels of VLDL remnants. Thus, agonists (either single or dual) of PPAR-alpha, PPAR-y, and PPAR-d have the potential to reduce cardiovascular risk via multiple independent and additive mechanisms, and reduce the burden of atherogenic postprandial lipoproteins, which would be expected to have favourable effects on cardiovascular risk. Consequently, research is focused on the development of compounds that maximize these potential cardiovascular benefits while minimizing any undesirable effects.

Data from the Insulin Resistance Atherosclerosis Study show that alanine aminotransferase (ALT) is associated with a wide range of atherogenic lipoprotein changes, at least partly associated with insulin resistance, adiposity, glucose tolerance status and chronic inflammation. This analysis included 824 subjects without diabetes (aged 40–69 years) none of whom reported excessive alcohol intake or were treated with lipid-lowering medications. Lipoproteins and apolipoproteins were measured by conventional methods and nuclear magnetic resonance (NMR) spectroscopy was used to assess lipoprotein heterogeneity. The study showed that ALT had a positive relationship with triacylglycerols, the ratio of low-density lipoprotein:high-density lipoprotein (LDL:HDL) cholesterol and apolipoprotein B (apoB). NMR spectroscopy also identified positive associations between ALT and large very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and small LDL subclass particles, as well as VLDL particle size (all p <0.001). There were also negative associations between ALT and large LDL subclass particles (p <0.05) and HDL particle sizes (p <0.01). The associations with IDL, small LDL subclass particles and apoB persisted after adjustment for glucose tolerance status, adiposity, insulin sensitivity and C-reactive protein. Further study to confirm these associations is merited.

A recent study has investigated the role of WNT1 inducible signalling pathway protein 2 (WISP2), a novel adipokine, highly expressed and secreted by adipose precursor cells, in obesity and the metabolic syndrome. Increased expression of WISP2 and other markers of WNT activation in human abdominal subcutaneous adipose tissue, but not in visceral fat, identified the metabolic syndrome in obese individuals. WISP2 appears to form a cytosolic complex with the peroxisome proliferator-activated receptor y (PPARy) transcriptional activator zinc finger protein 423 (Zfp423). This complex is dissociated by bone morphogenetic protein 4 (BMP4), thereby allowing Zfp423 to enter the nucleus, activate PPARy, and with resultant allocation of precursor cells to the adipose lineage. Secreted Wnt/Wisp2 also inhibits differentiation and PPARy activation, albeit not through Zfp423 nuclear translocation. In summary, these results indicate that adipogenic commitment and differentiation is regulated by the cross-talk between BMP4 and WNT signalling, in which WISP2 has a crucial role, thus linking WISP2 with obesity and the metabolic syndrome.

Results from a twins study showed that individuals who were persistently physically active had a more favourable metabolome, indicative of improved metabolic health, than those who were inactive. This study included 16 same-sex twin pairs (mean age, 60 years) who were selected from a cohort of twin pairs based on >30-year discordance for leisure-time physical activity. Persistently (=5 years) active and inactive groups in three population-based cohorts (mean ages, 31-52 years) were also studied (1037 age- and sex-matched pairs). Nuclear magnetic resonance spectroscopy was used to quantify the serum metabolome. Persistent physical activity was associated with an improved metabolic profile in twins (p=0.003), with similar findings reported in the population cohorts. There were favourable changes in serum fatty acid composition (with a shift to a less saturated profile, p<0.001) and lipoprotein subclasses (decrease in very low-density lipoprotein particles, and increase in large and very large high-density lipoprotein particles, p<0.001). These findings were not attenuated after adjustment for body mass index. In summary, the results of this study provide further support for the importance of regular physical activity in improving metabolic health.

Statin therapy has been shown to reduce the risk of major cardiovascular events in patients with chronic kidney disease. However, there are also questions whether high-doses of potent statins are associated with acute renal dysfunction. This retrospective observational analysis evaluated the effects of high-potency versus low-potency statins, relying upon data from nine population-based cohort studies and meta-analyses in Canada and the UK (n=2,067,639 patients aged 40 years or older, newly-treated with statins between 1 January 1997 and 30 April 2008). High-potency statin treatment was defined as =10 mg rosuvastatin, =20 mg atorvastatin, and =40 mg simvastatin; all other statins treatments were defined as low-potency. Statins potency groups were further divided into cohorts with or without chronic kidney disease (CKD). The main outcome was relative hospitalization rates for acute kidney injury. Within 120 days of starting treatment, there were 4,691 hospitalizations for acute kidney injury in patients with non-CKD, and 1,896 hospitalizations in those with CKD. In patients with non-CKD, current users of high-potency statins were 34% (95% CI 25-43) more likely to be hospitalized with acute kidney injury. However, in patients with CKD, there was a 10% (95% CI 1-23) increase in admission rate. The authors concluded that use of high-potency statins was associated with an increased rate of diagnosis for acute kidney injury, during the first 4 months of treatment. Thus while statins are the cornerstone of dyslipidemia management, intensive high-dose statin therapy is not without risk. Add-on or combination therapy may be an alternative approach with safety advantages, as well as improving global lipid control.

Investigators from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based prospective cohort study in adults free of clinical cardiovascular disease at baseline, tested for a relationship between non-alcoholic fatty liver disease (NAFLD) and serum lipoprotein size, cholesterol and particle concentrations. NAFLD was considered in the presence of a liver/spleen (L/S) attenuation ratio of <1 on a non-contrast cardiac CT scan, which was present in 17% (569/3362) of subjects. After adjustment for multiple metabolic risk factors, adiposity and measures of insulin resistance, CT-defined NAFLD was independently associated with elevated fasting serum triglycerides and low serum high-density lipoprotein concentration, as well as higher low-density lipoprotein (LDL) particle concentration and lower LDL size. There was no association with LDL cholesterol. With the L/S ratio as a continuous variable, there was a severity-dependent association between atherogenic lipoprotein abnormalities and CT-defined NAFLD. In conclusion, these findings suggest a pathophysiological link between CT-defined NAFLD and atherogenic dyslipidemia.

In this multicentre, double-blind, randomized study, 213 patients with type 2 diabetes (HbA1c 6-8%) were randomly allocated to treatment with pioglitazone (n=110) or placebo (n=103), in addition to metformin. Key variables were serum high-density lipoprotein cholesterol (HDL-C) concentration and changes in metabolic syndrome-specific parameters, evaluated from global changes in the independent components and expressed as a single factorial score. Patients in the pioglitazone group had a significant increase in HDL-C versus placebo (6.3 mg/dL vs. 3.0 mg/dL; p<0.01), as well as greater reduction in the extent of metabolic syndrome (- 13.2 vs. -4.9; p=0.006). At study completion, patients treated with pioglitazone also had lower levels of HbA1c (6.41±0.65 vs. 6.96±0.74%; p<0.001), reduction in insulin resistance (HOMA-IR 2.88±1.95 vs. 4.68±3.63; p=0.013) and a decrease in small, dense LDL (by 5.7%). The authors concluded that these beneficial effects of pioglitazone support this glucose-lowering treatment as an option to reduce metabolic risk in patients with type 2 diabetes and metabolic syndrome.

Despite marked predisposition to dyslipidemia and coronary heart disease, there is little understanding of the genetics of lipids in Mexican populations. The authors report a two-stage genome wide association study (GWAS) for atherogenic dyslipidemia, hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) concentration, in 4,361 Mexicans. The study identified a novel Mexican-specific genome-wide significant locus for serum triglycerides near the Niemann-Pick type C1 protein gene (p=2.43×10-08). Furthermore, three European loci for triglycerides (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in this group. Functional analysis showed a direct link between an APOA5 variant (rs964184) and postprandial serum apolipoprotein A-V protein levels, supporting rs964184 as the causative variant in both European and Mexican populations. Although about one-half of the 100 reported associations from European lipid GWAS meta-analysis were also generalised to Mexicans, in 82 of these 100 European loci, a different variant had the strongest regional evidence of association in Mexicans. Thus, results from European GWAS of known lipid loci may not necessarily extend to the Mexican population, highlighting the need for further regional ethnic-specific studies.

A recent study highlights an association between obstructive sleep apnoea syndrome (OSAS), atherogenic dyslipidemia and cardiovascular risk in women with type 2 diabetes. The current study included 305 patients (mean age 66 years, mean diabetes duration 15 years, 86% with metabolic syndrome); 25 with and 280 without OSAS. The presence of OSAS was diagnosed by anamnesis, Epworths score, oximetry and polysomnography. There were no differences in age, diabetes duration, education, smoking, and blood pressure between the two groups. Patients with OSAS had significantly higher BMI, waist, relative/absolute fat, and visceral fat (all p<0.0001) and lower skeletal muscle (p 0.0008). These individuals were also more insulin resistant, had lesser residual insulin secretion, increased hyperbolic product loss and poorer glycaemic control (HbA1c 69 vs. 62 mmol/L in those without OSAS, p 0.0099). All components of atherogenic dyslipidemia and inflammatory markers were worse with OSAS, and these patients also had a higher UKPDS risk score for coronary artery disease. In conclusion, the study adds to previous findings linking OSAS, a frequent comorbidity in type 2 diabetes, with central fat, atherogenic dyslipidemia, inflammation, worsening ß-cell function, poorer glycaemic control and CAD risk. This suggests that OSAS may increase residual vascular risk in women with type 2 diabetes.

This review highlights a potential role for novel lipid-modifying treatments, including drugs targeting PCSK9, apolipoprotein B100 antisense oligonucleotides and microsomal transfer protein inhibitors, for reducing residual cardiovascular risk in statin-treated patients. It is well recognised that despite optimal therapy, many patients do not achieve cholesterol treatment goals and remain at a significantly increased risk of cardiovascular events. There is therefore a critical need for additional lipid therapies that could augment the ability of statins to lower the burden of atherogenic lipoproteins, as well as manage atherogenic dyslipidemia. Although statin therapy is the primary treatment for dyslipidemia, emerging novel agents may become adjuvant therapies in the treatment of atherosclerotic cardiovascular disease.

Visceral adipose tissue (VAT) and liver fat are strongly associated with type 2 diabetes. This cross-sectional analysis investigated the level of VAT and liver fat in 3,984 patients enrolled in the INSPIRE ME IAA study, based on their treatment status and achievement of the American Diabetes Association (ADA) diabetes management goals. Patients were divided into four groups according to baseline status: 1) those without type 2 diabetes (1,003 men and 1,027 women); 2) those with type 2 diabetes but not treated with diabetes medications (248 men and 191 women); 3) those with type 2 diabetes and treated with oral glucose-lowering drug(s) (591 men and 484 women); and 4) those with type 2 diabetes and treated with insulin (233 men and 207 women). Abdominal and liver adiposity were measured by computed tomography. Fewer patients with high VAT or liver fat achieved the ADA goals for high-density lipoprotein cholesterol (HDL-C) or fasting triglycerides compared with those with low VAT or liver fat. The findings show that lipid-related, non-LDL residual cardiovascular risk exists in type 2 diabetes patients with elevated visceral adipose tissue and liver fat.

Data from a population longitudinal prospective observational study show that an elevated ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) was as effective as the presence of the metabolic syndrome in predicting the development of cardiovascular disease (CVD). Investigators surveyed a random sample from this study in 2003 (n=926) and 2012 (n=796, 527 women and 269 men) for new CVD events. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points (2.5 mg/dL and 3.5 mg/dL for low and high risk), and with or without metabolic syndrome, were estimated using Cox proportional hazard ratio. A similar number of subjects were considered at "high" CVD risk based on an elevated TG/HDL-C ratio (30%) or the presence of the metabolic syndrome (35%). The hazard risk, adjusted for age and sex, was higher for "high" vs. "low" risk groups, irrespective of whether risk was based on the presence of the metabolic syndrome (hazard ratio 2.09, 95% CI 1.18-3.72) or an elevated TG/HDL-C ratio ( hazard ratio 2.01, 95% CI 1.14-3.50). These findings reaffirm the relevance of an elevated TG/HDLC- ratio as a predictor for increased risk of CVD.

This post hoc analysis evaluated achievement of lipid targets or desirable levels of lipids/lipoproteins after 12-weeks treatment in 2,066 patients with mixed dyslipidemia. Patients were randomized to fenofibric acid 135 mg, rosuvastatin (5, 10, or 20 mg), or the combination. Data were pooled across doses. Combination treatment or rosuvastatin alone had a similar effect on achievement of risk-stratified LDL-C targets. However, the combination was superior to statin for achievement of goals related to measures of total atherogenic burden, with significantly superior achievement of non-HDL-C and apolipoprotein B targets. Additionally, more patients achieved desirable levels of triglycerides (<150 mg/dL) and HDL-C (>40 mg/dL in men and >50 mg/dL in women), with the combination treatment than statin monotherapy (p<0.001 for each analysis). Combination treatment with fenofibric acid plus rosuvastatin provided better comprehensive lipid control than rosuvastatin monotherapy across the spectrum of cardiovascular risk.

Data from the Framingham Heart Study Offspring cohort provides further support for the importance of targeting risk factors early to reduce the lifetime burden of cardiometabolic risk. This study included subjects free from cardiovascular disease (CVD) and diabetes (fasting plasma glucose =126 mg/dL or treatment) at baseline who were followed-up between 1979 and 2008. CVD risk factors (hypertension, high low-density lipoprotein cholesterol [LDL-C], low high-density lipoprotein cholesterol [HDL-C], high triglycerides, obesity) were measured at the time of diabetes diagnosis and at 10, 20, and 30 years beforehand. In total, 525 participants with new-onset diabetes were identified and matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who developed diabetes had a higher prevalence of hypertension (odds ratio [OR], 2.2; p = 0.003), high LDL-C (OR, 1.5; p = 0.04), low HDL-C (OR, 2.1; p = 0.0001), elevated triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P<0.0001) 30 years before diagnosis. The findings from this study highlight the importance of a proactive approach to reducing lifetime cardiometabolic risk

This longitudinal study based on a cohort in Northern Sweden investigated whether television (TV) viewing and low leisure-time physical activity at age 16 years was predictive of metabolic syndrome in mid-adulthood. TV viewing habits and participation in leisure-time physical activity were assessed by self-administered questionnaires. Evidence of the metabolic syndrome at age 43 years was defined using the International Diabetes Federation criteria. In 888 subjects, the overall prevalence of the metabolic syndrome at age 43 years was 26.9%. The adjusted risk of the metabolic syndrome at age 43 years was over two-fold higher (odds ratio 2.14, 95% CI 1.24–3.71) for those who reported “watching several shows a day” versus “one show/week” at age 16. Additionally those who exercised “several times/month” or less compared with “daily” leisure-time physical activity at age 16 years had an increased risk of metabolic syndrome in later life (odds ratio 2.31 95% CI 1.13-4.69). Increased TV viewing at age 16 years was associated with central obesity, low high-density lipoprotein cholesterol, and hypertension at age 43 years, and low leisure-time physical activity at age 16 years was associated with central obesity and triglycerides at age 43 years. Consistent with other studies, these data highlight the importance of regular physical activity to prevent the metabolic syndrome in later life.

Low-density lipoprotein cholesterol (LDL-C) is the primary lipid target in current guidelines. However, with the pandemic of diabetes, metabolic syndrome and obesity, the value of LDL-C as the key predictor for cardiovascular risk is questioned. Cardiometabolic disease is typically characterised by elevated triglyceride levels, low high-density lipoprotein-cholesterol (HDL-C) concentrations and increased levels of small, dense LDL. This common dyslipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins. LDL-C may be only modestly elevated. Increasing evidence suggests moving away from a LDL-C target-based approach to a more tailored treatment approach, using for example non-HDL-C as a target as this better reflects the burden of atherogenic lipoproteins.

Results of the mortality follow-up of EUROASPIRE I and II, a survey of the management of secondary prevention patients, highlight the continuing residual cardiovascular (CV) risk in coronary heart disease patients. The study cohort consisted of a consecutive sample of patients aged =70years from 12 European countries. Baseline data gathered in 1995-2000 were linked to subsequent CV mortality in 5,216 patients. During 28,143 person-years of follow-up, 332 patients died from CV disease, representing a CV mortality risk of 12.3 per 1000 person-years in men, and 10.2 per 1000 person-years in women. In multivariate analysis, fasting glucose, total cholesterol and smoking were the strongest independent modifiable predictors of CV mortality. These data highlight that management of secondary prevention patients is far from optimal. Moreover, even with best practice, there remains a high residual CV risk associated with conventional modifiable risk factors.

In the Chin-Shan Community Cardiovascular Cohort, an elevated ratio of high-density lipoprotein (HDL)-apolipoprotein (apo)CIII/very low-density lipoprotein (VLDL)-apoCIII was a better predictor of coronary artery disease (CAD) than conventional lipids or lipoproteins. This study evaluated the cross-sectional association between apo markers and CAD in 3,602 subjects from 1990 to 2001. These subjects were subcategorised as normolipidemic (total cholesterol <200 mg/dL, triglycerides <150 mg/dL); hypertriglyceridemic (total cholesterol <200 mg/dL, triglycerides =150 mg/dL); hypercholesterolemic (total cholesterol =200 mg/dL, triglycerides <150 mg/dL), and hyperlipidemic (total cholesterol =200 mg/dL, triglycerides =150 mg/dL). Patients with CAD had higher apoB and lower HDL cholesterol and apoAI concentrations than those without, although the differences were not significant in all groups. The ratio of HDL-apoCIII/ VLDL-apoCIII was the only universal determinant for CAD in all groups. In multivariate analyses, the HDL-apoCIII/VLDL-apoCIII ratio was the strongest predictor for CAD among all lipid factors investigated (odds ratio, 2.04; 95% CI 1.46--2.84; P<0.0001). These data therefore suggest that measurement of plasma apoCIII may improve CAD prediction in the general population.

Dietary intervention based on a typical Italian Mediterranean diet (IMD) promotes weight loss and improves the cardiometabolic risk profile in patients with metabolic syndrome. In this study, 80 Caucasian Italian subjects with metabolic syndrome were prescribed a balanced hypocaloric IMD. After 6 months, adherence to the IMD decreased body weight (by 10%, p <0.001), body mass index (by 9%, p <0.001) and waist circumference (by 18%, p < 0.001), with resolution of the metabolic syndrome in 52% of patients. There were also decreases in low-density lipoprotein cholesterol (from 128.7 ± 33.2 to 108.8 ± 38.6 mg/dL, p <0.001) and triglycerides (from 169.8 ± 80.8 to 131.0 ± 63.9 mg/dL, p <0.001). These data highlight the value of a hypocaloric IMD for management of cardiometabolic risk.

In a general population susceptible to metabolic syndrome, elevated apolipoprotein (apo)E concentrations are strongly linked to atherogenic dyslipidemia and elevated apolipoprotein B100 (apoB) levels, irrespective of apoE genotype, and are associated with coronary heart disease (CHD). In this cross-sectional study in 1,127 middle-aged adults, apoE concentrations showed log-linear associations with apoB and apoA-I levels, and waist circumference, independent of C-reactive protein (CRP), insulin resistance (homeostatic model assessment (HOMA) index) and other confounders. The likelihood of atherogenic dyslipidemia and of elevated apoB levels increased 3-fold per 1 standard deviation increase in apoE concentration. ApoA-I, otherwise inversely related to atherogenic dyslipidemia, appeared to promote elevated apoB concentration, suggestive of apoA-I dysfunctionality. Circulating apoE levels were predictive of prevalent and incident coronary heart disease, independent of apoE genotype and CRP (OR 1.32, 95 % CI 1.11; 1.58,). Thus, excess apoE may reflect a pro-inflammatory state and autoimmune activation.

Despite best standards of care, patients with type 2 diabetes mellitus remain at high residual risk of cardiovascular disease. Given evidence that peroxisome proliferator-activated receptor (PPAR) alpha agonists are effective in the management of atherogenic dyslipidaemia to reduce cardiovascular risk in type 2 diabetes patients, and that PPAR gamma agonists target glycaemic control and insulin resistance, dual PPAR alpha/gamma agonists may potentially offer therapeutic opportunities to lower this high residual vascular risk. This paper overviews the rationale and evidence for this strategy, including lessons learned from studies with thiazolidinediones, glitazars and investigational dual-PPAR alpha/gamma agonists. The later dual PPAR alpha/gamma agonists have been shown to produce reductions in HbA1c and fasting glucose, and improved management of atherogenic dyslipidaemia. However, data are needed from outcomes studies to evaluate whether these biochemical benefits translate into reduced cardiometabolic risk.

This study in 490 volunteers (mean age 46 years, 40% male), investigated the association between neck circumference (a surrogate measure of upper-body central adiposity), and biomarkers used to assess cardiovascular risk. Biomarkers evaluated included fasting glucose, total cholesterol, HDL-C, LDL-C, triglycerides, cystatin C, uric acid and hs CRP. Linear and logistic regression models were used to evaluate the association between neck circumference and biomarkers of cardiometabolic risk. The study showed a positive association between neck circumference and systolic and diastolic blood pressure, glucose, triglycerides, uric acid and hs-CRP, and a negative association with HDL-C. The relationship between neck circumference and HDL-C, glucose, triglycerides and uric acid remained significant after adjustment for body mass index and abnormal waist circumference, in addition to traditional cardiovascular risk factors. The findings suggest that neck circumference may have value as a simple means of identifying subjects at high risk for atherogenic dyslipidemia for further screening.

An ancillary study of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study suggests that FGF21 may be useful in assessment of fenofibrate-mediated reduction in cardiovascular risk in type 2 diabetes patients. This study included 216 patients, 108 in each group, who were randomly selected from the FIELD study cohort. Three novel biomarkers - adipocyte-fatty acid-binding protein (A-FABP), FGF21, and retinol-binding protein 4 (RBP4) – which are all downstream targets of peroxisome proliferator-activated receptor (PPAR)-apha or PPAR-gamma - were evaluated for their association with cardiovascular risk. Serum FGF21 and RBP4 levels over 5 years were significantly higher in the fenofibrate group (by 85%, p< 0.001 and 10%, p = 0.032, respectively), compared with placebo. There were no detectable effects on serum A-FABP levels. The effect of fenofibrate treatment on serum FGF21 remained significant after adjusting for fenofibrate-induced changes in glycated haemoglobin, lipids (including total cholesterol and triglycerides), fibrinogen, plasma creatinine and homocysteine. These findings suggest that FGF21 may have a potential role in modulating or assessing fenofibrate-mediated reduction of cardiovascular risk.

New insights from the Framingham Heart Study show that alanine aminotransferase (ALT) levels are correlated with multiple cardiometabolic risk factors beyond the effects of visceral adipose tissue and insulin resistance. This analysis included data from 2,621 subjects (mean age 51, 50% women). In multivariate models, increased ALT levels were associated with elevated blood pressure, fasting plasma glucose and triglycerides and lower high-density lipoprotein cholesterol levels (all p<0.01). Each 1 standard deviation increase in ALT was associated with an increased risk of cardiometabolic abnormalities, including diabetes mellitus and the metabolic syndrome. This association was still evident after adjustment for visceral adipose tissue, insulin resistance, and body mass index. Results were similar when only data for non-diabetic subjects with ALT levels <40 U/L were analysed. Given associations between the metabolic syndrome, diabetes and non-alcoholic fatty liver disease, ALT measurement could be a simple measure to refine assessment of cardiometabolic risk.

In the ACS Israeli Surveys (ACSIS), treatment with the combination of fibrate plus statin reduced the 30-day rate of major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS). The study population comprised 8,982 statin-treated patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 surveys, who were alive on discharge. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination therapy. MACE was defined as a composite of death, recurrent myocardial infarction, recurrent ischaemia, stent thrombosis, ischaemic stroke and urgent revascularization. Patients treated with fibrate/statin therapy had a significantly lower 30-day MACE rate compared with those on statin alone (14 (3.2%) versus 513 (6.0%), p=0.01). Additionally, multivariable analysis identified fibrate/statin combination treatment as an independent predictor of reduced risk of MACE (odds ratio 0.54, 95% CI 0.32-0.94). While acknowledging the limitations of the data, the authors concluded that targeting elevated triglycerides and low HDL cholesterol can reduce the high residual macrovascular risk in ACS patients.

In addition to a role in cellular cholesterol efflux and cholesterol homeostasis, experimental studies have shown that high-density lipoprotein (HDL) exhibit a number of novel biological activities which are potentially atheroprotective. These include attenuation of apoptosis, anti-oxidant effects, anti-inflammatory actions in both endothelial cells and leukocytes, as well as beneficial effects on the endothelium and platelets. Moreover, there is emerging evidence to indicate that HDL have beneficial effects on glucose homeostasis and pancreatic ß-cell function. These actions of HDL have been observed both in vitro and in vivo. Assessment of HDL functionality may offer therapeutic possibilities. However, before this is feasible, further work to investigate how best to assess these novel actions of HDL are needed.

This study evaluated genetic predisposition to elevated triglycerides and/or low high-density lipoprotein (HDL) cholesterol in 2,447 patients with type 2 diabetes and 3,052 control subjects included in the Nurses Health Study and the Health Professionals Follow-up Study. The evaluation was based on three genotype scores derived from established loci for blood lipids (low-density lipoprotein [LDL] cholesterol, HDL cholesterol, and triglycerides). Both the HDL cholesterol and triglyceride genotype scores were linearly related to elevated type 2 diabetes risk; there was no association for the LDL cholesterol genotype score. Comparing the extreme scores (lowest versus highest quartiles), the lowest quartile of the HDL cholesterol score and highest quartile of the triglyceride score was associated with 39% (95% CI 17-65%) and 19% (95% CI 1-41%) increased risk for type 2 diabetes. In conclusion, the findings of this study show that genetic predisposition to low HDL cholesterol or high triglycerides is related to elevated type 2 diabetes risk.

A previous study showed that the atherogenic ratio, log(triglycerides [TG])/high-density lipoprotein (HDL) cholesterol), has practical application in assessment of residual macrovascular risk in men with type 2 diabetes. However, it is not known whether this index is also appropriate for assessment of residual cardiovascular risk in women with type 2 diabetes. This cross-sectional study included 340 female patients with type 2 diabetes (mean age 67 years, mean diabetes duration 15 years, mean HbA1c 7.9%). Overall the prevalence of atherogenic dyslipidaemia (TGs =150 mg/dL and HDL cholesterol <50 mg/dL) was 35%. The presence of atherogenic dyslipidaemia was strongly associated with cardiometabolic abnormalities, residual risk of future coronary events, as well as ß-cell function loss, poorer glycaemic control and a higher frequency of microvascular disease. Thus, the atherogenic ratio, log(TG)/HDL cholesterol, represents a simple means of grading residual macrovascular risk, as well as identifying worsening glucose control.

Data from a cross-sectional study in India showed a persistent high prevalence of cardiovascular risk factors, including low HDL cholesterol and elevated triglycerides, among urban Indian subjects. In a cross-sectional study of 739 subjects (evaluated over the period 2009-2010), there were high prevalences of smoking (21% in men), low physical activity (70% in men and 52% in women), overweight/obesity (46% and 51%) and hypertension (40% and 25%). One-third of subjects had total cholesterol =200 mg/dL, 25% of men and 55% of women had low high-density lipoprotein (HDL) cholesterol (<40 mg/dL in men and <50 mg/dL in women), and about one-quarter had metabolic syndrome. There were age-related increases in the prevalence of measures of obesity, systolic blood pressure, total cholesterol, non-HDL cholesterol and triglycerides (p<0.01 for trend). Compared with the periods 2002-2003 and 2005-2006 there was evidence of an increasing trend in the prevalence of high non-HDL cholesterol and triglycerides.

Adipocyte fatty acid-binding protein (FABP4) plasma levels have been previously linked to metabolic changes that are associated with obesity, including the development of atherogenic dyslipidemia. This was investigated in a substudy of the PREDIMED study (Effects of the Mediterranean diet on the primary prevention of cardiovascular diseases), a large prospective multicentre study in Spain investigating the effect of dietary intervention in individuals at high risk of cardiovascular disease. FABP4 plasma levels were measured at baseline and the incidence of atherogenic dyslipidemia was evaluated over a median 4-year follow-up period in 578 subjects. FABP4 plasma levels were associated with new-onset atherogenic dyslipidemia during follow-up (p=0.02) in women but not in men. Women in the highest tertile for plasma FABP4 levels had more than 2-fold increased risk of developing atherogenic dyslipidemia (hazard ratio 2.54, 95% CI 1.31 to 4.93, p for trend 0.008). The authors concluded that FABP4 may be a potential predictive marker of subsequent development of atherogenic dyslipidemia in women.

Familial hypercholesterolaemia is due to genetic defect in either the LDL receptor, apolipoprotein (apo) B100 (the LDL receptor ligand), or PCSK-9 (proprotein convertase subtilisin/kexin type 9, a degrader of the LDL receptor). The condition is characterised by markedly elevated LDL cholesterol levels and increased cardiovascular risk. However, this study in 555 FH patients, also implicates the atherogenic index (log[triglycerides/HDL-cholesterol]) as a contributor to coronary heart disease risk.

This general population study included data from 687 individuals followed over 15 years. Overall, 74 (10.8%) individuals developed diabetes over this period. After adjustment, both elevated triglycerides (odds ratio [OR] 1.29, p =0.047) and a higher triglyceride-HDL cholesterol (OR 1.34, p=0.01) were shown to be predictive for the onset of diabetes. These data highlight the relevance of assessment of the triglyceride-HDL cholesterol in determining the risk of diabetes in a general population in China.

Data from the Chinese Multi-provincial Cohort Study in 30,378 participants (35-64 years) followed over 15 years highlight atherogenic dyslipidaemia as an important contributor to cardiovascular risk in people with well-controlled LDL cholesterol (<130mg/dL or 3.4 mmol/L). Elevated triglycerides were associated with an increased risk of coronary events (Hazard ratio [HR] 1.74, 95% CI 1.25-2.42, p=0.001), and low HDL cholesterol was associated with an increased risk of ischaemic stroke (HR=1.54, 95% CI 1.18-2.03, P=0.002) only in individuals with low LDL cholesterol. The authors called for a renewed focus on managing elevated triglycerides and low HDL cholesterol in individuals at LDL cholesterol goal to reduce this residual cardiovascular risk.

In a systematic review, elevated triglycerides were highlighted as a valid predictor for the onset or progression of nephropathy in patients with type 2 diabetes. The review included 15 studies evaluating 27 biomarkers; six studies with sufficient methodological quality were analysed. In addition to elevated triglycerides, other valid biomarkers for predicting the onset and progression of nephropathy included plasma high-sensitivity C-reactive protein, E-selectin, tissue-type plasminogen activator, and von Willebrand factor. The authors highlighted the need for further study of these predictors.

Data from Sri Lanka in 528 people with type 2 diabetes (over one-third newly diagnosed) highlight elevated triglycerides as a risk factor for distal peripheral neuropathy. This was assessed using the Diabetic-Neuropathy-Symptom (DNS) score in new cases, and both the DNS and Toronto-Clinical-Scoring-System (TCSS) in individuals with established type 2 diabetes. The sample had a mean age of 55 years, 37% were males, and 18% lived in urban areas. The prevalence of distal peripheral neuropathy was about one-quarter, both in individuals newly diagnosed (29%) or with established type 2 diabetes (24%). In those with established diabetes, foot ulcers (odds ratio [OR] 10.4; 95%CI 1.8-16.7), female (OR 6.7; 95%CI 2.0-9.8) and smoking (OR 5.9; 95%CI 1.4-9.7) were the strongest predictors for distal peripheral neuropathy. Among other predictors identified, higher triglycerides were associated with a 60% increase in risk for distal peripheral neuropathy (OR 1.6; 95%CI 1.2-2.0).

A Review in Lancet Neurology has highlighted the emerging role of components of the metabolic syndrome, including low HDL cholesterol and elevated triglycerides, in diabetic neuropathy. Diabetic neuropathy is a common microvascular complication which detrimentally influences patient quality of life, as well as increasing the risk of lower limb amputation. This complication is also an important contributor to the cost of diabetes care. In this review, the authors emphasise the limitations of current standards of care, and highlight associations between elevated triglycerides or low HDL cholesterol, as well as other components of the metabolic syndrome, and diabetic neuropathy. Given the growing burden of this diabetes complication, and the fact that all components of the metabolic syndrome are modifiable by lifestyle or pharmacological interventions, there is a strong case for further investigating these potential risk factors in diabetic neuropathy.

A study conducted in 555 heterozygous familial hypercholesterolemia patients shows significantly higher triglycerides levels in those with cardiovascular disease compared with those without. The association between CVD and the atherogenic index was also significant. The atherogenic index is also a good surrogate for the presence of atherogenic small LDL and small HDL particles.

The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) compared the effect of maximal doses of atorvastatin (80 mg daily) or rosuvastatin (40 mg daily) on the progression of coronary atherosclerosis assessed by intravascular ultrasonography in patients with at least one vessel with 20% stenosis on coronary angiography. Among the 1,039 patients eligible for analysis after 104 weeks of treatment, those in the rosuvastatin group had lower LDL-C levels (62.6 vs. 70.2 mg/dL [1.62 vs. 1.82 mmol/L], P<0.001), and higher HDL-C levels (50.4 vs. 48.6 mg/dL [1.30 vs. 1.26 mmol/L], P=0.01) than those in the atorvastatin group. Both statins induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for percent atheroma volume (P=0.07) and 64.7% and 71.3%, respectively, for total atheroma volume (P=0.02). Both high-dose statin regimens were well tolerated. Although treatment with rosuvastatin was associated with a more favorable lipid profile, there were no significant between-group differences in the rates of major clinical events. These rates were extremely low for such a population: 1.6% for myocardial infarction, 0.4% for stroke and 0.3% for cardiovascular death during 24 months follow-up at a central site. These results confirm that intensive lipid-lowering with statins is associated with favorable clinical outcomes but suggest that no substantial additional benefit can be obtained once a LDL-C level as low as 70 mg/dL has been reached in this high-risk population. However, the study was not powered to detect between-group differences in major adverse clinical events.

The authors of a meta-analysis published in the British Medical Journal report that compared to standard treatment, intensive glucose lowering treatment did not significantly affect all-cause mortality or cardiovascular death. However, the intensive treatment significantly reduced by 15% the risk of nonfatal myocardial infarction and by 10% the risk of microalbuminuria (P<0.01 for both comparisons) – with no effect on the other microvascular complications of diabetes. The intensive treatment was also associated with a more than twofold increase in the risk of severe hypoglycemia (P<0.01). “The harm associated with severe hypoglycemia might counterbalance the potential benefit of intensive glucose lowering treatment,” the authors write.

This review published by Prof. Michel P. Hermans analyses the current evidence on the residual risk of microvascular complications of diabetes persisting in patients treated according to current standards of care. In the second part of his review, the author comments on the beneficial impact on microngiopathies reported in recent fenofibrate trials and their potential implications for the management of microvascular residual risk in diabetic patients.

In a recently published article, Prof. Robert Rosenson, a member of the R3i International Steering Committee, and other prominent lipidologists designate “HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients.” But the authors stress that HDL cholesterol measurement does not reflect the physicochemical and functional heterogeneity of HDL particles. To refine cardiovascular risk prediction and assessment of agents that modulate HDL particle structure, these authors propose a new nomenclature of HDL subfractions based on their physical properties. Accordingly, one might be dealing, in the near future, with very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL), not to forget the pre-ß-1 HDL.

On behalf of the American Heart Association, a panel of experts published a scientific statement based on a comprehensive review of data establishing the links between triglycerides and cardiovascular disease. Owing to the conclusions of the panel, the optimal and normal fasting TG levels are <100 and <150 mg/dL, respectively., commensurate with a non-fasting level of <200 mg/dL. The panel also recommends measurements of non-HDL-cholesterol (non-HDL-C), apolipoprotein B100 (apoB), or both, in those with prominent TG/HDC abnormalities.

In a nested case-control study from the Treating to New Targets (TNT) trial, fasting plasma levels of standard lipids and of 18 nonlipid biomarkers were determined after an 8-week run-in period on atorvastatin 10 mg and again 1 year after being randomized to 10 or 80 mg atorvastatin in 507 patients who experienced major cardiovascular events (MCVEs) during the 4.9 years of study follow-up, and in 1,020 control subjects. LDL-C , HDL-C, and triglycerides were all predictive of recurrent MCVEs (p = 0.009). Concentrations of many of the 18 nonlipid biomarkers were lowered by atorvastatin therapy (independent of dose). However, almost none of the nonlipid biomarkers, such as C-reactive protein and lipoprotein(a), were predictive whether measured after the 8-week run-in period or after 1 year of treatment with 10 or 80 mg atorvastatin.

A retrospective study evaluated the lipid profiles of 393 patients with inflammatory bowel diseases (IBD: Crohn’s disease and ulcerative colitis). Compared with men of similar age and body mass index, men with IBD had significantly lower total cholesterol and HDL-C and higher LDL-C and triglycerides. The same type of comparison showed that in women with IBD, total cholesterol, HDL-C, and triglycerides were significantly decreased and LDL-C significantly increased. High circulatory levels of inflammatory cytokines in patients with IBD may decrease lipoprotein lipase activity, with a lipoprotein profile characterized by increased triglycerides and decreased HDL cholesterol levels, also observed in patients with systemic lupus erythematosus.

The Dyslipidemia International Study (DYSIS) evaluated over 22,000 statin-treated outpatients aged 45 years or older in Europe and Canada. Patients with diabetes represented 39.5% of that population. 58.5% were at LDL-C goal. Of those not at LDL-C goal, 16.2% had normal HDL-C and TGs. 3.9% had high TGs, 8.3% had low HDL-C with high TGs and 3.2% had low HDL-C. 25.4% had low HDL-C and/or high TGs. The CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS) also showed that only 55.3% of patients using lipid-lowering drugs achieved the LDL-C target recommended in the 2003 European guidelines. Therefore, patients with diabetes who are treated with a statin remain at high risk for cardiovascular events based on their achieved lipid values. A need for wider and more intensive lipid therapy with lifestyle management is demonstrated.

Data from the Framingham Offspring study support HDL cholesterol as a therapeutic target. Raising HDL cholesterol reduced cardiovascular risk across the spectrum of patients receiving lipid therapy. Clinical benefits were greater at lower HDL cholesterol values. These data reinforce the value of treating low HDL cholesterol to reduce lipid-related cardiovascular risk.

A high TG/HDL cholesterol ratio is a strong epidemiological measure of atherogenic dyslipidemia as well as a surrogate marker of insulin resistance. It better predicts occurrence of a first heart attack than LDL cholesterol, according to data from the MEtabolic Syndrome Active Subjects (MESYAS) study. In overweight male patients, a high TG/HDL cholesterol ratio increases coronary risk by up to 50%. These data not only highlight the role of non-LDL lipids in coronary risk, but also underline the usefulness of this simple BMI-independent cardiometabolic risk predictor.

In the Lipid Treatment Assessment Project (L-TAP) 2, dyslipidemic men and women aged at least 20 years on stable lipid-lowering therapy were assessed in 9 countries to compare LDL-C goal attainment between genders. Of 9,955 patients (45.3% women) evaluated, women had a significantly lower success rate for reducing LDL-C than men (71.5% vs 73.7%, P=0.014). This was due entirely to the difference in the high-risk/coronary heart disease (CHD) group (LDL-C goal <100 mg/dL, 62.6% vs 70.6%, P<0.0001). Among CHD patients with at least 2 additional risk factors, only 26.7% of women and 31.5% of men (P = 0.021) attained the optional LDL-C goal of <70 mg/dL. HDL-C was <50 mg/dL in 32.2% of women and <40 mg/dL in 26.8% of men (P<0.0001), including 38.2% of women and 29.8% of men in the high risk/CHD group. Despite cholesterol treatment improving substantially since the original L-TAP a decade ago, when only 39% of women attained their LDL-C goal, high-risk women are undertreated compared to men.

In an Austrian based study, vascular events were recorded over 5.6 years in 491 consecutive statin-treated patients with angiographically proven stable coronary artery disease, covering 2750 patient-years. Low HDL-C (standardized adjusted hazard ratio (HR) 0.73; p=0.001), low apolipoprotein A1 (HR, 0.77; p=0.003), a small LDL particle diameter (HR, 0.76; p=0.002), and high triglyceride levels (HR, 1.20; p=0.007) predicted vascular events, but not total cholesterol, LDL-C, or apolipoprotein B. Factor analysis in the lipid profiles revealed an HDL-related factor and an LDL-related factor. The HDL-related factor (HR, 0.69; p<0.001) but not the LDL-related factor (p=0.455) predicted vascular events. Patients with type 2 diabetes (n=116) were at a higher vascular risk than non-diabetic subjects (38.6% vs. 24.1%; p<0.001), and like in the total population the HDL-related factor (0.59; p<0.001) but not the LDL-related factor (p=0.591) predicted vascular risk in diabetic patients.

A total of 686 consecutive patients hospitalized in Pisa, Italy, as a result of left ventricular dysfunction (73% classified as New York Heart Association [NYHA] class I-II), completed a lipid profile and underwent coronary angiography, and were followed for a mean period of 23 months. Half of the patients (52%) had HDL-C values less than 40 mg/dl; in multivariate analysis, they showed the greater risk for cumulative mortality (hazard ratio (HR) 1.77, P<0.05) and for cardiac death (HR 2.06, P<0.05). This greater risk was observed in particular in patients with low HDL-C levels but without significant coronary stenosis.

Coronary endothelial function was assessed in 490 patients of both genders and endothelial dysfunction (epicardial constriction >20% or increase in coronary blood flow <50% in response to intracoronary acetylcholine) was diagnosed in 273 patients. Measurement of lipoprotein particle subclasses using nuclear magnetic resonance revealed that epicardial endothelial dysfunction was significantly correlated with total (p=0.03) and small LDL particles (p<0.01) and inversely correlated with total and large HDL particles (p<0.01).

Owing to follow-up data collected from 93 695 persons aged 19 to 77 years in 8 European countries (1 234 252 total observation-years), the risk of stroke was increased by 9% in men and by 10% in women with each year of age, and by 28% in men and 25% in women with each 10-mm Hg increase in systolic blood pressure. Smoking increased the risk of stroke by 104% in women and 82% in men. Conversely, high HDL-C levels decreased risk of stroke by 42% in women and 20% in men.

The ADVANCE trial was a factorial randomized trial of the antihypertensive combination perindopril-indapamide versus placebo, and intensive glucose control (target hemoglobin A1c = 6.5%) versus standard glucose control in patients with type 2 diabetes. A recent analysis shows that, during an average 4.3-years of follow-up, the effects of the two treatments were independent and additive. Compared with no intervention, combined antihypertensive and glucose-lowering treatment reduced all-cause mortality by 18% (p=0.04), new or worsening nephropathy by 33% (p=0.005), new-onset macroalbuminuria by 54% (p<0.0001) and new-onset microalbuminuria by 26% (P < 0.001). However, there was no significant reduction in new-onset or worsening retinopathy.

Data from18,422 subjects aged 40 years or more involved in a medical screening program showed a high prevalence (24.2%) of chronic kidney disease in middle-aged and elderly Taiwanese subjects. Chronic kidney disease was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2. The multiadjusted odds ratio of chronic kidney disease in participants with serum triglycerides = 200 mg/dL was 1.901 (p < 0.05).

Diagnostic tests, including an exercise treadmill test and exercise thallium scintigraphy or coronary computed tomography detected a significant stenotic coronary artery disease in 55 (25.7%) out of 214 outpatients with diabetic retinopathy. Coronary artery disease was not previously suspected in these patients. Forty-two patients showed indications of coronary revascularization (coronary artery bypass grafting in 17 and percutaneous coronary intervention in 25).

A cross-sectional study conducted in 11,042 hypertensive Spanish women aged 55 years or above showed a 24.7% prevalence of CVD in women with a low high-density lipoprotein cholesterol (HDL-C) concentration (<46 mg/dL) vs. a 18.4% prevalence in those with a normal concentration (p< 0.001). After adjustment for other risk factors, CVD prevalence was increased by 42% in women with low HDL-C levels compared to those with normal levels (p < 0.001). The study revealed an independent inverse association between HDL-C levels (in quintiles) and the prevalence of CVD, particularly for HDL-C levels <58 mg/dL.

A nested prospective case-control study conducted in the EPIC-Norfolk cohort included 1035 healthy men and women aged 45-79 years who developed fatal or nonfatal coronary heart disease (CHD), who were matched to 1920 controls remaining free of CHD over a follow-up period of 6 years. Men in the highest quartile of HDL particle size had an unadjusted odds ratio (OR) for future CHD of 0.75 (95% CI, 0.57-0.97) compared to those in the lowest quartile. For women, the equivalent OR was 0.50 (0.35-0.71). However, after additional adjustment for diabetes, body mass index, systolic blood pressure, LDL- and HDL-cholesterol levels, the ORs were 1.43 (1.01-2.03) in men and 0.84 (0.52-1.35) in women. The difference between unadjusted and adjusted ORs, the authors conclude, indicate that the association between HDL particle size and CHD risk is largely explained by traditional cardiovascular risk factors.

During a 5-year follow-up, chronic kidney disease (CKD) developed in 11.8% of 1987 patients with type 2 diabetes in whom kidney function was normal or near normal at baseline. Higher HDL-C levels were associated with a lower risk of incident CKD (multiple-adjusted hazard ratio, 0.76; 95% coefficient interval, 0.61-0.96; p=0.025) independently of potential confounding risk factors (age, gender, body mass index, hypertension, smoking history, diabetes duration, hemoglobin A1c, plasma triglycerides, LDL-cholesterol, presence of diabetic retinopathy, baseline albuminuria, and current use of anti-hypertensive, anti-platelet, lipid-lowering or hypoglycemic medications).

To investigate the effect of aspirin on cardiovascular event rates in secondary prevention patients with peripheral artery disease, data were extracted from 18 prospective randomized controlled trials involving 5269 patients, among whom 8.9% of those treated with aspirin and 11% of those in the control groups experienced a cardiovascular event (non-fatal myocardial infarction, stroke or cardiovascular death). Odds ratio calculation yielded a 12% reduction in cardiovascular events, which was not significant. Aspirin was not associated with significant reductions in all-cause or cardiovascular mortality, myocardial infarction or major bleeding. However, there was a 34% reduction in non-fatal stroke events.

A systematic review of 32 population-based studies investigating the association between baseline serum levels of triglycerides and HDL-C and the development of coronary heart disease (CHD: coronary events or coronary death) was carried out. The independent association between elevated triglycerides and risk of CHD was statistically significant in 16 out of of 30 populations without pre-existing CHD. Triglycerides and HDL-C were mutually exclusive predictors of coronary events in 12 out of 20 analyses of patients without pre-existing CHD. The association between triglycerides and primary CHD independently of HDL-C makes the authors suggest that both lipid abnormalities may be considered in cardiovascular risk prediction and as targets for preventive cardiocascular intervention.

Levels of activity were measured in 8764 African-American and white Caucasian participants of the Atherosclerosis Risk in Communities (ARIC) study aged 45-64 years at baseline. After 9 years of follow up, increases in the level of activity were associated with increases in HDL cholesterol in all participants and decreases in triglycerides among white participants. LDL cholesterol decreased in women of both ethnicities, while the association with total cholesterol was limited to African-American women.

Among 5610 individuals aged 20 years or older participating in the National Health and Nutrition Examination Survey conducted from 1999 to 2004, 33.1% had a triglycerides (TG) concentration =150 mg/dL, and 17.9% had TG concentration =200 mg/dL. Only 2.6% of participants with a TG concentration =150 mg/dL and 3.6% of those with a TG concentration =200 mg/dL used a prescription medication primarily aimed at reducing hypertriglyceridemia (fenofibrate, gemfibrozil, or niacin).

In 3,616 consecutive patients with LDL-cholesterol levels <70 mg/dL who underwent percutaneous coronary intervention, multivariate analysis showed that all-cause mortality over the subsequent 8 years was decreased by 32%, 45%, and 55% in patients with HDL-cholesterol levels of 40 to 49, 50 to 59, and =60 mg/dL, respectively, compared with those with HDL-cholesterol <40 mg/dL (multivariate analysis).

Despite its proven clinical efficacy in primary and secondary prevention of cardiovascular events, statin therapy is not sufficient to adequately address all lipid-related cardiovascular risk factors. The increased risk associated with elevated triglyceride levels should also be taken into account and combined statin and fibrate therapy should be contemplated in selected patients with acute coronary syndromes.

The main objective of the IDEAL trial was to compare the efficacy of high-dose potent statin therapy (atorvastatin 80 mg/day) with that of usual-dose average-potency statin therapy (simvastatin 20-40 mg/day) in the prevention of recurrent coronary events in patients with coronary heart disease. An analysis was also performed to study the relationships between on-treatment levels of lipoprotein components and clinical outcome. The on-treatment ratio of apoB (the main apolipoprotein of atherogenic low-density lipoproteins) to apoA-1 (the main apolipoprotein component of atheroprotective high-density lipopoproteins) was the best predictor of subsequent major coronary events.

Circulating CRP level is a marker of low-grade systemic inflammation. The JUPITER study reports a 44% reduction (p<0.00001) in relative risk of major CVD events (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization procedure, or confirmed death from cardiovascular causes) in apparently healthy patients with LDL-C <130 mg/dL and C-reactive protein (CRP) = 2.0 mg/L, treated with rosuvastatin 20 mg per day. However, the absolute risk reduction in this CVD low-risk population was only 0.9%.

Japanese investigators report no significant difference in the rate of first cardiovascular events (composite outcome: fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral artery disease) in 2,359 type 2 diabetes patients treated or not treated with low-dose aspirin (81 or 100 mg per day) as antiplatelet agent for a mean follow-up of 4.37 years. The authors do not draw firm conclusions, as they estimate that their study was underpowered due to an unexpected low rate of events.

A cross-sectional study conducted in 42,710 individuals aged 20-95 years living in Copenhagen, 1166 of whom developed cardiovascular events during 14 years of follow-up, shows that triglycerides levels were increased up to 6 hours after last meal (normal food intake). Highest versus lowest tertile of nonfasting triglycerides was associated with an increased risk of cardiovascular events, as were nonfasting levels of all other recognized lipid risk factors.

A total of 5,926 patients received the angiotensin-receptor blocker telmisartan 80 mg/d or placebo for a median duration of 56 months in order to assess whether telmisartan 80 mg/d was effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage. Telmisartan was well tolerated. Although the compound had no significant effect on the primary outcome (composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke.

This 12-week study evaluated the effects on lipoprotein subclasses of ezetimibe/simvastatin with or without co-administration of fenofibrate in 611 patients with mixed hyperlipidemia. Fenofibrate reduced cholesterol mass within VLDL and IDL, shifting cholesterol from dense LDL subfractions to the more buoyant subfractions and HDL, whilst ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein B-containing particles without modifying the LDL particle distribution profile. Following co-administration, the drug effects were complementary with more pronounced reductions in VLDL, IDL and LDL, preferential loss of more dense LDL subfractions and increased HDL.

Following 8-week open-label therapy with 10 mg/d of atorvastatin, 10,001 CHD patients received double-blind therapy with either 80 mg/d or 10 mg/d of atorvastatin for a median duration of 4.8 years. In contrast to previous observations, 80 mg of atorvastatin reduced the relative risk of major cardiovascular events by 35% in patients with diabetes and chronic kidney disease (CKD), and by 10% in those with diabetes and normal glomerular filtration rate, as compared to the low-dose regimen. In patients with diabetes and CKD, the absolute risk reduction was substantial, yielding a number needed to treat of 14 to prevent one major cardiovascular event over 4.8 years.

Among 199 diabetic subjects and 2,768 non diabetic subjects included in the Australian Blue Mountains Eye Study, retinopathy lesions were assessed from retinal photographs and cumulative coronary heart disease (CHD) deaths were ascertained from national death records. During the 12-year follow-up, the presence of retinopathy increased CHD mortality rate by an equivalent amount as the presence of diabetes itself. Both in subjects with diabetes and in those without, even after adjusting for cardiovascular disease risk factors, retinopathy remained an independent predictor of CHD death.

HDL-C levels were evaluated in 93,263 patients with non-ST-segment elevation acute coronary syndromes included in the CRUSADE initiative. Compared to patients with normal and high HDL-C levels, those with very low HDL-C levels (18.1% of study population) were more likely to be younger, male, obese and diabetic, and had the greatest risk of multi-vessel coronary disease on angiography and in-hospital mortality. According to the authors, strategies designed to raise HDL-C levels warrant further investigation in these high-risk patients.

A study performed in 98 UK practices reveals a large proportion of persisting dyslipidemia in patients with pre-existing CVD or diabetes and with both total cholesterol and LDL cholesterol at target levels, irrespective of the presence or absence of statin therapy. Low HDL-C levels were measured in 22.5% of such patients and high triglycerides in 37.2%. The authors suggest that such patients remain exposed to a significant residual cardiovascular risk, and that lipid management may often require intervention beyond simple total cholesterol lowering.