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Macrovascular Residual Risk Studies

19 July 2016
Analysis questions benefit of lowering LDL-C below current targets
This cohort study including over 30,000 patients with ischaemic heart disease showed no additional decrease in cardiac events from lowering low-density lipoprotein cholesterol (LDL-C) levels below 70 mg/dL (1.8 mmol/L) compared with that observed in patients with LDL-C levels between 70 and 100 mg/dL (1.8 and 2.6 mmol/L).
Leibowitz M, Karpati T, Cohen-Stavi CJ et al. Association between achieved low-density lipoprotein levels and major adverse cardiac events in patients with stable ischemic heart disease taking statin treatment. JAMA Intern Med 2016. Epub ahead of print doi:10.1001/jamainternmed.2016.2751
Objective: To assess the relationship between levels of LDL-C achieved with statin treatment and cardiovascular events in adherent patients with pre-existing ischaemic heart disease
Study design: Population-based observational cohort study using data from a health care organization in Israel covering more than 4.3 million members (exposure period 2009 to 2013).
Study population: 31,619 patients aged 30 to 84 years (mean age 67.3 years, 27% female) who were at least 80% adherent with statin treatment were included in the analysis; 29% had low LDL-C levels (≤70.0 mg/dL), 53% had moderate LDL-C levels (70.1-100.0 mg/dL), and 18% high LDL-C levels (100.1-130.0 mg/dL) when taking statin treatment. Compared with the group with moderate LDL-C levels, patients with low LDL-C levels had significantly more co-morbidities including diabetes (62.5% vs 52.0%, p<0.001) and congestive heart failure (18.7% vs 15.4%, p<0.001).
Efficacity measures: Major adverse cardiac events (MACE), a composite of acute myocardial infarction, unstable angina, stroke, angioplasty, bypass surgery, or all-cause mortality.
Methods: The hazard ratio of adverse cardiac events was estimated using two Cox proportional hazards models with low versus moderate LDL-C levels, and moderate versus high LDL-C levels. The covariates in this analysis were baseline characteristics measured during the year before the index event, and included socioeconomic status (low or mid-high), religion (Jewish or non-Jewish), pre-index body mass index and time taking statins (≥12 months). Statin treatment was assessed as low (equivalent to simvastatin ≤20 mg), moderate (equivalent to simvastatin 40mg), and high (equivalent to simvastatin 80 mg) potency. The analysis was further tested using propensity score matching analysis.
Main results:

Overall, 9,035 patients had a MACE or died during a mean 1.6 years of follow-up. The adjusted incidence of MACE did not differ between patients with low or moderate LDL-C levels, but was lower with moderate than high LDL-C levels (see Table).

 Table. Hazard ratio (95% confidence interval, CI) for MACE in patients with low, moderate or high LDL-C levels

No. of events (event rate/1000 person-years)

HR (95% CI)*



Moderate LDL-C


High LDL-C


Low vs. Moderate LDL-C

Moderate vs. High LDL-C

2681 (78.1)

4595 (71.0)

1759 (81.3)

1.10 (1.05-1.15), p<0.001

0.87 (0.83-0.92), p<0.001

*Upper hazard ratio for unadjusted analysis; lower hazard ratio after adjustment for age, sex, ethnicity, socioeconomic status, smoking status, diabetes, insulin use, duration of statin treatment, physician visits, chronic kidney disease stage, number of angioplasties, Charlson risk score, body mass index

Authors’ conclusion: Patients with LDL-C levels of 70 to 100 mg/dl had a lower risk of MACEs compared with those with higher LDL-C levels. However, no additional benefit was gained by lowering LDL-C to ≤70 mg/dl. These population-based data do not support treatment guidelines recommending very low target LDL-C levels for all patients with pre-existing heart disease


Despite attainment of guideline-recommended LDL-C targets with statin therapy, individuals with cardiovascular disease continue to be at risk of (recurrent) events. To reduce this risk, it has been proposed that LDL-C levels should be lowered below these targets. This approach is supported by evidence from the Cholesterol Treatment Trialists’ Collaboration, which showed greater reduction in cardiovascular events with greater absolute reduction in LDL-C levels with more intensive statin therapy.1 Additionally, results from the IMPROVE-IT study2 showed modest benefit (reduction by 6.4%) for the risk of recurrent cardiovascular events, predominantly myocardial infarction and ischaemic stroke, in individuals with acute coronary syndromes, with further lowering of LDL-C levels with the addition of ezetimibe to statin therapy (1 year mean LDL-C levels 53.2 mg/dl versus 69.9 mg/dl with simvastatin 40 mg monotherapy). In IMPROVE-IT, the reduction in CV events was essentially derived from a relatively large subgroup with diabetes at baseline, suggesting that patients with type 2 diabetes may derive more benefit that nondiabetic patients from achieving very low LDL-C levels. However, the overall modest treatment benefit with ezetimibe plus statin has led some to question a ‘lower is better’ approach in the general population. Moreover, while post hoc and exploratory analyses from PCSK9 inhibitor trials are encouraging for this approach,3,4 these are based on few absolute events and definitive evidence is needed from ongoing cardiovascular outcome studies.

 The ‘lower LDL-C is better’ approach supports LDL-C as the predominant contributor to lipid-related residual cardiovascular risk in high risk patients. Yet there is accumulating evidence for the atherogenicity of other cholesterol-rich apolipoprotein-B containing lipoproteins, notably triglyceride-rich lipoproteins and their remnants, especially in individuals with metabolic disease such as type 2 diabetes.5 Indeed, analysis of data from the Danish general population showed that while increasing plasma levels of nonfasting LDL-C or remnant cholesterol were associated equally with risk of cardiovascular events (ischaemic heart disease events and myocardial infarction), only nonfasting remnant cholesterol was associated with overall mortality risk.6

 These findings need to be borne in mind when considering the results of the current cohort study, which failed to show any significant benefit of further lowering LDL-C (beyond the recommended target for high risk patients of 70 mg/dl or 1.8 mmol/L) in patients with stable ischaemic heart disease. The findings from this study are robust, as shown by consistency in secondary and sensitivity analyses that adjust for differences in baseline characteristics between the groups, and strengthened by taking account of adequate adherence (at least 80%) and polypharmacy among the subjects. Consideration of other cholesterol-rich apolipoprotein-B containing lipoproteins as potential contributors to lipid-related residual cardiovascular risk is therefore warranted, a view consistent with the Residual Risk Reduction Initiative.


1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.

2. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.

3. Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.

4. Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.

5. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.

6. Varbo A, Freiberg JJ, Nordestgaard BG. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population. Clin Chem 2015;61:533-43.

Key words treatment goals; low-density lipoprotein cholesterol; residual cardiovascular risk; remnant cholesterol