DEFINING TOMORROW'S VASCULAR STRATEGIES
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17 February 2020
Real world data: Hypertriglyceridemia is common among patients with cardiovascular disease and confers higher cardiovascular risk
One in four patients with cardiovascular disease and controlled low-density lipoprotein cholesterol have elevated triglyceride levels (135–499 mg/dL or 1.52–5.63 mmol/L). The risk of cardiovascular events in this group increases as triglyceride levels increase.
Lawler PR, Kotrri G, Koh M et al. Real-world risk of cardiovascular outcomes associated with hypertriglyceridaemia among individuals with atherosclerotic cardiovascular disease and potential eligibility for emerging therapies. Eur Heart J 2019; doi:10.1093/eurheartj/ehz767
STUDY SUMMARY
Objective: To quantify the real-world risk of atherosclerotic cardiovascular disease (ASCVD) events associated with hypertriglyceridemia.
Study design: Population analysis using the CANHEART cohort, representing a linkage of 17 individual-level electronic databases.
Study population: The sample was derived from the Ontario population aged >40 years, of whom 2,424,865 individuals had lipid data (including triglycerides [TG], low-density lipoprotein cholesterol [LDL‑C], high-density lipoprotein cholesterol [HDL-C] and total cholesterol). Of these, 196,717 had established ASCVD (median [interquartile range] age 66 [58–73] years; 30.1% female); 23.9% of subjects had a TG > 2.0 mmol/L or 177mg/dL.
Study variable:

·  TG levels (taken at 1 year before inception)

·  The primary outcome was first occurrence of an ASCVD event, defined as myocardial infarction [MI], unstable angina, stroke or transient ischemic attack (TIA), coronary revascularization, or cardiovascular death.

Methods: TG levels were categorized as <1, 1.0–1.5, 1.5–2.0, 2.0–2.5, 2.5–3.0, 3.0–3.5, 3.5–4.0, and >4.0 mmol/L. Cox proportional hazards models adjusted for age, sex, income, LDL-C, baseline diabetes, and baseline hypertension were used to analyze ASCVD outcomes in relation to TG categories. Cardiovascular risk was assessed overall as well as stratified by sex, diabetes status, and LDL-C categories (≥ or < median LDL-C, 1.9 mmol/L or 74mg /dL ).
Main results: • Over a mean of 2.9 years follow-up, there were 24,097 ASCVD events. The age- and sex-standardized primary outcome rate was 38.6 per 1000 person-years, ranging from 32.2 to 57.6 per 1000 person-years for those in the lowest to highest TG category, respectively.
• Compared with the reference category (TG<1.0 mmol/L), increasing TG was associated with a graded higher hazard of ASCVD events. Patients in the highest TG category (> 4.0 mmol/L) had a 52% higher risk of ASCVD events (adjusted hazard ratio 1.52, 95% confidence interval 1.36–1.71; p< 0.0001). compared with those in the lowest TG category.
• The major contributor to this increased risk was an increase in MI/unstable angina and revascularization.
• Overall, 49,886 (25%) ASCVD subjects had controlled LDL-C (41–100 mg/dL or 1.06–2.59 mmol/L) and elevated TG levels. Over the mean follow-up of 2.9 years 6,327 (12.7%) experienced an ASCVD event.
Conclusion: Among patients with ASCVD, hypertriglyceridemia is common, and is associated with higher ASCVD risk across a range of TG levels. It is possible that as many as one in four patients with ASCVD may be candidate for emerging therapies.

COMMENT

This study provides important real-world information regarding the prevalence of hypertriglyceridemia among individuals with ASCVD, against a background of current evidence-based therapy.  The results show that elevated TG (> 2.0 mmol/L or 177 mg/dL) is common among those individuals with controlled LDL-C levels, present in about 25%. This is relevant as there appears to be a continuum of increasing ASCVD risk with increased TG levels.1,2 In this study, for example, the increase in relative ASCVD risk ranged from 11% among individuals with borderline hypertriglyceridemia (TG levels 1.5-2.0 mmol/L) to 52% in those with TG levels ≥4.0 mmol/L. These findings underline that elevated TG-rich lipoproteins and remnant cholesterol, for which elevated TG are a marker,1 represent a significant contributor to lipid-related residual cardiovascular risk in a real-world setting.

 This patient group also poses an unmet clinical challenge. Among current treatments, only high-dose eicosapentaenoic acid was shown to significantly reduce the residual cardiovascular risk associated with elevated TG in the REDUCE-IT study.3 Although this study is not without its limitations, including the choice of placebo (mineral oil) and possible involvement of mechanisms beyond TG-lowering,2 it does support the rationale of targeting elevated TG in both primary and secondary prevention patients with controlled LDL-C levels.

 Other studies focus on alternative approaches. Of these, the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) study is evaluating the selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α), pemafibrate, in type 2 diabetes mellitus patients with atherogenic dyslipidemia, of which elevated TG is an important component.4 The next 2-3 years offer the prospect of exciting times for the management of residual cardiovascular risk associated with elevated TG levels.

References

1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35.

2. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2020;41:99-109c.

3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.

4. Pradhan AD, Paynter NP, Everett B et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93

Key words hypertriglyceridemia; residual cardiovascular risk; real-world setting; REDUCE-IT; PROMINENT; pemafibrate