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High triglyceride levels are associated with cardiovascular (CV) events, but triglyceride reduction has not been shown to lower risk for such events. REDUCE-IT (NCT01492361) is an international, industry-sponsored study of icosapent ethyl (a highly purified eicosapentaenoic acid ethyl ester) in patients with established CV disease or diabetes in the setting of statin therapy. A total of 8179 eligible participants (fasting triglycerides, 135–499 mg/dL; median baseline age, 64; median LDL, 75 mg/dL) were randomized to icosapent ethyl (2 g twice daily) or placebo. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.
From baseline to 1 year, serum triglycerides fell by a median 18.3% (icosapent ethyl) and rose by a median 2.2% (placebo). During a median follow-up of 4.9 years, 1606 primary endpoint events occurred. Compared with placebo, icosapent ethyl resulted in a 25% relative risk reduction and a 4.8% absolute risk difference; the number needed to treat was 21. The benefit was seen across all the components of the primary endpoint, with similar effect sizes. Although adverse event rates were generally low, atrial fibrillation, peripheral edema, and serious bleeding were more common with icosapent ethyl.
Bhatt DL et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018 Nov 10; [e-pub]. (https://doi.org/10.1056/NEJMoa1812792)
Comment
For clinicians seeking to reduce residual CV risk after statin administration, these results may be practice changing. Unlike other triglyceride-lowering agents (niacin, fibrates, and other omega-3 fatty acids) that have failed to show CV benefits, high-dose icosapent ethyl appears to have impressive efficacy. These results confirm that the mechanism of lipid lowering matters and cannot be generalized, even among similar agents. More research is needed to identify the mechanism of action responsible for this observed benefit (as well as the slightly higher risk for certain adverse events). For now, I will recommend checking triglycerides for my patients at elevated cardiovascular risk and consider prescribing icosapent ethyl. More studies are needed to determine if the observed benefit extends to other omega-3 fatty acids and to lower-risk patients.