Differentiating EPA from EPA/DHA in cardiovascular risk reduction

None of the clinical trials of omega-3 fatty acids using combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were able to show any effect on cardiovascular outcomes, despite reductions in triglyceride levels. In contrast, the Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT), which employed high-dose (4 g) purified EPA, demonstrated a 25% reduction in atherosclerotic cardiovascular disease-related events compared with placebo (hazard ratio 0.75; 95% confidence interval 0.68-0.83; P < 0.001). Moreover, REDUCE-IT is the first clinical trial using a lipid-lowering agent as adjuvant therapy to a statin to show a significant reduction in cardiovascular mortality. Significant reductions in stroke, need for revascularization, and myocardial infarction were also observed. The pharmacology of EPA is distinct from that of DHA, with a differential effect on membrane structure, lipoprotein oxidation, and the production of downstream metabolites that promote the resolution of inflammation. Attained plasma levels of EPA may be an important determinant of efficacy, with a substudy of REDUCE-IT suggesting that the threshold for clinical benefit of EPA is approximately 100 μg/mL, a level achieved in only a minority of patients in other studies. No similar clinical trials of DHA monotherapy have been conducted, so no such threshold has been established. The results of the REDUCE-IT and the Japan EPA Lipid Intervention Study (JELIS) together affirm the efficacy of EPA therapy for cardiovascular disease risk reduction in certain patient populations.