Can pleiotropic effects of eicosapentaenoic acid (EPA) impact residual cardiovascular risk?

Abstract

Residual cardiovascular (CV) risk persists even in statin-treated patients with optimized low-density lipoprotein cholesterol (LDL-C) levels. Other pathways beyond cholesterol contribute to CV risk and the key to reducing residual risk may be addressing non-cholesterol risk factors through pleiotropic mechanisms. The purpose of this review is to examine the literature relating to the potential role of the omega-3 fatty acid eicosapentaenoic acid (EPA) in reducing residual CV risk. The literature shows that EPA can robustly lower plasma triglyceride (TG) levels without raising LDL-C levels and documents EPA to have a broad range of beneficial effects on the atherosclerotic pathway, including those on lipids, lipoproteins, inflammation, oxidation, phospholipid membranes, and the atherosclerotic plaque itself. Clinical imaging studies have consistently demonstrated that EPA decreases plaque vulnerability and prevents plaque progression. The evidence therefore points to a potential role for EPA to reduce residual CV risk. A large randomized study of statin-treated Japanese patients demonstrated that EPA ethyl ester reduced major coronary events by 19% (P = 0.011). However, while there has been significant benefit demonstrated in this and another Japanese CV outcomes study, the question as to whether EPA can play a role in reducing residual CV risk remains to be addressed in broader populations. The large, global, ongoing, randomized, placebo-controlled REDUCE-IT study of high-risk statin-treated patients with persistent hypertriglyceridemia is currently underway to investigate the potential of icosapent ethyl (high-purity prescription EPA ethyl ester) as an add-on therapy to reduce residual CV risk. ARTICLE HISTORY

Dyslipidemia Management in Adults With Diabetes

“…On consideration, the clinical benefits in REDUCE-IT seemed to exceed what would be expected from the 20% reduction in TG levels seen with icosapent ethyl. This idea is further supported by the observation that benefits were independent of baseline TG levels, and suggests that other mechanisms possibly contributed to the benefits (54). These include an anti-inflammatory effect because high-sensitivity C-reactive protein was lower by approximately 40% in the icosapent ethyl treated patients compared with the placebo group.…”

Rounding the corner on residual risk: Implications of REDUCE‐IT for omega‐3 polyunsaturated fatty acids treatment in secondary prevention of atherosclerotic cardiovascular disease

“…Reported biological actions of EPA and DHA extend well beyond TG lowering and include effects expected to be cardioprotective . As summarized by Mozaffarian and Rimm, and shown in Figure , fish oil omega‐3 PUFAs have been linked with reduced blood pressure and heart rate, as well as decreased platelet aggregation .…”

Critical Differences Between Dietary Supplement and Prescription Omega-3 Fatty Acids: A Narrative Review

“…Differences in OM-3 fatty acid composition may also have contributed to disparate CVOT findings. It is possible that, beyond TG lowering, pleiotropic effects of EPA on other lipids/ lipoproteins, inflammation, oxidation, phospholipid membranes, and plaque [2] may have contributed to the CV risk reduction demonstrated in JELIS, REDUCE-IT, and other smaller trials [29]. In light of the recent OM-3 dietary supplement CVOT data [25], the European Medicines Agency Committee for Medicinal Products for Human Use concluded that DHA ?…”

“…The omega-3 (OM-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may have a preventive role in the development and progression of atherosclerotic cardiovascular disease (ASCVD) [1][2][3][4]. While both EPA and DHA reduce triglycerides (TG), DHA may raise low-density lipoprotein cholesterol (LDL-C) [5,6].…”