Role of Omega-3 Fatty Acids in Cardiovascular Disease: the Debate Continues

Abstract

Purpose of Review The omega-3 fatty acids (n3-FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently undergone testing for their ability to reduce residual cardiovascular (CV) risk among statin-treated subjects. The outcome trials have yielded highly inconsistent results, perhaps attributable to variations in dosage, formulation, and composition. In particular, CV trials using icosapent ethyl (IPE), a highly purified ethyl ester of EPA, reproducibly reduced CV events and progression of atherosclerosis compared with mixed EPA/DHA treatments. This review summarizes the mechanistic evidence for differences among n3-FAs on the development and manifestations of atherothrombotic disease. Recent Findings Large randomized clinical trials with n3-FAs have produced discordant outcomes despite similar patient profiles, doses, and triglyceride (TG)-lowering effects. A large, randomized trial with IPE, a prescription EPA only formulation, showed robust reduction in CV events in statin treated patients in a manner proportional to achieved blood EPA concentrations. Multiple trials using mixed EPA/DHA formulations have not shown such benefits, despite similar TG lowering. These inconsistencies have inspired investigations into mechanistic differences among n3-FAs, as EPA and DHA have distinct membrane interactions, metabolic products, effects on cholesterol efflux, antioxidant properties, and tissue distribution. EPA maintains normal membrane cholesterol distribution, enhances endothelial function, and in combination with statins improves features implicated in plaque stability and reduces lipid content of plaques. Summary Insights into reductions in residual CV risk have emerged from clinical trials using different formulations of n3-FAs. Among high-risk patients on contemporary care, mixed n3-FA formulations showed no reduction in CV events. The distinct benefits of IPE in multiple trials may arise from pleiotropic actions that correlate with on-treatment EPA levels beyond TG-lowering. These effects include altered platelet function, inflammation, cholesterol distribution, and endothelial dysfunction. Elucidating such mechanisms of vascular protection for EPA may lead to new interventions for atherosclerosis, a disease that continues to expand worldwide.

Eicosapentaenoic and Docosahexaenoic Acid Supplementation Increases HDL Content in n-3 Fatty Acids and Improves Endothelial Function in Hypertriglyceridemic Patients

“…Our results showed that 2 g/d of EPA and DHA effectively improved endothelial function assessed using FMD. This beneficial effect of n-3 on vascular function is still controversial [ 20 , 21 , 22 ]. Treatment with omega 3 failed to improve FMD in a group of 38 patients with T2DM, HbA1c < 7%, high cardiovascular risk, and optimal medical therapy for hypertension and plasma lipids [ 21 ].…”

Comparative Effects of Mineral Oil, Corn Oil, Eicosapentaenoic Acid, and Docosahexaenoic Acid in an In Vitro Atherosclerosis Model

“…Therapeutic administration of omega‐3 fatty acids has yielded discordant results in clinical trials. 1 In the Reduction of Cardiovascular Events with Icosapent Ethyl‐Intervention Trial (REDUCE‐IT), treatment with icosapent ethyl (IPE), an ethyl ester of the active ingredient eicosapentaenoic acid (EPA, 20:5; n−3), at 4 g/d to patients with high cardiovascular risk showed a 25% relative risk reduction of the primary end point (5‐point composite major adverse cardiac event) compared with placebo. 2 By contrast, the Long‐Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) trial, which used a mixed combination of EPA/docosahexaenoic acid (DHA, 22:6; n−3) free carboxylic acids (4 g/d) in a similar high cardiovascular risk population, did not reduce the same primary end point compared with placebo.…”

“…It has been suggested that MO even at 2 mL BID interferes with statin absorption or promotes intestinal inflammation compared with CO, although laboratory studies have failed to substantiate these claims. 1 …”

“…Achieved blood levels of EPA were associated with cardiovascular benefit in REDUCE‐IT, compatible with a direct mechanistic effect on atherosclerosis. 1 Plaque volume measurement techniques found that EPA, but not EPA with DHA, significantly reduced total plaque and lipid volume when added to statins in patients with stable coronary artery disease or acute coronary syndrome. 1 Laboratory findings have also observed differences between EPA and DHA with respect to cholesterol efflux, endothelial function, and membrane stability.…”

“… 1 Plaque volume measurement techniques found that EPA, but not EPA with DHA, significantly reduced total plaque and lipid volume when added to statins in patients with stable coronary artery disease or acute coronary syndrome. 1 Laboratory findings have also observed differences between EPA and DHA with respect to cholesterol efflux, endothelial function, and membrane stability. 1 , 4 Importantly, EPA and DHA also exhibit antagonistic effects on membrane structure where they concentrate as components of phospholipids.…”