Mechanistic Insights from REDUCE-IT STRENGTHen the Case Against Triglyceride Lowering as a Strategy for Cardiovascular Disease Risk Reduction.

Elevated triglyceride (TG) levels have been linked to residual atherosclerotic cardiovascular risk in patients with controlled low-density lipoprotein cholesterol. However, outcome trials testing TG-lowering agents have failed to demonstrate cardiovascular risk reduction in statin-treated subjects. One such example is the recent STRENGTH trial, which tested mixed omega fatty acids (n3-FAs, 4 g/d) in high-risk patients with elevated TGs. Similar to trials using fibrates and niacin, the STRENGTH trial failed despite effective TG lowering. Results from these studies have contributed to skepticism about the use of TG-lowering therapy for cardiovascular risk. However, new mechanistic insights are provided by the REDUCE-IT trial that used icosapent ethyl (IPE), a purified formulation of the n3-FA eicosapentaenoic acid. In high-risk patients, IPE reduced a composite of cardiovascular events (25%, P < .001) in a manner not predicted by TG lowering. Benefits with IPE appear linked to broad pleiotropic actions associated with on-treatment eicosapentaenoic acid levels. These studies indicate that although TGs are a potential biomarker of cardiovascular risk, there is no evidence that TG lowering itself is an effective strategy for reducing such risk.