Reducing residual cardiovascular risk in patients with hypertriglyceridemia: the unique role of eicosapentaenoic acid

Elevated triglyceride levels have been associated with an elevated risk of cardiovascular disease, even when triglyceride levels are below common guidelines. This elevated risk of cardiovascular disease exists independent of total cholesterol or low-density lipoprotein cholesterol levels. Genetic analyses have demonstrated that elevated remnant lipoprotein, a product of triglyceride-rich lipoprotein, is a factor for coronary heart disease, indicating that the association between elevated triglyceride levels and elevated cardiovascular disease risk is causal rather than correlated. Despite this correlation between triglyceride levels and cardiovascular disease risk, treatments targeted at lowering triglyceride levels in patients receiving statin therapy, such as niacin or fibrates, have not demonstrated reduction in cardiovascular disease risk despite lowering triglyceride levels. In addition, omega-3 fatty acids containing a combination of docosahexaenoic acid plus eicosapentaenoic acid failed to demonstrate significant reductions in cardiovascular events in similar patients. Triglyceride-lowering therapies in development include monoclonal antibodies targeted against angiopoietin-like 3 (ANGPTL3); however, these newer ANGPTL3-targeted agents have not yet demonstrated a reduction in cardiovascular disease risk. In contrast, the landmark REDUCE-IT trial demonstrated significant cardiovascular protective effects for icosapent ethyl (IPE) in high cardiovascular risk patients with hypertriglyceridemia despite statin therapy. The protective effects of IPE may be due to unique mechanisms affecting the metabolism of E-series resolvins that may reduce atherosclerotic plaque. IPE also exhibits antiplatelet, antithrombotic, anti-inflammatory, and anti-oxidant effects, all of which contribute to an overall anti-atherosclerotic effect and an overall reduction in cardiovascular disease risk. As a result, treatment guidelines in the United States, China, and other countries recommend IPE for patients with hypertriglyceridemia that persists despite statin therapy.