A Comprehensive Monograph on Omega-3-Acid Ethyl Esters: Pharmacology, Clinical Evidence, and Evolving Regulatory Landscape

Executive Summary

Omega-3-acid ethyl esters represent a specific, prescription-grade pharmaceutical formulation composed of a purified mixture of ethyl esters of omega-3 polyunsaturated fatty acids, principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), derived from fish oil. This agent holds a single, undisputed indication in the United States and Europe: as an adjunct to diet for the reduction of triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (sHTG), defined as TG levels of 500 mg/dL or greater. Its mechanism of action is multifactorial but centered on the liver, where it reduces triglyceride synthesis and VLDL particle production while enhancing fatty acid oxidation.

The clinical profile of omega-3-acid ethyl esters is characterized by a fundamental dichotomy. On one hand, its efficacy in lowering markedly elevated triglycerides is well-established through numerous clinical trials, demonstrating TG reductions of 20% to 45%. On the other hand, its role in reducing the risk of major cardiovascular events is highly controversial and largely unsupported by the weight of modern, high-quality clinical evidence. The initial promise suggested by early studies has not been consistently replicated in subsequent, more rigorous cardiovascular outcome trials (CVOTs). This has led to a significant divergence in its regulatory status, with European authorities withdrawing the post-myocardial infarction secondary prevention indication, a status it never formally held in the U.S.