Addressing the “failed” omega-3 clinical trials: Problems with omega-3 or trial design and execution?

Abstract: Long-chain omega-3 fatty acids, eicosapentaenoic and docosahexaenoic acids (EPA and DHA), have been shown to have a myriad of beneficial effects on human health, leading to the creation of pharmaceutical omega-3 products. These products differ from most dietary supplements in their higher concentrations of EPA/DHA, their recommended doses (~4g/d) and their restriction to patients with certain medical conditions. In addition, unlike dietary supplements, they are monitored by the FDA for safety and quality. The current FDA-approved pharmaceutical omega-3 products are Epanova (omega-3-carboxylic acids, EPA+DHA), Lovaza (omega-3-acid ethyl esters, EPA+DHA), and Vascepa/Epadil (EPA ethyl ester). The primary indication for all three is severe hypertriglyceridemia ( >500 mg/dL), whereas Vascepa is also indicated for preventing cardiovascular disease in certain high-risk patients. Virtually all the major randomized clinical trials (RCTs) with omega-3 fatty acids have used one of these products, and the results have been inconsistent as evidenced in the Figure. The rates (vs placebo) of major adverse cardiovascular events (MACE) in the STRENGTH (Epanova), REDUCE-IT and JELIS trials (Vascepa in the latter two) were significantly reduced in the latter two, but not in the former. There are multiple possible reasons for these inconsistent outcomes including doses, the nature of the placebos, background omega-3 intake/blood levels, etc. Other reasons for the failure of some omega-3 trials which appears to have affected the outcome of the largest study in pregnant women which targeted premature birth. These issues will be considered as will their implications for designing future of omega-3 RCTs.