Deep Dive: Is there an optimal way to take omega-3s for improved cardiovascular outcomes in people at high risk?

Cardiovascular disease (CVD) is the leading cause of mortality in the U.S., causing more than 850,000 deaths per year, according to the American Heart Association. Investigations^[1] have shown an inverse association between intake of omega-3 long-chain polyunsaturated fatty acids^[2] (n-3 PUFA) and CVD. There is evidence^[3] that intake of n-3 PUFA, particularly EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), may be involved in many physiological and biochemical processes that act to decrease the risk of cardiovascular-related diseases. Mechanistic studies have shown^[4] that n-3 PUFA may inhibit inflammatory signaling pathways, downregulate fatty acid synthesis gene expression, and upregulate gene expression involved in fatty acid oxidation, which could help explain their putative cardioprotective effects. These mechanisms may modulate cell membrane function and positively affect lipoprotein metabolism^[5] and pathways involved in atherosclerosis^[6].

While the mechanistic and observational studies evaluating this relationship have produced promising results, randomized controlled trials have yielded conflicting results. Some trials have shown^[7] a benefit^[8], while other trials^[9] have not. However, the scales have recently been tipped pretty strongly in favor of efficacy thanks to the REDUCE-IT study published in January 2019, which showed a 25% decrease in cardiovascular events and a 20% reduction of risk from cardiovascular death in a high cardiovascular disease risk population with elevated triglyceride levels upon administration of statins and four daily grams of icosapent ethyl (a highly purified and stable EPA ethyl ester). Since this trial differed from some of the others in a few key ways, it’s possible that the inconsistency between previous studies could be due to differences in disease risk, dose, and n-3 type.

Given the inconsistent results of the randomized controlled trials and the relatively recent publication of the REDUCE-IT trial, the authors of the study under review decided to meta-analyze the literature. Their goal was to examine the state of the evidence and determine which aspects of study design may be responsible for the inconsistency. They did this by focusing on the role of dose and type of n-3 PUFA administered and the effect of n-3 PUFA on populations with different baseline CV risk.