EPA's pleiotropic mechanisms of action: a narrative review

Treatment with icosapent ethyl 4 g/day, a highly purified and stable ethyl ester of eicosapentaenoic acid (EPA), demonstrated a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events and death in REDUCE-IT. However, analyses of REDUCE-IT and meta-analyses have suggested that this clinical benefit is greater than can be achieved by triglyceride reduction alone. EPA therefore may have additional pleiotropic effects, including anti-inflammatory and anti-aggregatory mechanisms. EPA competes with arachidonic acid for cyclooxygenase and lipoxygenase, producing anti-inflammatory and anti-aggregatory metabolites rather than the more deleterious metabolites associated with arachidonic acid. Changing the EPA:arachidonic acid ratio may shift metabolic status from pro-inflammatory/pro-aggregatory to anti-inflammatory/anti-aggregatory. EPA also has antioxidant effects and increases synthesis of nitric oxide. Incorporation of EPA into phospholipid bilayers influences membrane structure and may help to prevent cardiac arrhythmias. Clinically, this may translate into improved vascular health, including regression of atherosclerotic plaque. Overall, EPA has a range of pleiotropic effects that contribute to a reduction in ASCVD.