EPA’s pleiotropic mechanisms of action: a narrative review

ABSTRACT

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.

KEYWORDS:

• Triglycerides
• eicosapentaenoic acid
• atherogenesis
• resolvins
• nitric oxide

Transparency

Declaration of funding

This article was funded by Amarin Pharma, Inc., Bridgewater, NJ.

Declaration of financial/other relationships

JRN serves as a speakers bureau member, consultant, and advisor to Amarin Pharma, Inc., from which he has received honoraria.

MJB has served as a speaker for Amarin Pharma, Inc., and has received grant/research funding from Amarin Pharma, Inc.

ORW has served as a speaker for Amarin Pharma, Inc., and Amgen.

VL has served as a speaker for Amarin Pharma, Inc., and has received grant/research funding from Amarin Pharma, Inc., both paid to institution.

DKP has served as a speaker for Amarin Pharma, Inc., AstraZeneca, Boehringer Ingelheim, Dexcom, Lilly, Merck, Novo Nordisk, Xeris and Zealand, and as a consultant to Amarin Pharma, Inc., Bayer, Dexcom, Lilly, Insulet and Sanofi.

RLN has served as an unpaid consultant for Amarin Pharma, Inc.

AN reports no conflicts of interest.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Medical writing assistance was provided by James Street, Rohan Shah, and Jim Wood of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ and was funded by Amarin Pharma, Inc.

Declaration of interest

No potential conflict of interest was reported by the author(s).