Can pleiotropic effects of eicosapentaenoic acid (EPA) impact residual cardiovascular risk?

ABSTRACT

Residual cardiovascular (CV) risk persists even in statin-treated patients with optimized low-density lipoprotein cholesterol (LDL-C) levels. Other pathways beyond cholesterol contribute to CV risk and the key to reducing residual risk may be addressing non-cholesterol risk factors through pleiotropic mechanisms. The purpose of this review is to examine the literature relating to the potential role of the omega-3 fatty acid eicosapentaenoic acid (EPA) in reducing residual CV risk. The literature shows that EPA can robustly lower plasma triglyceride (TG) levels without raising LDL-C levels and documents EPA to have a broad range of beneficial effects on the atherosclerotic pathway, including those on lipids, lipoproteins, inflammation, oxidation, phospholipid membranes, and the atherosclerotic plaque itself. Clinical imaging studies have consistently demonstrated that EPA decreases plaque vulnerability and prevents plaque progression. The evidence therefore points to a potential role for EPA to reduce residual CV risk. A large randomized study of statin-treated Japanese patients demonstrated that EPA ethyl ester reduced major coronary events by 19% (P = 0.011). However, while there has been significant benefit demonstrated in this and another Japanese CV outcomes study, the question as to whether EPA can play a role in reducing residual CV risk remains to be addressed in broader populations. The large, global, ongoing, randomized, placebo-controlled REDUCE-IT study of high-risk statin-treated patients with persistent hypertriglyceridemia is currently underway to investigate the potential of icosapent ethyl (high-purity prescription EPA ethyl ester) as an add-on therapy to reduce residual CV risk.

KEYWORDS:

• Atherosclerotic plaque
• eicosapentaenoic acid
• endothelial function
• icosapent ethyl
• omega-3 fatty acids
• residual risk

Acknowledgments

Medical scientific reference checks and associated assistance were provided by Sephy Philip, RPh, PharmD, and Loree Levine, RPh, MS, MBA of Amarin Pharma Inc., Bedminster, NJ, USA.

Declaration of interest

JR Nelson has received research support from, is a stock shareholder of, is a consultant/advisory to, and is on the speaker’s bureau of Amarin Pharma Inc. RP Mason has received grant/research support from Amarin Pharma Inc., Pfizer, and Novartis, and provides speaking and consultancy services for and has received honoraria from Novartis and Amarin Pharma Inc. Medical writing assistance was provided by Peloton Advantage, LLC, Parsippany, NJ, USA, and funded by Amarin Pharma Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by Amarin Pharma Inc.