Icosapent ethyl for reduction of persistent cardiovascular risk: a critical review of major medical society guidelines and statements

ABSTRACT

Introduction

REDUCE-IT demonstrated that adding 4 g/day of icosapent ethyl (IPE; purified ethyl ester of eicosapentaenoic acid [EPA]) to statins substantially reduced cardiovascular disease (CVD) events, with few adverse effects. These data prompted numerous leading medical societies across five continents, including the American College of Cardiology, the European Society of Cardiology, and the Japanese Circulation Society, to update their guidelines or scientific/consensus statements to recommend use of IPE for primary and secondary prevention of CVD events.

Areas Covered

This review discusses the incorporation of IPE into international guidelines and scientific statements, noting areas of consensus and distinction. As background, this review also describes the CVD benefits and risks of IPE as a statin adjunct, and outlines current data regarding the potential mechanisms of CVD risk reduction by EPA (as IPE) beyond triglyceride reduction.

Expert Opinion/Commentary

IPE is unique among ‘triglyceride-lowering’ treatments in having strong CVD outcomes data and, therefore, a broad international consensus among professional medical society guidelines and statements endorsing its use for CVD risk reduction in patients generally meeting REDUCE-IT inclusion criteria. IPE should be considered for CVD prevention as a statin adjunct in all such patients.

Plain Language Summary

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Statin monotherapy is conventionally used first-line to reduce the risk of CV events, such as heart attacks and strokes, in patients with elevated cholesterol. However, considerable risk remains despite appropriate control of cholesterol levels with a statin. Consequently, research has focused on treatment of additional therapeutic targets to reduce this remaining CV risk. One such target is elevated blood triglyceride levels. Unfortunately, most drugs that lower triglyceride levels, such as niacin, fibrates, and mixed omega-3 fatty acids, have not reduced the risk of cardiovascular events in clinical trials when added to statin therapy. However, the omega-3 fatty acid eicosapentaenoic acid (‘EPA’) administered in highly purified form as icosapent ethyl (IPE) has emerged as the first omega-3 fatty acid, and the first triglyceride-lowering agent to prevent CV events when added to statins. This was demonstrated most notably in the pivotal REDUCE-IT trial, in which IPE reduced the risk of major CV events by 25% in high-risk patients with mildly to moderately elevated triglyceride levels despite statin-controlled cholesterol levels. The mechanisms responsible for this reduction in CV events appear to go far beyond lowering triglyceride levels alone. In light of the positive results from the REDUCE-IT trial, IPE was approved for CV disease risk reduction globally, including in the United States, Canada, European Union, and the United Kingdom, and its use is being increasingly endorsed in United States and international statements and guidelines for managing CV risk. Despite minor differences among guidelines, there is strong consensus that IPE should be considered for use in CVD prevention in all patients who meet the proposed criteria.

KEYWORDS:

• Atherosclerotic cardiovascular disease
• icosapent ethyl
• REDUCE-IT
• guidelines
• hypertriglyceridemia

Article highlights

• Icosapent ethyl (IPE) is approved for reducing persistent cardiovascular disease (CVD) risk in Canada, EU, US, UK, Hong Kong, and parts of the Middle East

• IPE is widely recommended for CVD prevention by several leading US and non-US medical societies (in their guidelines and/or scientific statements)

• These approvals and endorsements are based on strong evidence of CVD reduction with IPE in high-risk patients with mild-to-moderate triglyceride (TG) elevation despite control of low-density lipoprotein cholesterol (LDL-C) by statins

• Most of these recommendations endorse IPE for patients with TG levels in the range studied in REDUCE-IT (1.5–5.6 mmol/L [135–499 mg/dL])

• Most of these recommendations explicitly exclude other omega-3 products, which have not demonstrated CVD benefits in contemporary trials

• Some guidelines recommend statin treatment sufficient to ‘control’ LDL-C levels, whereas others recommend ‘maximally tolerated statin’ therapy

• The Japanese, the National Institute for Health and Care Excellence, and the US Department of Veterans Affairs/US Department of Defense guidelines recommend IPE use only for secondary prevention

• The CVD risk reduction in REDUCE-IT appears unrelated to on-treatment TG levels, but instead may be due to anti-inflammatory, anti-oxidant, membrane-stabilizing, and/or endothelial function effects

• IPE should be considered for use in CVD prevention in all patients meeting relevant guideline and/or regulatory criteria

Acknowledgments

Medical writing assistance was provided by Kulvinder Katie Singh, Noud van Helmond, and Lilly Shelomyanov, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ and was funded by Amarin Pharma, Inc.

Declaration of interest

M Miller is a scientific advisor for Amarin and Steering Committee member for the REDUCE-IT trial. He is also an advisor for 89Bio and Pfizer. L Tokgozoglu has received honoraria and served as a consultant to Abbott, Amgen, Bayer, Daiichi Sankyo, Janssen, MSD, Mylan, Novartis, Novo Nordisk, Sanofi, Servier, Pfizer, Recordati, and Abdi-Ibrahim. KG Parhofer has received research funding and/or honoraria for consultancy and/or speaker’s bureaus and/or DMC activity from Akcea, Amarin, Amgen, Boehringer-Ingelheim, Dr. Schär, Daiichi-Sankyo, Ionis, MSD, Novartis, Pfizer, Regeneron, Sanofi, and Silence Therapeutics. Y Handelsman has received research grants and consultant/speaker honoraria from Amarin, Amgen, Applied Therapeutic, AstraZeneca, Esperion, Merck, Merck-Pfizer, Novartis, Regeneron, and Sanofi. LA Leiter has received research funding from, has provided CME on behalf of, and/or has acted as an advisor to Amarin, Amgen, AstraZeneca, Esperion, HLS, Kowa, Merck, Novartis, Sanofi, and The Medicines Company. U Landmesser has received research grants from Novartis, Bayer, and Amgen and advisory or speaker honoraria from Bayer, Amgen, Sanofi, Novartis, Daichi Sankyo, Pfizer, and Amarin. EA Brinton is a scientific advisor for Amarin, a Steering Committee member for the REDUCE-IT and PROMINENT trials, and receives research support from Regeneron. He is also an advisor for 89Bio, Dalcor, and Pfizer and a speaker bureau member for Amarin, Amgen, Amryt, and Esperion.

AL Catapano has received honoraria, lecture fees, and/or research grants from Sigma-Tau, Manarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron, and Daiichi-Sankyo. His research is supported in part from Ministero della Salute Ricerca Corrente.

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.

Reviewer disclosures

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

Additional information

Funding

This paper was funded by Amarin Pharma, Inc.