Mechanisms of action, efficacy, and safety of icosapent ethyl: from bench to bedside

It has been a remarkable journey from bench to bedside for icosapent ethyl. This prescription medication is a highly purified ethyl ester of eicosapentaenoic acid (EPA), an omega-3 fatty acid. The landmark Reduction of Cardiovascular Events with Icosapent Ethyl—Intervention Trial (REDUCE-IT) demonstrated that this medication significantly reduced first cardiovascular events by 25% and total (first plus subsequent) cardiovascular events by 32%.^1–3 Since the time of those initial results, several additional analyses have been published, providing a comprehensive assessment of the efficacy and safety of icosapent ethyl.

A question that has arisen after the publication of REDUCE-IT has been how did this drug produce such large reductions in multiple cardiovascular endpoints? This supplement brings together experts who review the basic biology and mechanisms of action of icosapent ethyl. It is fascinating science about a compound we are only starting to understand. Beyond triglyceride reduction, there are beneficial effects on cell membrane stabilization, plaque progression, and lipid oxidation. There are anti-inflammatory and anti-thrombotic properties. It is a drug that truly merits categorization as pleiotropic.⁴

In the next article, distinguished authors from Europe describe unmet needs in cardiovascular prevention and then focus on the highlights from REDUCE-IT, including the multiple robust efficacy and safety analyses that have been performed. In this large, placebo-controlled trial, the drug was tolerated as well as the placebo. A number of analyses have now shown that the results are generalizable to a substantial proportion of patients with persistent cardiovascular risk despite lifestyle modification efforts and use of standard evidence-based therapies. In a variety of economic analyses, the drug has been found to be highly cost-effective. Thus, the drug really does ‘usher in a new era in dyslipidaemia therapeutics’.⁵

The placebo used in the trial was a minute quantity of mineral oil, considered an inert substance. Mineral oil was chosen as the placebo to mimic the colourless, odourless icosapent ethyl capsules. A prior Japanese open-label trial of a lower dose of pure EPA found a 19% reduction in ischaemic events, with consistent results in the secondary and primary prevention cohorts. However, that trial was criticized for lack of a placebo, among other methodologic issues. Therefore, it was felt REDUCE-IT needed a placebo, and due to icosapent ethyl’s appearance, potential choices were quite limited. After the enormous degree of benefit was noted in REDUCE-IT, some observers found the results quite unexpected, given the failure of other omega-3 fatty acid trials using different compounds and formulations. One odd theory touted by a vocal minority was that the results were not due to the drug, but rather the placebo. The US Food and Drug Administration had signed off on the use of this inert placebo. The fact that the drug and placebo had identical tolerability, as noted above, further argued against any meaningful action by mineral oil. The chairman and a member of the REDUCE-IT data and safety monitoring committee, along with physicians and scientists from the sponsoring company, have authored a review that puts to bed any lingering concerns about this rather silly issue.

The penultimate paper puts it all in perspective and reviews the data and guidelines pertaining to the fascinating story of omega-3 fatty acids in cardiovascular medicine. There were several promising signals along the way from earlier trials and observational data, but it took REDUCE-IT to establish that therapy with pure EPA in the form of icosapent ethyl definitively reduced ischaemic events. As such, it is truly a breakthrough trial that will be viewed through the prism of history as opening up an entirely novel axis for cardiovascular risk reduction.

The final article in this series explores the study of icosapent ethyl outside of cardiovascular medicine. There are evaluations underway exploring its effects in dementia, cancer, and infection, for example. Ongoing trials will help us understand the full potential of this amazing molecule and its remarkable journey from bench to bedside.

Funding

This paper was published as part of a supplement supported by an unrestricted educational grant from Amarin Pharma, Inc.

Conflict of interest: Dr. Deepak L. Bhatt serves as the Chair and International Principal Investigator for REDUCE-IT, with research funding from Amarin to Brigham and Women’s Hospital. Dr. Bhatt discloses the following relationships - Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda.

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