While elevated levels of triglycerides have been shown to be useful as a predictor of cardiovascular risk, lowering triglyceride levels has not been demonstrated to lower cardiovascular risk. Triglyceride lowering may have contributed to the cardiovascular risk reduction demonstrated in the REDUCE-IT® study, but it was not a major contributor. In REDUCE-IT, all patients had elevated cardiovascular risk, as represented by elevated triglyceride levels and other risk factors; however, the level of cardiovascular risk reduction appeared to be independent of the baseline or on-treatment triglyceride levels. The science behind the development of cardiovascular disease is complex, as is lipid management. VASCEPA® (icosapent ethyl) is not a drug focused on LDL-cholesterol management. Instead, it targets persistent cardiovascular risk reduction in a specified patient population on statin therapy.
MECHANISMS OF ACTION
In more than a decade of development and clinical study of VASCEPA considerable effort has been spent not just in exploring the safety and efficacy of VASCEPA (as reported in three Phase 3 studies, including REDUCE-IT), but also in seeking to better understand how VASCEPA works. The mechanisms of action (MoA) of VASCEPA for cardiovascular risk reduction are thought to be multi-factorial (click HERE for section 12.1 of the VASCEPA label, Mechanism of Action), but as is true with many drugs (e.g., aspirin, statins, metformin), these MoA may never be fully understood. A full understanding of a drug’s mechanism of action is not required for regulatory approval or commercial success, as evidenced by the success of multiple therapies, including widely used therapies for diabetes and cholesterol management.
Examples of recent research exploring the MoA of icosapent ethyl include the following:
- Scientific studies have examined the question of whether icosapent ethyl may have an impact on atherosclerotic processes (e.g., plaque formation and instability) by potentially affecting cellular functions thought to contribute to atherosclerosis and cardiovascular events or affecting lipid, lipoprotein and inflammation biomarkers.1 A review of the potential mechanisms, published in Atherosclerosis in 2015, examined the cellular effects and molecular mechanisms of action of eicosapentaenoic acid (EPA) in atherosclerosis.2 Note that these are exploratory studies and the clinical significance of their findings is unknown.
- Research has also included evaluations of the potential effects on cell membranes. The active ingredient in VASCEPA is a small molecule that is capable of incorporating into endothelial cells as EPA and may impact their function. This small molecule is relatively short in length and has relatively few double bonds.
- The possible effects of EPA on cell membranes are illustrated in this animation created by Drs. Peter Libby and Preston Mason of Brigham & Women's Hospital and Harvard Medical School. Click HERE for animation. The animation is based, in part, on scientific evaluations that Dr. Mason has led as President of Elucida Research. These evaluations, and the science discussed in the animation are exploratory in nature. The biologic plausibility of EPA as an anti-atherosclerotic agent has not been established, nor has research supporting biologic plausibility been reliably predictive of cardiovascular benefit. VASCEPA has not been approved for the treatment of atherosclerosis.
- Dr. Mason’s work includes evaluation of the differentiated effects of a pure and stable form of EPA, the active ingredient in VASCEPA, and the potential relation to oxidative stress, crystal domain formations, oxidation of LDL and preservation of HDL function. Additionally, reduction in inflammation markers in patients treated by VASCEPA has been examined in multiple clinical studies of VASCEPA, including REDUCE-IT.1,3
- The potential for halting plaque progression and/or regression in patients treated with VASCEPA was evaluated in the EVAPORATE study, presented in August 2020 by Dr. Matthew Budoff, M.D., Director of Cardiovascular CT at The Lundquist Institute and Professor of Medicine at the David Geffen School of Medicine at UCLA, and subsequently published online in the European Heart Journal. The results of the EVAPORATE study have been published and are summarized here. Mechanistic work, like the EVAPORATE study, may be helpful in developing further understanding of the potential mechanisms of action of VASCEPA.
- For further discussion of the potential mechanisms of action of VASCEPA and its active ingredient, click here.
As noted above, the mechanisms of action by which VASCEPA (icosapent ethyl) reduces the risk of certain cardiovascular events in certain patients are not completely understood but are likely multi-factorial. The studies and data presented in this section are exploratory in nature and their clinical significance is unknown. The FDA-approved label for VASCEPA (icosapent ethyl), which contains discussion of mechanism of action, can be found here.
This website at amarincorp.com is not intended to promote the use of VASCEPA in the United States, Europe or anywhere in the world. If you are a healthcare professional or patient and require medical information regarding VASCEPA or you have witnessed or experienced an adverse event in a patient being treated with VASCEPA, please call (in the United States) 1-855-VASCEPA (1-855-827-2372).
1Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl in Hypertriglyceridemia. N Engl J Med. 2019;380:11-22.
2Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis. 2015;242:357-366.
3Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent Ethyl, a Pure Ethyl Ester of Eicosapentaenoic Acid: Effects on Circulating Markers of Inflammation from the MARINE and ANCHOR Studies. Am J Cardiovasc Drugs. 2013;13:37–46.