When Should We Use Icosapent Ethyl?

As one of the few significant new treatment options approved for reducing the risk of cardiovascular events since statins were approved about 30 years ago, when should icosapent ethyl (Vascepa) actually be used?

Icosapent ethyl, sold as Vascepa by Amarin, is a purified form of the ethyl ester of eicosapentaenoic acid (EPA) that was approved in 2012 as an adjunctive treatment to diet for severe hypertriglyceridemia (triglycerides >500 mg/dL). Then in December of 2019, it was granted approval for reducing the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (>150 mg/dL) and either established cardiovascular disease or diabetes mellitus and 2+ additional risk factors for CV disease adjunctive to maximally tolerated statin therapy. The effect on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined and is one limitation of use for this medication.

The cardiovascular risk reduction potential was shown in the results of the REDUCE-IT trial, a multinational, double-blind, randomized controlled event-driven trial with over 8,000 patients enrolled. Patients in this trial had elevated TG levels, LDL-C between 40 and 100 mg/dL, current therapy with a statin, and either established cardiovascular disease or diabetes mellitus with at least 2 other cardiovascular risk factors, such as hypertension, history of smoking (within the previous 3 months), low HDL cholesterol, or creatinine clearance of 30-59 mL/min. These patients were followed for a median of 4.9 years. The patients who were treated with icosapent ethyl had a 25% reduced risk of the primary outcome of a 5-point MACE: CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. 

Icosapent ethyl also had a fairly similar side effect profile to placebo, with the most commonly reported side effects including musculoskeletal pain, peripheral edema, and constipation. Of note, there is also a risk of atrial fibrillation or atrial flutter requiring hospitalization with the use of this medication, with a greater incidence in patients with a previous history. Icosapent ethyl is also associated with an increased risk of bleeding, which was also greater in patients on concomitant anticoagulant medications. 

The mechanisms through which icosapent ethyl reduces cardiovascular risk are not well understood at this time, but it is thought that the increased EPA lipid composition from carotid plaques and increased circulating EPA/arachidonic acid ratio may have something to do with it. The mechanisms relevant to reducing TG levels include the ability to reduce hepatic VLDL-TG synthesis and secretion and enhances TG clearance from circulating VLDL particles. This effect may be achieved through increased beta-oxidation, inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT), decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity.

The 2018 AHA/ACC/Multisociety guidelines on the management of blood cholesterol were completed prior to the publication of the REDUCE-IT trial results, but the National Lipid Association, one of the participating professional societies in the 2018 guidelines, published a statement on the use of icosapent ethyl (IPE) in 2019. They make a Class I recommendation that IPE be used for patients 45 years or older with clinical ASCVD or aged 50 years or older with diabetes mellitus requiring medication and at least 1 additional cardiovascular risk factor. Additionally, recommended patients should have a fasting TG level of 135-499 mg/dL and be on high-intensity or maximally tolerated statin therapy, with or without concurrent ezetimibe. Patients with fasting TG levels of >500 mg/dL fall into the indication for adjunct use with diet to reduce TGs. The ADA and AHA have both also released statements recommending IPE for patients with T2DM and CAD whose TGs remain elevated (>135 mg/dL) despite maximally tolerated statin therapy and lifestyle changes.

The approval of icosapent ethyl provides another CV risk reduction strategy to utilize alongside statin therapy for patients who have elevated TG levels and meet the labeling requirements. Have you seen icosapent ethyl use increasing since its CV indication approval in 2019?

This article was written by Lincoln Haiby, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP

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References: 

Amarin Pharma, Inc. Vascepa (icosapent ethyl) capsules [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202057s035lbl.pdf. Accessed July 19, 2021.

Grundy, Scott M, Stone, Neil J, Bailey, Alison L, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2019;73(24):e285-e350. Accessed July 19, 2021.

Bhatt, Deepak L, Steg, P. Gabriel, Miller, Michael, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England Journal of medicine. 2019;380(1):11-22. Accessed July 19, 2021.

Orringer, Carl E, Jacobson, Terry A, Maki, Kevin C. National Lipid Association Scientific Statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk. Journal of clinical lipidology. 2019;13(6):860-872. Accessed July 19, 2021.

Written By Eric Christianson

August 18, 2021

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