By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved icosapent ethyl as add-on therapy to reduce the risk of cardiovascular (CV) events in adults with elevated triglyceride. Icosapent ethyl is an ethyl ester of eicosapentaenoic acid, an omega-3 fatty acid derived from fish oil. It was approved in 2012 to treat severe hypertriglyceridemia. This new indication received a priority review. It is distributed as Vascepa.
Icosapent is an adjunct to maximally tolerated statin therapy to reduce the risk of coronary revascularization, myocardial infarction (MI), stroke, and unstable angina requiring hospitalization in adults with elevated triglyceride (≥ 150 mg/dL) and existing cardiovascular disease (CVD) or diabetes mellitus and two or more additional risk factors for CVD.1 It was previously approved as an adjunct to diet to reduce triglyceride in patients with severe hypertriglyceridemia (≥ 500 mg/dL).
The recommended dose is 4 g (4 × 500 mg or 2 × 1 g capsules) taken twice daily with food.1 Icosapent is available as 500 mg and 1 g capsules.
Icosapent is the first drug approved to reduce the risk of CV events in patients with established CVD and hypertriglyceridemia on maximally tolerated statin therapy.1,2
Icosapent was associated with a higher risk of atrial fibrillation or atrial flutter compared to placebo-treated subjects (3.1% vs. 2.1%; P = 0.004).1,2 There is potential for allergic reaction to icosapent in patients with fish and/or shellfish allergies.1 Bleeding risk has been associated with icosapent (12% vs. 10% for placebo), with serious bleeding 2.7% vs. 2.1% for placebo (P = 0.06).1,2 The risk is higher in patients on anticoagulant/antithrombotic therapy.
Icosapent’s efficacy and safety were demonstrated in a randomized, double-blind, placebo-controlled trial in subjects (age ≥ 45 years) with established CVD (secondary prevention) or ≥ age 50 years with diabetes mellitus and at least one additional risk factor (primary prevention).1,2 Eligible subjects had fasting triglyceride between 150 and 499 mg/dL and LDL-cholesterol between 41 and 100 mg/dL. A total of 8,179 subjects were randomized to icosapent or placebo. The median age was 64 years, 71% were male, 90% were white, 71% were on a secondary prevention, 62% were on a moderate-intensity statin, 30% were on a high-intensity statin, 60% recorded triglyceride levels ≥ 200 mg/dL, and 58% presented with type 2 diabetes. The primary efficacy endpoint was a composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina. The median follow-up was 4.9 years.
Events occurred in 17.2% of those randomized to icosapent vs. 22% randomized to placebo (hazard ratio, 0.75; 95% confidence interval, 0.69-0.83; P < 0.001). The key secondary composite endpoint of CV death, MI, and stroke was reduced by 26%. Other secondary endpoints (fatal or nonfatal MI, emergent or urgent coronary revascularization, fatal or nonfatal stroke, and hospitalization for unstable angina) also declined significantly (range, 20-32%). Those on secondary prevention, younger subjects (< age 65 years), and those with baseline triglyceride ≥ 200 mg/dL and HDL cholesterol ≤ 35 mg/dL tended to benefit more. Death from any cause was not significantly different between treatment groups (6.7% vs. 7.4%). The timing of the benefit appears to begin after two years of treatment. After one year, there was an 18.3% reduction in triglyceride levels vs. 2.2% in the placebo group (median baseline, 216 mg/dL). LDL-cholesterol increased by 3.1% vs. 10.2%, respectively (median baseline, 74 mg/dL).
Icosapent is the first FDA-approved treatment to reduce the risk of CV events in patients with elevated triglyceride when added on to maximally tolerated statin therapy. There have been numerous studies that have attempted to show the benefit of omega-3-fatty acids supplementation (generally with combined eicosapentaenoic and docosahexaenoic acids) for reducing the risk of CV events, particularly in secondary prevention, but results have been mixed.3 A Cochran review and a meta-analysis of 10 randomized trials (n = 47,803) did not show clear CV benefit.4,5 The American Heart Association recommends omega-3 fatty acid supplements as secondary prevention for CVD death for patients with prevalent coronary heart disease as well as prevalent heart failure with reduced left ventricular function.3 Icosapent has shown efficacy in patients with hypertriglyceridemia, established CV diseases, and those on moderate- to high-intensity statin therapy. The cost for icosapent is $397 (4 × 1 g/day) or $465 (8 × 0.5 g/day) for a 30-day supply.
- Amarin Corporation. Vascepa Prescribing Information, December 2019. Available at: http://bit.ly/39outQt.
- Bhatt DL, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
- Siscovick DS, et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: A science advisory from the American Heart Association. Circulation 2017;135:e867-e884.
- Abdelhamid AS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev 2018; Nov 30;11:CD003177. doi: 10.1002/14651858.CD003177.pub4.
- Aung T, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77 917 Individuals. JAMA Cardiol 2018;3:225-234.