Study Finds Icosapent Ethyl May Be Beneficial for Treating Cardiovascular Disease

Icosapent ethyl (Vascepa, Amarin) is highly purified eicosapentaenoic acid ethyl ester, a derivative of fish oil, that is FDA-approved to reduce high triglycerides (≥500 mg/dL).

It is not approved to treat cardiovascular disease (CVD) or reduce cardiovascular risk.¹

A normal triglyceride level is <150 mg/dL and may be treated if higher.² Because high triglycerides have been associated with increased risk for CVD, lowering this lab value should also reduce cardiovascular risks.³ However, no fish oil or fish oil derivative to date has been approved for the reduction of cardiovascular outcomes.

The REDUCE-IT trial was conducted to determine whether icosapent ethyl is effective in reducing cardiovascular events. This trial was agreed upon as part of a Special Protocol Assessment with the FDA.^4,5

Study Design and Methodology

The REDUCE-IT study was a double-blind, placebo-controlled, randomized trial. The population the drug studied was people aged 45 years or older with CVD or those aged 50 years or older with diabetes and 1 additional CVD risk factor. Participants also needed to have been on a statin therapy for 4 weeks and still had a triglycerides level of 135 to 499 mg/dL and a low-density lipoprotein (LDL) level of 41 to 100 mg/dL. The primary outcome was a composite of cardiovascular death, coronary revascularization, nonfatal myocardial infarction (MI) or stroke, or unstable angina. Although the results were positive, the sponsor added additional secondary endpoints and tertiary endpoints after the study began, which included separating out cardiovascular death or nonfatal MI.^6,7

Results

A total of 4089 patients were randomized to the icosapent ethyl group, and 4090 were in the placebo group. Overall, taking 4 grams of icosapent ethyl a day had a significant benefit for reducing time to the primary outcome in patients with established CVD (HR 0.75 [95%CI 0.68 to 0.83]), with an absolute difference between groups of 4.8% over a median follow up of 4.9 years, and a number needed to treat of 21.

There was no significant difference in patients without established CVD (individuals 50 or older with diabetes and 1 additional CVD risk factor).⁷

In addition, low-intensity statin use was associated with worse outcomes compared with higher-intensity or moderate statins. And while male members were associated with significant benefit, females did not show a significant benefit (HR 0.82 [95%CI 0.66 to 1.01).⁷

Icosapent ethyl had a significant difference compared with the placebo on the mean change of triglycerides (18.3% decrease versus 2.2% increase P<0.0001) and LDL level (3.1% increase vs 10.2% increase P<0.0001).⁷

Adverse events that occurred in 5% of patients, and were statistically higher, in patients who took icosapent ethyl compared with the placebo were peripheral edema (6.5% versus 5.0%), constipation (5.4% versus 3.6%), and atrial fibrillation (5.3% versus 3.9%). Other significant events that were higher in icosapent ethyl compared with the placebo were atrial fibrillation/flutter requiring hospitalization (3.1% versus 2.1% [P=0.004]) and treatment emergent serious bleeding (2.7% versus 2.1% [P=0.06]).⁸

Discussion

Icosapent ethyl manufacturer Amarin plans to submit a supplemental new drug application for an expanded FDA indication before the end of the first quarter of 2019. The published study focused on the secondary endpoints, with an emphasis on reducing CVD and ischemic events.

The FDA review committee will review and evaluate the application based on objective study results. A possible indication would be the prevention of cardiovascular risk in patients 45 or older with CVD, who have been on a statin (moderate to high intensity) for at least 4 weeks with triglycerides of 135 to 499 mg/dL and an LDL level of 41 to 100 mg/dL.

References

• Vascepa [package insert]. Bedminster, NJ; Amarin Pharma Inc.: 2017
• US National Library of Medicine. Cholesterol levels: what you need to know. MedlinePlus website. medlineplus.gov/cholesterollevelswhatyouneedtoknow.html?rel=0" ?rel=0". Accessed January 12, 2019.
• Lee JS, Chang PY, Zhang Y, Kizer JR, Best LG, Howard BV. Triglyceride and HDL-C Dyslipidemia and Risks of Coronary Heart Disease and Ischemic Stroke by Glycemic Dysregulation Status: The Strong Heart Study. Diabetes Care. 2017;40(4):529-537. doi: 10.2337/dc16-1958.
• Results from the Vascepa (icosapent ethyl) CV Outcomes trial (REDUCE-IT). investor.amarincorp.com/static-files/7eed9f2b-3f7a-493f-9113-99d981a198b1?rel=0" ?rel=0". Accessed January 11, 2019.
• Examining the Amarin VASCEPA saga. Camargo website. camargopharma.com/2015/08/examining-the-amarin-vascepa-saga/?rel=0" ?rel=0". Updated Published August 15, 2015. Accessed January 11, 2019.
• Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: reduction of cardiovascular events with Icosapent ethyl-intervention trial. Clin Cardiol. 2017;40(3):138-148. doi: 10.1002/clc.22692.
• Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi: 10.1056/NEJMoa1812792.
• Amarin Provides preliminary 2018 Results and 2019 Outlook [news release]. Bedminster, NJ and Dublin, Ireland; January 4, 2019: Amarin Investor Relations. investor.amarincorp.com/news-releases/news-release-details/amarin-provides-preliminary-2018-results-and-2019-outlook?rel=0" ?rel=0". Accessed January 12, 2019.