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ByProfessional Communications, Inc.
Fact checked byErik Swain

Icosapent Ethyl Topic Review

ByProfessional Communications, Inc.
Fact checked byErik Swain

Icosapent ethyl is a prescription-grade derivative of the omega-3 fatty acid eicosapentaenoic acid, a component of fish oil.

Icosapent ethyl may be used for the management of severe hypertriglyceridemia and atherosclerotic cardiovascular disease (ASCVD) risk in adult patients. It is the first fish oil product to receive FDA approval for the reduction of ASCVD risk in adults. [Huston J, et al. Am J Cardiovasc Drugs. 2023;1a]

Fish oil contains a variety of fatty acids, some of which — like eicosapentaenoic acid (EPA) — are beneficial, while others, including arachidonic acid, have been linked to an increase in low-density lipoprotein cholesterol (LDL-C) and higher ASCVD risk. Many fish oil products (eg, omega-3-acid ethyl ester and omega-3-carboxylic acid combination products) contain both EPA and docosahexaenoic acid (DHA); in contrast, icosapent ethylis 99.99% EPA. [Huston J, et al. Am J Cardiovasc Drugs. 2023;2a]

EPA has a wide spectrum of biological activity, including reduction of platelet aggregation, vasodilation, antiproliferative effects, atherosclerotic plaque stabilization and lipid-lowering effects. Many of these effects are believed to be mechanistically linked to changes in cell membrane properties following the incorporation of EPA into the lipid bilayer. Given the association between elevated cardiovascular risk and the reduction of nitric oxide (NO) derived from the endothelium, as well as NO-mediated vasodilation, it is noteworthy that EPA has also demonstrated an ability to enhance the coupling efficiency of endothelial NO synthase and the ratio of NO to peroxynitrite (ONOO−) release. [Huston J, et al. Am J Cardiovasc Drugs. 2023;2b]

Indications

The FDA initially approved icosapent ethyl (Vascepa, Amarin) in 2012 [Vascepa prescribing information;1a] for the treatment of hypertriglyceridemia, either as an adjunct to statin therapy or for patients with statin-associated side effects. [Huston J, et al. Am J Cardiovasc Drugs. 2023;1a] As of 2023, icosapent ethyl is FDA-approved for the following indications: [Vascepa prescribing information;1a]

  • as an adjunct to maximally tolerated statin therapy to reduce the risk for myocardial infarction, stroke, coronary revascularization and unstable angina requiring
  • hospitalization in adult patients with elevated triglyceride levels (≥ 150 mg/dL) and
  • established cardiovascular disease (CVD) or
  • diabetes and two or more additional risk factors for CVD.
  • as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

Limitations of Use: [Vascepa prescribing information;1a]

  • The effect of icosapent ethyl on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

Dosage and administration

Prior to initiating icosapent ethyl, lipid levels should be assessed, and other causes of high triglyceride levels should be identified and managed as appropriate. Patients should engage in appropriate nutritional intake and physical activity before and during treatment with icosapent ethyl. [Vascepa prescribing information;1a]

The recommended dosage of icosapent ethyl is 4 g per day taken as either four 0.5-g capsules twice per day with food, or as two 1-g capsules twice per day with food. The capsules should be swallowed whole. Icosapent ethyl is contraindicated in patients with known hypersensitivity to icosapent ethyl or any of its components. [Vascepa prescribing information;1a]

Guideline recommendations

The 2018 Multisociety (including the American College of Cardiology [ACC] and American Heart Association [AHA]) Guideline on the Management of Blood Cholesterol contains the following recommendation on the use of omega-3 fatty acids for the treatment of hypertriglyceridemia: [Grundy SM, et al. J Am Coll Cardiol. 2018;33a]

  • In adults with severe hypertriglyceridemia (fasting TG ≥ 500 mg/dL), and especially fasting triglycerides ≥ 1,000 mg/dL, it is reasonable (Class of Recommendation IIa) to identify and address other causes of hypertriglyceridemia, and if triglycerides are persistently elevated or increasing, to further reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy.

Since icosapent ethyl was approved for ASCVD risk-lowering only in 2019 on the basis of data from the REDUCE-IT trial published that same year, the 2018 cholesterol guideline did not provide any recommendations for the use of icosapent ethyl in ASCVD risk reduction.

The 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia stated that icosapent ethyl may be considered for ASCVD risk reduction and prevention of pancreatitis in patients with persistent fasting triglycerides 500-999 mg/dL and for ASCVD risk reduction in patients with persistent fasting triglycerides 100-499 mg/dL aged 50 years and older with at least one ASCVD risk factor, both in conjunction with optimizing diet and lifestyle, optimizing glucose if the patient has diabetes and optimizing statin therapy of the patient is eligible. [Virani SS, et al. J Am Coll Cardiol. 2021;20a,23a]

The 2023 ACC/AHA/Multisociety Guideline for the Management of Patients With Chronic Coronary Disease contains the following recommendation on the use of icosapent ethyl: [Virani SS, et al. J Am Coll Cardiol. 2023;32a]

  • In patients with chronic coronary disease on maximally tolerated statin therapy with an LDL-C level < 100 mg/dL and a persistent fasting triglyceride level of 150 to 499 mg/dL after addressing secondary causes, icosapent ethyl may be considered (Class of Recommendation IIb) to further reduce the risk of major adverse cardiovascular events and cardiovascular death.

Efficacy and safety

The first trials to explore the triglyceride- and lipid-lowering effects of icosapent ethyl were MARINE and ANCHOR. The MARINE trial demonstrated significant triglyceride-lowering effects of icosapent ethyl in patients with very high triglyceride levels (> 500 mg/dL), [Bays HE, et al. Am J Cardiol. 2011;1a] while the ANCHOR trial showed significant reductions in triglycerides and non-HDL cholesterol in patients with high triglyceride levels (200-500 mg/dL) despite statin therapy. [Ballantyne CM, et al. Am J Cardiol. 2012;1a]

The first indication that icosapent ethyl may affect ASCVD outcomes came from the Japan EPA Lipid Intervention Study (JELIS) trial. The JELIS trial involved more than 18,000 participants in Japan with hypercholesterolemia who were randomly assigned 1:1 to receive icosapent ethyl 300 mg three times daily plus statin therapy or statin therapy alone over an approximate 5-year follow-up period. JELIS found that icosapent ethyl supplementation reduced the risk for major coronary events (sudden cardiac death, fatal and nonfatal myocardial infarction, and other nonfatal events including unstable angina pectoris, angioplasty, stenting or coronary artery bypass grafting) by 19% compared with no icosapent ethyl supplementation. [Yokoyama M, et al. Lancet. 2007;1a] These results led to the design of the REDUCE-IT trial, with the goal of testing the ASCVD risk-reducing efficacy of icosapent ethyl in a placebo-controlled trial.

The REDUCE-IT trial, a phase 3b study, enrolled 8,179 participants ≥ 45 years of age with established ASCVD or ≥ 50 years of age with diabetes and one or more additional ASCVD risk factor(s). Eligible patients had a fasting triglyceride level of 135 to 499 mg/dL and an LDL-C level of 41 to 100 mg/dL, and had been receiving statin therapy for a minimum duration of 4 weeks prior to randomization. Exclusion criteria included severe heart failure, active severe liver disease, glycated hemoglobin levels greater than 10%, imminent coronary intervention or surgery, a history of acute or chronic pancreatitis or documented hypersensitivity to fish, shellfish, or the ingredients of icosapent ethyl or placebo. In the randomized population, 70.7% of patients had established ASCVD and 29.3% had diabetes and at least one ASCVD risk factor. [Bhatt DL, et al. N Engl J Med. 2019;1a,4a]

Patients were randomly assigned to receive 4 g of icosapent ethyl daily (2 g twice per day) or a placebo containing mineral oil. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization or unstable angina. The key secondary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. [Bhatt DL, et al. N Engl J Med. 2019;1a]

In the icosapent ethyl group, a primary endpoint event was observed in 17.2% of patients, compared with 22% of patients in the placebo group, as shown in the Table. Over a median follow-up duration of 4.9 years, the number needed to treat to prevent one primary endpoint event was 21 (95% CI, 15-33). [Bhatt DL, et al. N Engl J Med. 2019;5a]

Enlarge
Source: Adapted from Bhatt DL, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1812792.

A key secondary efficacy endpoint event was observed in 11.2% of patients in the icosapent ethyl group, compared with 14.8% of patients in the placebo group (Table)). Over a median follow-up duration of 4.9 years, the number needed to treat to prevent one key secondary endpoint event was 28 (95% CI, 20-47). [Bhatt DL, et al. N Engl J Med. 2019;5a,5b,6a]

Common adverse reactions (with an incidence of ≥ 3% in the icosapent ethyl group and ≥ 1% more frequent than placebo) included musculoskeletal pain, peripheral edema, constipation, gout and atrial fibrillation. [Vascepa prescribing information;1b]

Controversy surrounding the results of the REDUCE-IT trial and the efficacy of icosapent ethyl for ASCVD risk reduction emerged following the publication of the STRENGTH trial. This randomized, double-blind clinical trial involved 13,078 patients receiving statin therapy and at high cardiovascular risk, [Nicholls SJ, et al. JAMA. 2020;1a] and compared a mixture of EPA and DHA (Epanova, AstraZeneca), at a total daily dose of 4 g per day, with corn oil also at a dose of 4 g per day. The STRENGTH trial was terminated prematurely due to futility, with the primary endpoint, major adverse cardiovascular events (MACE), occurring at an identical rate of 12% in both groups. These results contradicted the positive outcomes seen in REDUCE-IT, where icosapent ethyl demonstrated a significant reduction in MACE compared with mineral oil. [Curfman G, et al. Open Heart. 2021;1a]

The different outcomes between the REDUCE-IT and STRENGTH trials might be attributed to differences in the omega-3 formulations employed. REDUCE-IT used purified icosapent ethyl/EPA (4 g per day), while STRENGTH used a mixture containing both EPA and DHA at the same total dose (4 g per day). Thus, the levels of EPA were not equivalent in the two trials. An alternative perspective suggests that the mineral oil placebo in REDUCE-IT might have adversely affected cardiovascular risk, rather than icosapent ethyl exerting a benefit. Supporting this notion are data from REDUCE-IT, where mineral oil administration was associated with increases in LDL-C, apolipoprotein B and high-sensitivity C-reactive protein relative to icosapent ethyl, potentially contributing to elevated cardiovascular risk. [Curfman G, et al. Open Heart. 2021;3b,4a] Potentially contradicting this notion is that icosapent ethyl also reduced MACE in the JELIS trial, which did not have a placebo arm.  [Curfman G, et al. Open Heart. 2021;4a] Further research with carefully designed trials will be needed to answer the question.

Reference:



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icosapent ethyl
acute coronary syndrome
ischemic heart disease
hypertriglyceridemia
omega-3 fatty acid
 

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