What is icosapent ethyl?

Icosapent Ethyl: A Prescription Omega-3 Fatty Acid for Cardiovascular Risk Reduction

Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester that reduces triglyceride levels and cardiovascular events in high-risk patients, with FDA approval for severe hypertriglyceridemia and cardiovascular risk reduction in select populations. 1, 2

Chemical Structure and Formulation

• Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA) with the empirical formula C₂₂H₃₄O₂ and molecular weight of 330.51 2
• Available as a 1-gram transparent soft gelatin capsule for oral administration 2
• Contains ≥96% pure EPA ethyl ester without docosahexaenoic acid (DHA), which is an advantage over some other omega-3 preparations 1

Mechanism of Action

Icosapent ethyl works through multiple mechanisms:

• Reduces hepatic very low-density lipoprotein triglyceride (VLDL-TG) synthesis and/or secretion 2
• Enhances triglyceride clearance from circulating VLDL particles 2
• Increases β-oxidation and plasma lipoprotein lipase activity 2
• Decreases lipogenesis in the liver 2
• Exhibits significant anti-inflammatory effects, with a 39.9% reduction in high-sensitivity C-reactive protein (hs-CRP) 1, 3
• Reduces oxidized low-density lipoprotein (Ox-LDL) and lipoprotein-associated phospholipase A₂ (Lp-PLA₂) levels 3

Clinical Efficacy

Icosapent ethyl has demonstrated significant clinical benefits:

• In the REDUCE-IT trial, icosapent ethyl reduced cardiovascular events by 25% in patients with established cardiovascular disease or diabetes plus additional risk factors 4, 1
• Reduces triglyceride levels by approximately 20-33% compared to placebo in patients with triglyceride levels between 135-499 mg/dL 1, 5
• Unlike other triglyceride-lowering therapies, icosapent ethyl does not increase LDL-C levels 1, 6
• Shows dose-dependent increases in EPA concentrations in plasma and red blood cells, which correlate with the degree of triglyceride lowering 5

FDA-Approved Indications

1. Severe Hypertriglyceridemia: Adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia 2, 6

2. Cardiovascular Risk Reduction: For patients with established cardiovascular disease or diabetes with at least two additional cardiovascular risk factors who have triglyceride levels >150 mg/dL while on statin therapy 4, 1

Dosage and Administration

• Recommended dosage: 2 grams twice daily with food, for a total daily dose of 4 g/day 1
• Should be taken with or following meals 2
• Peak plasma concentrations of EPA are reached approximately 5 hours following oral administration 2
• Maximum effects on triglyceride levels typically occur after 4-12 weeks of treatment 1

Safety Profile and Adverse Effects

Icosapent ethyl is generally well-tolerated but has some notable adverse effects:

• Increased risk of atrial fibrillation: 5.3% vs. 3.9% with placebo 1
• Atrial fibrillation requiring hospitalization: 3.1% vs. 2.1% 1
• Peripheral edema: 6.5% vs. 5.0% 1
• Constipation: 5.4% vs. 3.6% 1
• Bleeding tendency: A trend toward more bleeding-related disorders, especially in patients on anticoagulants 1

Patient Selection

Optimal candidates for icosapent ethyl therapy include:

• Patients with established cardiovascular disease or diabetes plus additional risk factors 4, 1
• Patients with triglyceride levels between 135-499 mg/dL while on statin therapy 4, 1
• Patients with controlled LDL-C levels 4

Important Distinctions from Other Omega-3 Products

• Icosapent ethyl contains only EPA without DHA, unlike many over-the-counter omega-3 supplements 1, 7
• Low-dose mixtures of EPA and DHA have not demonstrated cardiovascular risk reduction in clinical trials 4
• Only high-purity prescription icosapent ethyl (not combination EPA/DHA products) is indicated for cardiovascular risk reduction 7

Monitoring Recommendations

• Monitor for symptoms of atrial fibrillation 1
• Watch for bleeding events, especially in patients taking anticoagulants or antiplatelet therapies 1
• In patients with hepatic impairment, monitor ALT and AST levels periodically 2
• Assess lipid levels to evaluate treatment efficacy 1

Icosapent ethyl represents an important advancement in cardiovascular risk reduction therapy, offering benefits beyond traditional lipid-lowering approaches for selected high-risk patients.