What is Vascepa (icosapent ethyl)?

What is Vascepa (Icosapent Ethyl)?

Vascepa (icosapent ethyl) is a highly purified prescription formulation of eicosapentaenoic acid (EPA) ethyl ester—an omega-3 fatty acid—that is FDA-approved for reducing triglycerides in severe hypertriglyceridemia and, more importantly, for reducing cardiovascular events in high-risk patients with elevated triglycerides already on statin therapy. 1

Chemical Composition and Formulation

• Icosapent ethyl is an ethyl ester of the omega-3 fatty acid EPA with the chemical formula C₂₂H₃₄O₂ and molecular weight of 330.51 1
• Each capsule contains 1 gram of icosapent ethyl (≥96% pure EPA ethyl ester) in a liquid-filled soft gelatin capsule 1, 2
• Critically, it contains NO docosahexaenoic acid (DHA), which distinguishes it from mixed omega-3 products and is clinically important because DHA can increase LDL cholesterol 2, 3
• After oral administration, icosapent ethyl is de-esterified during absorption and converted to active EPA in the small intestine 1

FDA-Approved Indications

Primary Indication: Cardiovascular Risk Reduction

• The American Heart Association and American College of Cardiology support icosapent ethyl 4 grams daily (2 g twice daily with food) for patients with:
  • Established atherosclerotic cardiovascular disease (ASCVD) ≥45 years OR diabetes ≥50 years with additional cardiovascular risk factors 4
  • Already on statin therapy with controlled LDL-C (41-100 mg/dL) 4
  • Elevated triglycerides (135-499 mg/dL, median baseline 216 mg/dL) 5

Secondary Indication: Severe Hypertriglyceridemia

• Approved as adjunct to diet for adults with severe hypertriglyceridemia (≥500 mg/dL) to reduce triglycerides and pancreatitis risk 2, 3

Cardiovascular Benefits: The REDUCE-IT Trial Evidence

The landmark REDUCE-IT trial of 8,179 patients demonstrated that icosapent ethyl produces a 25% relative risk reduction in major cardiovascular events—a magnitude of benefit that exceeds what would be expected from triglyceride lowering alone. 5

Primary Outcomes

• Primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) occurred in 17.2% with icosapent ethyl vs 22.0% with placebo (HR 0.75, p<0.001) 5
• This represents an absolute risk reduction of 4.8% and number needed to treat of 21 over 4.9 years 5

Key Secondary Outcomes

• Cardiovascular death, nonfatal MI, or nonfatal stroke reduced by 26.5% (11.2% vs 14.8%, HR 0.74, p<0.001) 5
• Number needed to treat of 28 for this hard endpoint 5
• Cardiovascular death alone reduced by 20% (p=0.03) 5
• Cardiac arrest reduced by 48% (HR 0.52, p<0.001) 5
• Sudden cardiac death reduced by 31% (HR 0.69, p<0.05) 5

Mechanism of Benefit: Beyond Triglyceride Lowering

The cardiovascular benefit appears disproportionate to the modest lipid effects, suggesting mechanisms beyond simple triglyceride reduction. 5

• Triglyceride reduction of only 19.7% from baseline 5
• Non-HDL-C reduction of 13.1% 5, 4
• LDL-C reduction of 6.6% (importantly, no increase in LDL-C unlike DHA-containing products) 5, 4
• Apolipoprotein B reduction of 9.7% 5, 4

Importantly, cardiovascular benefit was identical in patients with baseline triglycerides ≥200 mg/dL and those <150 mg/dL, indicating the benefit is not primarily triglyceride-mediated. 5

Proposed Additional Mechanisms

• 358% increase in EPA concentration correlates more strongly with benefit than triglyceride changes 5
• 39.9% reduction in high-sensitivity CRP suggesting anti-inflammatory effects 5
• Potential anti-arrhythmic or membrane-stabilizing effects based on cardiac arrest and sudden death reductions 5
• Enhanced triglyceride clearance through increased β-oxidation and lipoprotein lipase activity 1

Safety Profile and Adverse Events

Icosapent ethyl was generally well-tolerated with treatment-emergent adverse events occurring at similar rates to placebo, but specific adverse events require monitoring. 5

Significant Adverse Events

• Atrial fibrillation or flutter: 5.3% vs 3.9% with placebo (p=0.003) 5
• Atrial fibrillation requiring hospitalization: 3.1% vs 2.1% with placebo (HR 1.5, p=0.004)—particularly concerning in patients with prior atrial fibrillation history 4
• Peripheral edema: 6.5% vs 5.0% with placebo (p=0.002) 5
• Constipation: 5.4% vs 3.6% with placebo (p<0.001) 5
• Bleeding-related disorders showed a trend toward increase but did not reach statistical significance 5

Monitoring Requirements

• The American Heart Association and American College of Cardiology recommend monitoring for signs and symptoms of atrial fibrillation, particularly in patients with prior history 4
• Monitor ALT and AST periodically in patients with hepatic impairment 1
• Evaluate triglyceride levels at 4-12 weeks to document efficacy 6

Dosing and Administration

• Standard dose: 2 grams twice daily (4 grams total daily) with or following meals 5, 1
• Peak plasma EPA concentrations reached approximately 5 hours after dosing 1
• Maximum triglyceride-lowering effect occurs within 4-12 weeks 6
• Plasma elimination half-life of EPA is approximately 89 hours 1
• No renal excretion; no dose adjustment needed for renal impairment 1

Critical Distinction from Other Omega-3 Products

Icosapent ethyl is superior to mixed EPA/DHA formulations for cardiovascular outcomes—this is a crucial clinical distinction. 4

• Meta-analyses of low-dose EPA+DHA mixtures (like standard fish oil) show NO effect on cardiovascular events 5, 4
• Two large trials of 840 mg/day omega-3 fatty acids (EPA+DHA) failed to meet cardiovascular endpoints 5
• The American Diabetes Association explicitly states that results should not be extrapolated to other omega-3 products 5
• DHA-containing products may increase LDL-C, which icosapent ethyl does not 2, 3

Patient Selection Algorithm

Use icosapent ethyl in patients who meet ALL of the following criteria: 5, 4

1. Age ≥45 years with established ASCVD OR age ≥50 years with diabetes plus additional cardiovascular risk factors
2. Already on stable moderate- or high-intensity statin therapy (±ezetimibe) for ≥4 weeks
3. Fasting triglycerides 135-499 mg/dL (median baseline in REDUCE-IT was 216 mg/dL)
4. LDL-C controlled at 41-100 mg/dL (median baseline 75 mg/dL)
5. HbA1c <10% if diabetic
6. No history of severe heart failure, pancreatitis, or recurrent atrial fibrillation

Common Pitfalls to Avoid

• Do not substitute generic fish oil or mixed EPA/DHA products—the cardiovascular benefit is specific to high-dose purified EPA 5, 4
• Do not use in patients with severe hypertriglyceridemia (≥500 mg/dL) as first-line therapy for pancreatitis prevention—fenofibrate is preferred for this indication 7
• Do not combine with fibrates for cardiovascular benefit—statin plus fibrate combination has not shown cardiovascular outcome improvement 5, 7
• Do not ignore atrial fibrillation risk—screen patients with prior history carefully and monitor during treatment 4
• Do not expect benefit in patients not on statin therapy—all REDUCE-IT patients were on statins 5