Icosapent ethyl (brand name Vascepa, made by Amarin) is a prescription drug made of highly purified eicosapentaenoic acid (EPA), one of the omega-3 fatty acids in fish oil. At 4 grams a day it lowers triglycerides, and in the REDUCE-IT trial it cut major cardiovascular events by 25% in statin-treated, high-risk adults. That result is debated because REDUCE-IT’s placebo was mineral oil, which appears to have raised LDL cholesterol and inflammation markers in the comparison group, and a similar trial of an EPA plus DHA product using corn oil found no benefit.
The FDA label warns of atrial fibrillation and bleeding. Icosapent ethyl is not the same as over-the-counter fish oil capsules, and none of its trials enrolled people using anabolic steroids, whose main lipid changes (low HDL, high LDL and apolipoprotein B) are not what it targets.
This page summarizes what the FDA label, the outcome trials and the analyses of the placebo question report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Omega-3 fatty acid; ethyl ester of EPA |
| Brand / maker | Vascepa (Amarin); Vazkepa in the EU; generics in the US since 2020 |
| US approval | NDA 202057, approved July 26, 2012 (severe hypertriglyceridemia); cardiovascular risk reduction added December 13, 2019 |
| EU approval | Vazkepa, authorized March 26, 2021 |
| Route and strengths | Oral soft-gel capsules, 0.5 g and 1 g |
| Labeled dose | 4 g/day, taken as 2 g twice daily with food |
| Half-life | EPA ≈89 h in plasma |
| Key trial | REDUCE-IT: 8,179 statin-treated patients; primary events 17.2% vs 22.0% (HR 0.75) |
| Warnings | Atrial fibrillation or flutter; bleeding; possible allergy in people allergic to fish or shellfish |
| US status | Prescription only |
| WADA status | Not named on the 2026 Prohibited List |
What it is
Icosapent ethyl is EPA (a 20-carbon omega-3 fatty acid) bound to ethanol as an ethyl ester, with the formula C₂₂H₃₄O₂ and molecular weight 330.51. It is obtained from fish oil and contains EPA only, without docosahexaenoic acid (DHA), the other main omega-3 in fish oil (Vascepa label).
How it differs from fish oil
| Product | Contents | Daily dose in outcome trials | Outcome evidence |
|---|---|---|---|
| Icosapent ethyl (Vascepa) | EPA only, prescription grade | 4 g | REDUCE-IT positive (mineral oil comparator) |
| Omega-3 carboxylic acids (tested in STRENGTH) | EPA + DHA | 4 g | STRENGTH neutral (corn oil comparator) |
| Over-the-counter fish oil | EPA + DHA, variable | 840 mg/day EPA + DHA in VITAL and ASCEND (see the fish oil page) | No reduction in major cardiovascular events in those trials |
The fish oil page covers supplement-dose fish oil and the other prescription omega-3, Lovaza. The REDUCE-IT dose is 4 g of EPA ethyl ester daily. Ordinary capsules supply EPA mixed with DHA and other fats, so taking more of them is not the same as what REDUCE-IT tested.
Mechanism
According to the label, studies suggest EPA reduces the liver’s production and secretion of VLDL triglycerides and speeds their clearance, through increased fat burning (beta-oxidation), inhibition of the enzyme DGAT, less fat synthesis in the liver and higher lipoprotein lipase activity. The label says the mechanisms behind the reduction in cardiovascular events “are not completely understood but are likely multi-factorial”; observed effects include more EPA in carotid plaque, a higher EPA to arachidonic acid ratio and inhibition of platelet aggregation under some laboratory conditions (Vascepa label). The drop in triglycerides in REDUCE-IT (median −18% at 1 year) was too small to explain the 25% reduction in events, so other effects of EPA, or of the comparator, have been proposed (discussed below).
Pharmacokinetics
From the label (Vascepa label):
| Parameter | Value |
|---|---|
| Absorption | De-esterified in the gut; EPA enters the circulation mainly through the lymphatic system |
| Time to peak | About 5 h |
| Food | All trials gave it with or after a meal; take with food |
| Volume of distribution | About 88 L |
| Protein binding | Over 99% of unesterified EPA |
| Metabolism | Mainly beta-oxidation in the liver, like dietary fat; cytochrome P450 is a minor pathway |
| Clearance | 684 mL/h |
| Half-life | About 89 h |
| Renal excretion | None |
In interaction studies, 4 g/day did not change blood levels of omeprazole, rosiglitazone, warfarin (or warfarin’s anticoagulant effect) or atorvastatin.
Approved medical use
The US label approves icosapent ethyl for adults in two settings (Vascepa label):
- Cardiovascular risk reduction, as an add-on to maximally tolerated statin therapy, to reduce heart attack, stroke, coronary revascularization and unstable angina requiring hospitalization, in people with triglycerides of 150 mg/dL or more and either established cardiovascular disease or diabetes plus 2 or more other risk factors.
- Severe hypertriglyceridemia (500 mg/dL or more), as an add-on to diet. The label states that its effect on pancreatitis risk is not known.
Approval history from Drugs@FDA: the original approval for severe hypertriglyceridemia was July 26, 2012, and the cardiovascular indication was approved December 13, 2019 (openFDA, NDA 202057). The first generic version (Hikma) was approved May 21, 2020, and several others followed. In the EU, Vazkepa received a marketing authorization valid throughout the Union on March 26, 2021 (EMA).
Triglyceride lowering
In a 12-week trial of 151 adults with triglycerides of 500–2,000 mg/dL (median 684 mg/dL), 4 g/day lowered triglycerides by a median 33% more than placebo (95% CI −47% to −22%). LDL did not change significantly (difference −2%, 95% CI −13% to +8%) (Vascepa label).
What the research shows
REDUCE-IT
REDUCE-IT randomized 8,179 adults on statins with fasting triglycerides of 135–499 mg/dL and LDL of 41–100 mg/dL; 70.7% had established cardiovascular disease and the rest had diabetes plus other risk factors. Patients took 2 g twice daily or placebo for a median of 4.9 years. The trial was funded by Amarin (Bhatt et al., NEJM 2019). Results as shown in the label:
| Endpoint | Icosapent ethyl (n = 4,089) | Placebo (n = 4,090) | Hazard ratio (95% CI) |
|---|---|---|---|
| Primary: CV death, heart attack, stroke, revascularization, unstable angina | 17.2% | 22.0% | 0.75 (0.68–0.83) |
| Key secondary: CV death, heart attack, stroke | 11.2% | 14.8% | 0.74 (0.65–0.83) |
| Fatal or nonfatal heart attack | 6.1% | 8.7% | 0.69 (0.58–0.81) |
| Urgent coronary revascularization | 5.3% | 7.8% | 0.65 (0.55–0.78) |
| Cardiovascular death | 4.3% | 5.2% | 0.80 (0.66–0.98) |
| Hospitalization for unstable angina | 2.6% | 3.8% | 0.68 (0.53–0.87) |
| Fatal or nonfatal stroke | 2.4% | 3.3% | 0.72 (0.55–0.93) |
From baseline to year 1, median triglycerides changed by −18% on icosapent ethyl and +2% on placebo. Median LDL changed by +3% on icosapent ethyl and +10% on placebo (Vascepa label).
The mineral oil placebo controversy
REDUCE-IT’s placebo was pharmaceutical-grade mineral oil. The concern is that mineral oil is not inert: if it made the placebo group worse, part of the 25% “benefit” would reflect harm in the comparison group.
Evidence that the placebo group worsened:
- In a biomarker substudy, markers linked to atherosclerosis rose over time in the mineral oil group but changed little on icosapent ethyl. At 12 months, the mineral oil group’s median increases were 10.9% for oxidized LDL, 16.2% for interleukin-6, 21.9% for high-sensitivity C-reactive protein (hs-CRP) and 28.9% for interleukin-1β. LDL rose 10.9% on mineral oil vs −1.2% on icosapent ethyl. Ridker and colleagues wrote that the effect of these findings on interpreting the trial is uncertain (Ridker et al., Circulation 2022).
- Danish researchers applied the lipid and CRP changes from each trial’s active and comparator arms to 106,088 people in the Copenhagen General Population Study. The changes seen in REDUCE-IT predicted an active-vs-comparator hazard ratio of 0.88, compared with the 0.75 actually observed; for STRENGTH, the prediction was 0.96 vs the observed 0.99. They concluded that the contrasting results “can partly be explained by a difference in the effect of comparator oils (mineral vs. corn),” and that the remaining 13% risk reduction in REDUCE-IT was likely through other effects of EPA or mineral oil (Doi et al., Eur Heart J 2021).
Evidence offered against a major placebo effect:
- A review of 80 studies that used mineral oil placebos found its side effects were mainly gastrointestinal and its effects on lipids, hs-CRP and blood pressure were inconsistent and generally not significant, with no consistent evidence that it reduces absorption of statins. The authors, including the lead EVAPORATE investigator, concluded that mineral oil “does not meaningfully affect study conclusions” at trial doses (Olshansky et al., Eur Heart J Suppl 2020).
- In the Danish analysis above, mineral oil’s predicted effect accounted for only part of the gap; a residual benefit remained (Doi et al., 2021).
The question is unresolved. The FDA approved the cardiovascular indication with the trial as designed, and the label describes the comparator simply as “placebo.”
STRENGTH: the contrasting trial
STRENGTH gave 13,078 statin-treated, high-risk patients 4 g/day of omega-3 carboxylic acids (EPA plus DHA) or corn oil. It was stopped early for a low probability of benefit: the primary outcome occurred in 12.0% vs 12.2% (Nicholls et al., JAMA 2020). A secondary analysis found that even patients in the top third of achieved plasma EPA levels had no benefit compared with corn oil (HR 0.98, 95% CI 0.83–1.16) (Nissen et al., JAMA Cardiol 2021). That finding argues against the idea that STRENGTH simply did not raise EPA enough, though the products also differ (EPA alone vs EPA plus DHA).
Other purified EPA trials
| Trial | Design | Dose | Main result |
|---|---|---|---|
| JELIS (Yokoyama et al., Lancet 2007) | Open-label, 18,645 Japanese patients with high cholesterol on statins; no placebo; 4.6 years | EPA 1,800 mg/day | Major coronary events 2.8% vs 3.5% (19% relative reduction); no difference in sudden or coronary death |
| RESPECT-EPA (Miyauchi et al., Circulation 2024) | Open-label, 2,506 Japanese patients with coronary disease and a low EPA/arachidonic acid ratio; no placebo; median 5 years | Icosapent ethyl 1,800 mg/day | Primary outcome 9.1% vs 12.6% (HR 0.79, 95% CI 0.62–1.00, P = 0.055, not significant); new atrial fibrillation 3.1% vs 1.6% |
| EVAPORATE (Budoff et al., Eur Heart J 2020) | Double-blind imaging trial, 80 statin-treated patients with coronary plaque; 18 months; mineral oil placebo | 4 g/day | Low-attenuation plaque volume −17% vs +109% on placebo |
EVAPORATE also used mineral oil, so it shares REDUCE-IT’s comparator question. A 2025 meta-analysis of 16 randomized trials (127,771 patients) found purified EPA lowered cardiovascular death (HR 0.79, 95% CI 0.67–0.94), with a smaller effect for EPA plus DHA (HR 0.92) (Sheppard et al., JACC Adv 2025). Pooled analyses that include REDUCE-IT inherit its placebo issue.
Relevance to anabolic steroid use
No trial of icosapent ethyl has enrolled AAS users. The typical AAS lipid pattern is not the one icosapent ethyl was tested for:
- In athletes self-administering AAS, HDL fell from about 42 to 17 mg/dL and apolipoprotein B rose, while total cholesterol and triglycerides did not change significantly (Hartgens et al., Br J Sports Med 2004). In a 100-man prospective cohort, LDL and apolipoprotein B rose and HDL fell during a cycle (Smit et al., Andrologia 2022).
- Icosapent ethyl is approved for raised triglycerides in people already on a statin. In the label trial it did not meaningfully change LDL, and it is not an HDL-raising drug.
- For LDL and apolipoprotein B, the drugs with outcome evidence are atorvastatin, rosuvastatin, ezetimibe and evolocumab.
- Its two main warnings, atrial fibrillation and bleeding, are relevant to people who also take low-dose aspirin, nattokinase or other agents that affect clotting.
Side effects and risks
Atrial fibrillation
The label warns that icosapent ethyl increases the risk of atrial fibrillation (AF) or atrial flutter requiring hospitalization. In REDUCE-IT this occurred in 127 patients (3%) vs 84 (2%) on placebo, HR 1.5 (95% CI 1.14–1.98), and the risk was higher in people with a history of AF (Vascepa label). The signal is consistent across omega-3 trials. A meta-analysis of 7 trials (81,210 patients) found a 25% higher AF risk overall, a larger increase in trials using more than 1 g/day (HR 1.49) than 1 g/day or less (HR 1.12), and an 11% rise in risk per extra gram per day (Gencer et al., Circulation 2021). RESPECT-EPA also found more new AF (3.1% vs 1.6%).
Bleeding
In REDUCE-IT, 12% on icosapent ethyl had a bleeding event vs 10% on placebo, and serious bleeding occurred in 3% vs 2%. Bleeding was more common with aspirin, clopidogrel or warfarin. The label advises monitoring people on anticoagulants or antiplatelet drugs (Vascepa label). The NEJM paper reported serious bleeding in 2.7% vs 2.1% (P = 0.06) (Bhatt et al., 2019).
Other side effects
| Setting | Adverse reactions more common than placebo |
|---|---|
| Outcome trial (≥3% and ≥1% above placebo) | Musculoskeletal pain, peripheral edema (swelling), constipation, gout, atrial fibrillation |
| Triglyceride trials (≥1% above placebo) | Joint pain, throat pain |
| Postmarketing reports | Diarrhea, abdominal discomfort, pain in the extremities, increased triglycerides |
Source: Vascepa label.
Who should be cautious
- Fish or shellfish allergy: EPA is obtained from fish oil; whether allergic people are at higher risk is not known.
- Known hypersensitivity to icosapent ethyl or its ingredients is the only contraindication.
- Liver or kidney impairment: not studied.
- Capsules must be swallowed whole, not broken, crushed or chewed.
Legal status and use in sport
Icosapent ethyl is a prescription drug in the US and the EU. It is not named on the WADA 2026 Prohibited List.
Key takeaways
- Purified prescription EPA. Icosapent ethyl is EPA alone at 4 g/day, not the EPA plus DHA found in fish oil capsules.
- A positive but debated outcome trial. REDUCE-IT showed 17.2% vs 22.0% major events (HR 0.75), but its mineral oil placebo raised LDL by about 10% and inflammation markers, which may explain part of the effect.
- The EPA plus DHA trial was neutral. STRENGTH, with corn oil as comparator, found 12.0% vs 12.2%; patients with the highest EPA levels still saw no benefit.
- Atrial fibrillation and bleeding are labeled risks. AF hospitalization 3% vs 2%; any bleeding 12% vs 10%, higher with antiplatelet drugs or anticoagulants.
- Approved for a narrow group. Adults on maximally tolerated statins with triglycerides of 150 mg/dL or more and high cardiovascular risk, or with triglycerides of 500 mg/dL or more.
- Not tested in steroid users. AAS mainly lower HDL and raise LDL and apo B; icosapent ethyl does not target either, and no trial has studied it in this group.
Sources
- Amarin Pharma. Vascepa (icosapent ethyl) capsules prescribing information (revised March 2026). DailyMed.
- US Food and Drug Administration. Drugs@FDA data for NDA 202057 (Vascepa) and icosapent ethyl generic approvals. Accessed November 2026. openFDA.
- European Medicines Agency. Vazkepa (icosapent ethyl): EPAR. 2021, updated 2026. EMA.
- 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. PubMed.
- Ridker PM, Rifai N, MacFadyen J, et al. Effects of randomized treatment with icosapent ethyl and a mineral oil comparator on interleukin-1β, interleukin-6, C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2: a REDUCE-IT biomarker substudy. Circulation. 2022;146(5):372–379. PubMed.
- Doi T, Langsted A, Nordestgaard BG. A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Eur Heart J. 2021;42(47):4807–4817. PubMed.
- Olshansky B, Chung MK, Budoff MJ, et al. Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies. Eur Heart J Suppl. 2020;22(Suppl J):J34–J48. PubMed.
- Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA. 2020;324(22):2268–2280. PubMed.
- Nissen SE, Lincoff AM, Wolski K, et al. Association between achieved ω-3 fatty acid levels and major adverse cardiovascular outcomes in patients with high cardiovascular risk: a secondary analysis of the STRENGTH trial. JAMA Cardiol. 2021;6(8):910–917. PubMed.
- Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–1098. PubMed.
- Miyauchi K, Iwata H, Nishizaki Y, et al. Randomized trial for evaluation in secondary prevention efficacy of combination therapy-statin and eicosapentaenoic acid (RESPECT-EPA). Circulation. 2024;150(6):425–434. PubMed.
- Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J. 2020;41(40):3925–3932. PubMed.
- Sheppard JP, Palatnic L, Lakshmanan S, et al. Effects of eicosapentaenoic acid vs eicosapentaenoic/docosahexaenoic acids on cardiovascular mortality: meta-analysis of clinical trials. JACC Adv. 2025;4(10 Pt 2):102149. PubMed.
- Gencer B, Djousse L, Al-Ramady OT, et al. Effect of long-term marine ω-3 fatty acids supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes: a systematic review and meta-analysis. Circulation. 2021;144(25):1981–1990. PubMed.
- Hartgens F, Rietjens G, Keizer HA, et al. Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a). Br J Sports Med. 2004;38(3):253–259. PubMed.
- Smit DL, Grefhorst A, Buijs MM, et al. Prospective study on blood pressure, lipid metabolism and erythrocytosis during and after androgen abuse. Andrologia. 2022;54(4):e14372. PubMed.
- World Anti-Doping Agency. The 2026 Prohibited List (in effect January 1, 2026). 2025. WADA.