REDUCE-IT: Icosapent ethyl reduces cardiovascular risk even with low LDL-C
August 2025
In this analysis from REDUCE-IT, high-dose icosapent ethyl reduced cardiovascular events by 34% among high cardiovascular risk patients with elevated triglycerides, even among those with low-density lipoprotein cholesterol levels below guideline-recommended targets.
Aggarwal R, Bhatt DL, Steg PG, et al. Cardiovascular outcomes with icosapent ethyl by baseline low-density lipoprotein cholesterol: a secondary analysis of the REDUCE-IT randomized trial. J Am Heart Assoc. 2025;14(5):e038656.
STUDY SUMMARY
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Objective |
To determine the efficacy of icosapent ethyl compared with placebo for cardiovascular event reduction among patients stratified by baseline low-density lipoprotein cholesterol (LDL-C).
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Study design |
REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) was a double-blind, randomized, placebo-controlled trial in high cardiovascular risk patients (aged ≥45 years with cardiovascular disease or ≥50 years with diabetes and ≥1 cardiovascular risk factor). Patients were required to be on statin treatment for at least 4 weeks, and had triglyceride levels between 135 and 499 mg/dL and LDL- C levels between 41 and 100 mg/dL. Eligible patients were randomized to icosapent ethyl (2 g twice daily) or placebo. This report discusses a post hoc secondary analysis of REDUCE-IT.
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Main study variable
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The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.
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Methods |
Patients were stratified by baseline LDL-C (<55 mg/dL or ≥55 mg/dL), according to guideline recommended LDL-C targets for very high-risk patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined using a Cox proportional hazards model to determine the risk of the primary end point according to the use of icosapent ethyl compared with placebo. The model included an interaction term for baseline LDL-C group and treatment group.
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Key results |
The study population included 8175 patients, 7117 (87.1%) with baseline LDL-C ≥55 mg/dL, and 1058 (12.9%) with LDL-C <55 mg/dL. Baseline characteristics are summarized in Table 1.
Table 1. Baseline characteristics stratified by baseline LDL-C group
Treatment with icosapent ethyl was similarly effective in patients with baseline LDL-C ≥55 mg/dL or LDL-C <55 mg/dL. In patients with LDL-C <55 mg/dL, the primary composite end point was reduced by 34% (incidence 16.2% with icosapent ethyl vs. 22.8% on placebo, HR 0.66 [95% CI, 0.50–0.87]). The absolute risk reduction (ARR) was 6.6% and number needed to treat (NNT) was 15 (p=0.003). Similar relative and absolute risk reductions were observed in patients with LDL-C ≥55 mg/dL (17.4% vs. 21.9% on placebo, HR 0.76 [95% CI, 0.69–0.85) with an ARR 4.5% and NNT 22 (p<0.0001).
Among patients with established cardiovascular disease, the relative and absolute risk reductions in the primary end point with icosapent ethyl vs. placebo were numerically more pronounced among patients with LDL-C <55 mg/dL (HR 0.56 [95% CI 0.41–0.77]; ARR 11.6%; p=0.0002) than in those with LDL-C ≥55 mg/dL (HR 0.75 [95% CI 0.67–0.85]; ARR 5.4%; p<0.0001).
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Author conclusions |
Among statin-treated patients with elevated triglycerides and high cardiovascular risk, icosapent ethyl reduced the rate of cardiovascular end points irrespective of baseline LDL-C, including among eligible patients with optimal LDL-C control. |
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Comment
The results of this secondary analysis of REDUCE-IT show that the cardiovascular benefit derived from treatment with high-dose icosapent ethyl in high-risk patients with elevated triglycerides was consistent even among those with very well controlled LDL-C levels, below guideline-recommended goals (1,2). The underlying mechanisms contributing to this benefit continue to be debated, although recent consensus implicates non-triglyceride-related pathways (3-5), especially given neutral results from other cardiovascular outcomes studies testing triglyceride-lowering therapies in high cardiovascular risk patients, notably PROMINENT and STRENGTH (6,7). Irrespective of the specifics of these mechanisms, the findings of this analysis support a strategy of comprehensive lipid management of residual cardiovascular risk which persists even among high cardiovascular risk patients with very well controlled LDL-C levels.
Admittedly there are caveats given the post hoc design of this analysis. Furthermore, in REDUCE-IT randomization was not stratified by baseline LDL-C, which have may have confounded the results. Despite this, the take home message from this study is that icosapent ethyl has value in reducing residual cardiovascular risk even among high cardiovascular risk patients who attain guideline-recommended LDL-C levels. However, translating guideline recommendations to the clinical setting remains problematic (8). Indeed, recent data from the CALLINICUS-Hellas Registry (9) show that among patients with a recent acute coronary syndrome, about one 1 in 4 who are eligible for treatment with icosapent ethyl do not routinely receive this therapy, leaving them at increased risk of myocardial reinfarction within 12 months. Improved guideline implementation is needed to counter this low uptake to improve the management of residual cardiovascular risk.
References
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and
European Atherosclerosis Society (EAS). Eur Heart J 2020;41:111–88.
- Lloyd- Jones DM, Morris PB, Ballantyne CM, et al. ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution set Oversight Committee. J Am Coll Cardiol 2022;80:1366–418.
- Bhatt DL, Steg PG, Miller M, et al. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol 2019;74:1159–61.
- Mason RP, Libby P, Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega- 3 fatty acid eicosapentaenoic acid. Arterioscler Thromb Vasc Biol 2020;40:1135–47.
- Sherratt SCR, Libby P, Budoff MJ, et al. Role of omega-3 fatty acids in cardiovascular disease: the debate continues. Curr Atheroscler Rep 2023;25:1–17.
- Das Pradhan A, Glynn RJ, Fruchart J-C, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923–34.
- 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;324:2268–80.
- Gaba P, Bhatt DL, Boden WE. Icosapent ethyl for hypertriglyceridaemia and atherosclerosis: greater RESPECT for increased therapeutic use. Eur Heart J 2023;45:ehad668.
- Rallidis LS, Tsamoulis D, Papathanasiou KA, et al. Eligibility for icosapent ethyl 1–3 months after acute coronary syndrome and the risk for myocardial re-infarction: Data from the CALLINICUS-Hellas Registry. Int J Cardiol 2025; 440: 133684.
Key words: REDUCE-IT; residual cardiovascular risk; triglycerides;
