Consistent effect of icosapent ethyl on MACE across a range of Lp(a) levels


Among statin-treated participants in REDUCE-IT with hypertriglyceridemia and well-controlled LDL-c, baseline Lp(a) levels were associated with MACE. Icosapent ethyl reduced MACE risk consistently across a range of Lp(a) levels compared placebo.

This summary is based on the publication of Szarek M, Bhatt DL, Miller M, et al. - Lipoprotein(a) Blood Levels and Cardiovascular Risk Reduction With Icosapent Ethyl. J Am Coll Cardiol. 2024 Mar 15:S0735-1097(24)00384-X. doi: 10.1016/j.jacc.2024.02.016.

Introduction and methods


There is a relationship between elevated Lp(a) concentrations and CV risk in various CV outcomes trials which enrolled participants with elevated LDL-c levels [1-6]. In REDUCE-IT, treatment with icosapent ethyl versus placebo reduced CV outcomes in statin-treated patients with CVD or DM and elevated triglyceride levels [7]. It is unknown whether there is an association between Lp(a) concentrations and CV outcomes in trails which selected participants on the basis of elevated levels of other lipids than LDL-c.

Aim of the study

The aim of this post hoc analysis of REDUCE-IT was to investigate the association between baseline Lp(a) levels and CV risk among participants in REDUCE-IT with well-controlled LDL-c, and whether the treatment effect of icosapent ethyl varies across the range of Lp(a) levels.


The REDUCE-IT trial was an international, double-blind, placebo-controlled trial in which 8179 statin-treated patients with controlled LDL-c (41-100 mg/dL [1.06-2.59 mmol/L]) and elevated triglycerides (150-499 mg/dL [1.69-5.63 mmol/L]), and with either established CVD or with diabetes and at least one additional risk factor, were randomized to either IPE 4g/day or placebo. In the present analyses, 7026 patients from REDUCE-IT with available Lp(a) measurements at baseline were included. The median Lp(a) concentration was 11.6 mg/dL (Q1-Q3: 5.03-37.4). The median follow-up period was 4.9 years (Q1-Q3: 3.6-5.3)


The primary outcome was time to first MACE, a composite of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization or hospitalization for unstable angina.

Main results

MACE predictors

  • There was a positive relationship between baseline Lp(a) concentration and first MACE after adjusting for baseline triglycerides, baseline LDL-c and treatment assignment (P<0.0001). The estimated HRs for first MACE across various Lp(a) concentrations were: 1.03 (95%CI: 0.98-1.09) at 25 mg/dL, 1.12 (95%CI: 1.06-1.19) at 50 mg/dL, and 1.32 (95%CI: 1.17-1.49) at 100 mg/dL.
  • In models without interaction terms, there was a significant relationship between first MACE and baseline triglycerides (P=0.0002), but not between first MACE and baseline LDL-c (P=0.77).

Treatment effect of icosapent ethyl

  • Icosapent ethyl reduced the risk of first MACE and total (first and subsequent) MACE across the range of baseline Lp(a) concentrations compared with placebo. The estimated HRs for first MACE were 0.74 (95%CI: 0.66-0.84) at the median 11.6 mg/dL concentration, 0.78 (95%CI: 0.65-0.94) at 25 mg/dL, 0.79 (95%CI: 0.68-0.92) at 50 mg/dL, and 0.81 (95%CI: 0.66-0.99) at 100 mg/dL.
  • The relative treatment effect of icosapent ethyl on first MACE was comparable between participants with lower versus higher Lp(a) concentrations at baseline (HR: 0.75 in <50 mg/dL; and HR: 0.79 in ≥50 mg/dL; P for interaction=0.68).
  • The absolute first MACE risk reduction with icosapent ethyl at 5 years was 5.7% vs. 6.5% in the <50 mg/dL and ≥50 mg/dL groups, respectively.


In this post hoc analysis of REDUCE-IT, baseline Lp(a) concentrations were associated with first MACE among participants with elevated triglycerides who were receiving background statin therapy. Moreover, icosapent ethyl reduced MACE risk across the range of Lp(a) levels compared with placebo.


  1. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020;75:133–144.
  2. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. 2019;139:1483–1492.
  3. Willeit P, Ridker PM, Nestel PJ, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018;392:1311–1320.
  4. Szarek M, Reijnders E, Jukema JW, et al. Relating lipoprotein(a) concentrations to cardiovascular event risk after acute coronary syndrome: a comparison of 3 tests. Circulation. 2024;149:192– 203.
  5. Szarek M, Bittner VA, Aylward P, et al. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J. 2020;41: 4245–4255.
  6. Khera AV, Everett BM, Caulfield MP, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129:635– 642.
  7. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.

Find this article online at J Am Coll Cardiol.

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