Physicians' Academy for Cardiovascular Education

Icosapent ethyl has minimal effect on 7 atherosclerotic biomarkers

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

Literature - Ridker PM, Rifai N, MacFadyen J, et al. - Circulation. 2022 Aug 2;146(5):372-379. doi: 10.1161/CIRCULATIONAHA.122.059410

Introduction and methods


In the previous REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) study, treatment with icosapent ethyl led to a 25% relative risk reduction in first MACE and a 30%-reduction in total ischemic events compared with mineral oil in patients with elevated triglyceride levels [1,2]. However, it is not clear which mechanisms underlie these clinical benefits. Icosapent ethyl may inhibit the interleukin (IL)-1β/IL-6/CRP pathway (which is important for atherosclerosis development [3-5]) or have beneficial effects on biomarkers such as oxidized LDL-c (oxLDL-c), homocysteine, Lp(a), and Lp-associated phospholipase A2 (Lp-PLA2) [6-8].

Aim of the study

The authors sought to investigate these potential mechanisms by measuring the concentrations of several biomarkers that are part of pathways known to be associated with atherosclerotic disease, in patients with elevated triglyceride levels throughout the REDUCE-IT trial.


In the multicenter, randomized, double-blind, placebo-controlled REDUCE-IT trial, 8179 statin-treated patients with established atherosclerotic disease (or DM plus ≥1 additional CVD risk factor) and with increased triglyceride levels (135–499 mg/dL ) were randomized to icosapent ethyl or pharmaceutical-grade mineral oil, both 2 g twice daily. The median follow-up duration was 4.9 years (maximum: 6.2 years).

For this biomarker substudy of the REDUCE-IT trial, 8175 trial patients with serum samples at baseline, 12 months, 24 months, and end-of-study visit were included. Changes in the levels of IL-1β, IL-6, hs-CRP, oxLDL-c, homocysteine, Lp(a), and Lp-PLA2 between baseline and 1 of the 3 later time points were assessed

Main results


In patients with elevated triglyceride levels who are taking statins as primary or secondary prevention, the intake of icosapent ethyl 4 g daily for a few years had little to no effect on the serum levels of 7 biomarkers associated with atherosclerotic disease (IL-1β, IL-6, hs-CRP, oxLDL-c, homocysteine, Lp(a), and Lp-PLA2), while these levels increased in those receiving the same quantity of mineral oil instead.

It is not apparent why the biomarker levels were raised in the mineral oil group. Previously, the STRENGTH trial showed neutral effects of treatment with eicosapentaenoic acid plus docosahexaenoic acid in statin-treated patients at high CVD risk with elevated triglyceride levels and low HDL-c levels [9,10]. This sparked controversy about the use of mineral oil as a comparator in the REDUCE-IT trial [11-13]. The authors of the current biomarker substudy state that “[t]he core design of REDUCE-IT does not make it possible to resolve convincingly whether any adverse effects associated with mineral oil use as a comparator may have affected clinical outcomes.”


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Find this article online at Circulation.

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