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

  • While median levels of each biomarker at baseline were similar in the 2 treatment groups, they increased in the group receiving mineral oil.
  • At 12 months, the median percent increase from baseline was 1.5% for homocysteine, 2.2% for Lp(a), 10.9% for oxLDL-c, 16.2% for IL-6, 18.5% for Lp-PLA2, 21.9% for hs-CRP, and 28.9% for IL-1β in the mineral oil group (all P<0.0001). Similar changes were observed at 24 months.
  • In contrast, in the icosapent ethyl group, there were little to no changes in the 7 biomarkers between baseline and 12 or 24 months. For example, the median percent change from baseline to 12 months was 0.4% for homocysteine, 0.0% for Lp(a), 2.9% for oxLDL-c, –2.6% for IL-6, –3.5% for Lp-PLA2, –12.4% for hs-CRP, and 0.0% for IL-1β (all P≤0.005).
  • At the end-of-study visit, the between-group treatment differences therefore largely reflected increases in the mineral oil group. The median percent changes between the 2 groups were: 2.4% for Lp(a), 3.0% for homocysteine, 4.2% for oxLDL-c, 19.8% for IL-6, 26.2% for Lp-PLA2, 38.5% for hs-CRP, and 48.7% for IL-1β (all P≤0.007).
  • These data were consistent with the previous REDUCE-IT results. For example, at 12 months, the median percent change in LDL-c was –1.2% in the icosapent ethyl group and 10.9% in the mineral oil group (P<0.0001), whereas the median percent change in triglycerides was −18.3% and 2.2%, respectively (P<0.0001).
  • When looking at associations between changes in LDL-c, triglycerides, and biomarkers over time, moderately positive pairwise correlations (Spearman’s r=0.32–0.53; all P<0.001) were found in the icosapent ethyl and mineral oil groups between the change in hs-CRP and that in IL-6, the changes in Lp-PLA2 and oxLDL-c, the changes in LDL-c and Lp-PLA2, and the changes in LDL-c and oxLDL-c, with similar effect sizes in both groups.


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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2. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Juliano RA, Jiao L, Granowitz C, et al. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019;73:2791–2802. doi: 10.1016/j.jacc.2019.02.032

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7. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, placebo-controlled, randomized, double-blind, 12-week study with an open-label extension [MARINE] trial). Am J Cardiol. 2011;108:682–690. doi: 10.1016/j.amjcard.2011.04.015

8. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984–992. doi: 10.1016/j.amjcard.2012.05.031

9. Nicholls SJ, Lincoff AM, Garcia M, Dash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, 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;324:2268–2280. doi: 10.1001/jama.2020.22258

10. Nissen SE, Lincoff AM, Wolski K, Ballantyne CM, Kastelein JJP, Ridker PM, Ray KK, McGuire DK, Mozaffarian D, Koenig W, et al. Association between achieved omega-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;6:910–917. doi: 10.1001/jamacardio.2021.1157

11. Olshansky B, Chung MK, Budoff MJ, Philip S, Jiao L, Doyle RT, Copland C, Giaquinto A, Juliano RA, Bhatt DL. Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies. Eur Heart J Suppl. 2020;22:J34–J48. doi: 10.1093/eurheartj/suaa117

12. 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;42:4807–4817. doi: 10.1093/eurheartj/ehab555

13. Steg PG, Bhatt DL. The reduction in cardiovascular risk in REDUCE-IT is due to eicosapentaenoic acid in icosapent ethyl. Eur Heart J. 2021;42:4865–4866. doi: 10.1093/eurheartj/ehab760

Find this article online at Circulation.

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