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 Aug 2;146(5):372-379. doi: 10.1161/CIRCULATIONAHA.122.059410. Epub 2022 Jun 28.


Background: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk.

Methods: Serum levels of interleukin-1β, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels 135 mg/dL and <500 mg/dL who were randomly allocated to treatment with either 4 grams daily of icosapent ethyl or mineral oil used as a comparator.

Results: At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1β (all P values <0.001), with similar changes at 24 months. In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months. As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized low-density lipoprotein cholesterol, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for high-sensitivity C-reactive protein, and 48.7% for interleukin-1β (all P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was -1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator.

Conclusions: Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT01492361.

Keywords: atherosclerosis; biomarkers; clinical trial; mineral oil.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / therapeutic use
  • Atherosclerosis* / drug therapy
  • Biomarkers
  • C-Reactive Protein
  • Cholesterol
  • Cholesterol, LDL
  • Double-Blind Method
  • Eicosapentaenoic Acid / analogs & derivatives
  • Homocysteine / therapeutic use
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Hypertriglyceridemia*
  • Interleukin-1beta
  • Interleukin-6
  • Lipoprotein(a)
  • Mineral Oil / therapeutic use


  • Biomarkers
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • IL1B protein, human
  • Interleukin-1beta
  • Interleukin-6
  • Lipoprotein(a)
  • Homocysteine
  • eicosapentaenoic acid ethyl ester
  • Mineral Oil
  • C-Reactive Protein
  • Cholesterol
  • Eicosapentaenoic Acid
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase

Associated data

  • ClinicalTrials.gov/NCT01492361