Explanation for Contrasting Results of REDUCE-IT vs. STRENGTH Trials

Quick Takes

  • The contrasting results of REDUCE-IT vs. STRENGTH trials can partly be explained by a difference in the effect of comparator oils (mineral vs. corn) on lipids and CRP.
  • It appears the active oils (EPA vs. EPA and DHA), did not explain the variation between the two trials on lipids or CRP.

Study Questions:

Can the differences in results of the REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) and STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia) trials be explained by the active and comparator oils on lipid traits and C-reactive protein (CRP)?


Data from the CGPS (Copenhagen General Population Study) were used for the present study. A total of 106,088 CGPS participants were evaluated for the key inclusion criteria in REDUCE-IT (n = 5,684; atherosclerotic cardiovascular disease [ASCVD] = 852) and STRENGTH (n = 6,862; ASCVD = 697). ASCVD incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. The primary outcome of ASCVD was defined using the two trial’s definitions, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, and coronary revascularization. Information on ASCVD was collected until December 2018 through a review of the National Danish Causes of Death Registry and all hospital admissions and diagnoses entered in the Danish National Patient Registry.


When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and CRP observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 (95% confidence interval 0.93–0.99) mimicking REDUCE-IT and 0.94 (0.91–0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04–1.10) and 0.99 (0.98–0.99). Combining these results, the active oil versus comparator oil hazard ratio was 0.88 (0.84–0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68–0.83) in the REDUCE-IT trial. The corresponding hazard ratio was 0.96 (0.93–0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90–1.09) in the STRENGTH trial.


The investigators concluded that the contrasting results of REDUCE-IT vs. STRENGTH trials can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils (eicosapentaenoic acid [EPA] vs. EPA + docosahexaenoic acid [DHA]), on lipid traits and CRP. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil.


This study highlights the importance of comparator groups when comparing similar trials. As noted by the authors, additional trials comparing EPA versus EPA + DHA, or versus corn oil for the assessment of ASCVD prevention, are warranted.

Keywords: Angina, Stable, C-Reactive Protein, Cholesterol, LDL, Corn Oil, Docosahexaenoic Acids, Dyslipidemias, Eicosapentaenoic Acid, Fish Oils, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Lipids, Mineral Oil, Myocardial Infarction, Myocardial Revascularization, Primary Prevention, Risk Factors, Risk Reduction Behavior, Stroke, Triglycerides

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