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The magnitude of success for icosapent ethyl (Vascepa) in REDUCE-IT could be partly explained by the control's effects on lipid and inflammatory traits, a study found, adding to the ongoing controversy of how much omega-3 fatty acids really prevent major adverse cardiovascular events in atherosclerotic cardiovascular disease (ASCVD).

In a REDUCE-IT-like population from Denmark's Copenhagen General Population Study (CGPS), the magnitude of differences in biomarkers (i.e., triglycerides, LDL cholesterol, non-HDL cholesterol, apolipoprotein B, and C-reactive protein) between icosapent ethyl and mineral oil arms of the trial would have corresponded to a 12% reduced risk of ASCVD in the real world.

Thus, approximately half of icosapent ethyl's 25% treatment effect in REDUCE-IT is still unaccounted for, reported Takahito Doi, MD, PhD, of Herlev Hospital in Denmark, during a late-breaking session on prevention at the European Society of Cardiology (ESC) virtual meeting. The results were simultaneously published in .

"Therefore, the unexplained additional 13% risk reduction in REDUCE-IT likely is through other beneficial effects of EPA [eicosapentaenoic acid], or deleterious effects of mineral oil," the investigators suggested.

Reconciling the Effects of EPA vs Mineral Oil

REDUCE-IT is controversial as critics have discounted the success of icosapent ethyl's purified EPA, calling it a false positive on account of unfavorable biomarker changes associated with the mineral oil that was supposed to be an inert control.

The very large change in EPA levels in REDUCE-IT, not factoring into the present analysis, likely explains the bulk of the benefit seen in that trial, argued Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, the lead author of REDUCE-IT.

Indeed, Doi's group noted that EPA may affect ASCVD risk factors like blood pressure, platelet activation, oxidative stress, inflammation, endothelial function, and plaque phenotype, as well as lipid levels and metabolism. Icosapent ethyl was associated with a mechanism of action related to plaque regression and stabilization in the EVAPORATE study.

However, Steven Nissen, MD, of Cleveland Clinic, commented that the REDUCE-IT investigators did not measure all the potential inflammatory effects of mineral oil.

Nissen's own STRENGTH trial dealt omega-3 fatty acids a blow, though this study had a corn-oil control and tested a different omega-3 formulation combining EPA and docosahexaenoic acid (DHA).

To reconcile the two studies, Doi and colleagues performed their modeling of Danish data based on STRENGTH as well, and found the lipid and inflammatory differences between corn oil and omega-3s in that trial to be associated with ASCVD outcomes that were a closer match to the real world (HR 0.96 vs 0.99).

"Taken together, increased lipid traits and C-reactive protein may account for increased risk of ASCVD in the mineral oil arm of REDUCE-IT, explaining part of the contrasting results of REDUCE-IT vs. STRENGTH," Doi and colleagues concluded.

Bhatt emphasized that the mineral oil issue alone cannot explain icosapent ethyl's benefits.

"The issue of placebo choice and potential changes in biomarkers has been thoroughly reviewed by the FDA, Health Canada, and the European Medicines Agency, all of whom have granted a broad approval for icosapent ethyl that largely mirrors the REDUCE-IT inclusion criteria," he said.

"Furthermore, for anyone who cannot get over the issue of placebo choice, icosapent ethyl has also been studied in two other randomized trials which did not use any placebo that still show its benefits – with a significant 19% reduction in clinical endpoints and with a significant benefit on intravascular ultrasound endpoints," he added.

The CGPS Analysis and Beyond

For their analysis, Doi and colleagues identified CGPS participants who would have hypothetically met the inclusion criteria for REDUCE-IT (n=5,684) and STRENGTH (n=6,862).

The authors' reliance on a Danish cohort study was a major caveat that meant their results were derived from white individuals alone. Moreover, the CGPS database only let them access patients' one-time, non-fasting lipid profiles with no information on statin dosing, they acknowledged.

Nevertheless, the present findings "support a more skeptical interpretation of REDUCE-IT's large effect size and should limit the use of icosapent ethyl until a second cardiovascular outcomes trial is performed," according to Jennifer Robinson, MD, MPH, of University of Iowa in Iowa City, who was a site investigator for both REDUCE-IT and STRENGTH.

"This is a good example of why strong class I recommendations to use a treatment require two well-done trials," she added.

For now, another head-to-head comparison of EPA versus mineral oil placebo is in the works -- this time testing icosapent ethyl in preventing and treating COVID-19. This trial will provide another opportunity to assess mineral oil's effects on C-reactive protein levels, Bhatt said.

Recently, ahead of the ESC conference, he had presented REDUCE-IT data supporting icosapent ethyl's reduction of ischemic events among participants with a .

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