In a recent newsletter, I explained that science is a trial-and-error process in which hypotheses can rarely be proven – as new information comes to light, we must often change our thinking about previous observations. A recent secondary analysis by Paul Ridker et al. of data from REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl—Intervention Trial) perfectly exemplifies this process – and adds fuel to the controversy over purported cardiovascular benefits of omega-3 fatty acid supplements.
A Brief Refresher on REDUCE-IT
REDUCE-IT was a randomized, double-blind, placebo-controlled trial designed to investigate whether supplementation with icosapent ethyl – an ester derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA) – would reduce incidence of major adverse cardiovascular events (MACE) in statin-treated participants with established cardiovascular disease (CVD) or diabetes. A total of 8179 patients were randomized to receive either 4 g daily of icosapent ethyl or a mineral oil placebo and were followed for a median of 4.9 years. The results revealed a lower incidence of MACE, including cardiovascular death, in the icosapent ethyl group vs. the placebo group (17.2% vs. 22.0% of participants, respectively, P < 0.001), corresponding to a hazard ratio of 0.75 and an absolute risk reduction of 5%. The apparent health benefits of icosapent ethyl indicated by this trial subsequently prompted the U.S. Food and Drug Administration to approve commercial use of this drug for reduction of cardiovascular risk.
What did the new analysis show?
Ridker et al.’s analysis examined biomarkers of lipid metabolism and inflammation among icosapent ethyl- and placebo-treated REDUCE-IT participants at baseline, 1 year into the study, and 2 years into the study. No significant differences between treatment groups were observed in any biomarkers at baseline, but examination of subsequent time points revealed a remarkable trend. The icosapent ethyl group exhibited virtually no changes from baseline in any of the biomarkers investigated, but the placebo group demonstrated worsening of many of these markers.
In the mineral oil-treated placebo group, inflammatory markers interleukin 6 (IL-6) and interleukin 1β (IL-1β) increased 26% and 48%, respectively (from 3.27 to 3.97 pg/mL for IL-6, from 0.06 to 0.09 pg/mL for IL-1β). Homocysteine, a known marker of CVD risk, increased from 1.69 to 1.84 mg/L (9.5%), while Lp(a) rose 8%, from 11.4 to 13.6 mg/dL and lipoprotein-associated phospholipase A2 rose 26%, from 134 to 167 nmol/min/mL. Mineral oil also produced smaller but noteworthy increases in LDL-C (6%) and oxidized low-density lipoprotein (5%). All of these changes were highly statistically significant (P < .001), indicating the mineral oil is likely not a neutral placebo and instead results in net negative effects. (It’s not entirely clear how clinically significant these findings were, mind you, but it’s noteworthy that every biomarker moved in exactly the wrong direction.)
These findings raise the possibility that the apparent “benefits” of icosapent ethyl in REDUCE-IT may be an artifact caused by comparison with a harmful placebo. In other words, if the mineral oil caused harm, did the drug, by doing nothing, merely seem beneficial by comparison?
An Open Debate
Unfortunately, we can’t know the answer to this question based on the information from the original study or the follow-up analysis. Further, it remains a possibility that these biomarkers would have demonstrated a gradual worsening over the follow-up period even if the placebo had been innocuous, and that icosapent ethyl thus had a positive effect of slowing or preventing that progress. However, data from the STRENGTH trial – which compared treatment with 4 g of combined EPA and DHA (the omega-3 docosahexaenoic acid) vs. corn oil placebo – showed no worsening of biomarkers among the placebo group at 1-year follow-up, suggesting that the trends observed with mineral oil in REDUCE-IT do indeed reflect a net harmful effect. (Notably, no significant differences in MACE incidence were observed between EPA/DHA and control groups in this trial.)
Still, biomarker data don’t necessarily predict net clinical outcomes, so the only reliable way of knowing whether or not the icosapent ethyl is effective in reducing incidence of MACE or cardiovascular death would be to perform a new randomized trial with a more truly neutral placebo. Commentaries published in response to Ridker et al.’s analysis echo calls for such a study, though the prospects for funding are dubious. And yet, after years of serious investigation, no one – including the manufacturers of icosapent ethyl – has a plausible mechanism of action of how EPA would reduce residual risk of MACE. Combined with the results from Ridker et al.’s analysis, that certainly suggests that it may be time for the FDA to reevaluate its recommendations regarding the use of icosapent ethyl as a treatment for CVD – as we all must do whenever new and relevant information arises.
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