This week’s publication of RESPECT-EPA , adds more data to the 2 prior clinical trials JELIS and REDUCE-IT that found purified eicosapentanoic acid (EPA) to reduce the risk of cardiovascular disease (CVD) in patients with pre-existing CVD (or elevated risk). The 3 independently conducted, randomized clinical trials (RCTs), evaluated more than 30,000 men and women from across the globe and found that the significant reduction of coronary events was unrelated to triglyceride (TG) lowering, severity of pre-existing CVD or whether a placebo or open-label design (as customary in Japanese studies) was used. By contrast, RCTs containing the combination of EPA and docosahexanoic acid (DPA) have been consistently negative thereby raising the possibility that high levels of purified EPA (e.g., Icosapent ethyl) possesses anti-inflammatory, antioxidant, cell-membrane stabilizing and (ventricular) arrhythmia suppressing properties not seen at lower levels of EPA as reported in EPA/DHA combination studies. Because patients with high TG are subjected to a pro-inflammatory, pro-oxidative/pro-thrombotic state, it should not be surprising that therapies directly impacting these pro-atherothrombotic parameters, such as purified EPA, will translate into favorable cardiac outcomes, even if TG lowering effects are relatively modest. In fact, the failure of robust TG lowering therapies, as was recently the case of pemafibrate suggests that TG-lowering, per se, is highly unlikely to yield benefit vis-à-vis CVD risk, unless the agent used also attacks the atherogenic milieu associated with HTG.
Nonetheless, this does not imply that robust TG lowering may not have other benefits. As illustrated in our review, Pemafibrate and other triglyceride-lowering therapies to reduce risk of cardiovascular and metabolic disease HTG may also be associated with non-alcoholic fatty liver disease (NAFLD) and risk of pancreatitis. To this end, fibrates such as Pemafibrate and the FGF21 analog, Pegozafermin, have been shown to improve the former phenotype whereas APOC3 inhibitors such as Olezarsen appear to reduce the latter. Thus, triglyceride-lowering should focus on the associated HTG phenotype to identify the most effective therapy to reduce cardiometabolic risk.
Michael Miller, MD is a cardiologist and Chief of Medicine at the Corporal Michael J Crescenz VA Medical Center and Professor of Medicine, University of Pennsylvania. Dr. Miller is Scientific Advisor to Amarin, Inc and 89bio. Prior to his arrival in Philadelphia, he was Professor of Cardiovascular Medicine, Epidemiology and Public Health at the University of Maryland School of Medicine. He is the author of numerous scientific publications and several books, including Heal Your Heart published by Penguin Random House. Check him out on twitter: @mmillermd1
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