Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, did not lower the incidence of cardiovascular events compared with placebo in the phase 3 PROMINENT trial of patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels. The agent reduced levels of triglycerides, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. However, its effects on cardiovascular events may have been negated by increased apolipoprotein B and LDL cholesterol levels in participants taking pemafibrate.
Participants were receiving guideline-directed lipid-lowering therapy (unless they could not receive statin therapy) when they were randomized to pemafibrate 0.2 mg tablets twice daily or matching placebo. Based on a primary efficacy endpoint of a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes, the study showed: “Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were −26.2% for triglycerides, −25.8% for very-low-density lipoprotein (VLDL) cholesterol, −25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), −27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.”
Editorial: “What do these findings mean for the future of fibrates and other therapies that primarily target triglycerides?” asks an editorialist. “First, fibrates should not be used to reduce the risk of atherosclerotic cardiovascular disease among statin-treated patients, although they may still have a role to play in decreasing the risk of pancreatitis associated with severe hypertriglyceridemia and perhaps nonalcoholic fatty liver disease. Alternatively, triglyceride lowering without decreases in the apolipoprotein B level will probably not suffice if therapies in development are to produce meaningful decreases in the risk of atherosclerotic cardiovascular disease.”