Triglyceride lowering with pemafibrate to reduce cardiovascular risk
High levels of triglycerides are associated with increased cardiovascular risk, but it is uncertain whether lowering these levels will reduce the frequency of cardiovascular events. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.
In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild to moderate hypertriglyceridemia (triglyceride levels, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2 mg tablet twice daily) or matching placebo. Eligible patients received guideline-directed lipid-lowering therapy or were unable to receive statin therapy without side effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy endpoint was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.
Among 10,497 patients (66.9% with prior cardiovascular disease), the mean baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. Median follow-up was 3.4 years. Compared to 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 residual cholesterol (cholesterol transported in triglyceride-rich lipoprotein after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III and 4.8% for apolipoprotein B. The primary endpoint occurred in 572 patients in the pemafibrate group and 560 in the received placebo (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent change in effect in any prespecified subgroup. The overall incidence of serious adverse events was not significantly different between groups, but pemafibrate was associated with a higher incidence of renal adverse events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.
Among patients with type 2 diabetes, mild to moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those receiving pemafibrate than among those receiving placebo, although pemafibrate lowered triglycerides, VLDL cholesterol, residual cholesterol and apolipoprotein C-III levels. (Funded by Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)