1. In patients with type 2 diabetes and hypertriglyceridemia, pemafibrate did not alter the incidence of cardiovascular events compared to placebo.
2. Pemafibrate was associated with higher rates of adverse renal events, venous thromboembolism, and a lower rate of non-alcoholic fatty liver disease as compared to placebo control.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Increased triglyceride levels, especially in the context of low high-density lipoprotein (HDL) cholesterol and concomitant type 2 diabetes, are associated with a higher risk of adverse cardiovascular events. Nevertheless, evidence for the impact of triglyceride-lowering therapies on cardiovascular risk has been equivocal. Pemafibrate is a triglyceride-lowering and HDL cholesterol-raising drug which works by modulating peroxisome proliferator-activated receptor α. The current study was a multi-national randomized controlled trial evaluating the effects of pemafibrate on cardiovascular risk among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL cholesterol. At the median follow-up of 3.4 years, pemafibrate was associated with significantly reduced triglyceride, very-low-density lipoprotein (VLDL) cholesterol, remnant cholesterol, and apolipoprotein C-III levels. Nevertheless, pemafibrate use had no impact on the risk of cardiovascular events. Consistent with the specific mechanism via which pemafibrate exerts its triglyceride-lowering effects, the trial results demonstrated that the drug did not alter the risk of adverse cardiovascular adverse events in the study participants, despite favorable changes in lipid profiles.
In-Depth [randomized controlled trial]: The current study was a multinational, double-blind, randomized, controlled trial to investigate the impact of pemafibrate on cardiovascular risk in patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, low HDL cholesterol, and well-controlled low-density lipoprotein (LDL) cholesterol levels. Patients were eligible for the primary-prevention cohort if they were at 50 (male) or 55 (female) years of age and older and did not have atherosclerotic cardiovascular disease. Those in the secondary-prevention cohort were 18 years of age or older and had atherosclerotic cardiovascular disease. The primary outcome was the first occurrence of a major adverse cardiovascular event, defined as a composite of myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Overall, 10,497 patients were randomized to receive pemafibrate (0.2mg twice daily) or placebo and followed for a median period of 3.4 years. It was observed that by four months, pemafibrate use was associated with reduced levels of triglycerides, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III, as well as increased levels of LDL cholesterol and apolipoprotein B. The primary composite outcome occurred in 572 patients in the pemafibrate group and 560 patients in the placebo group (Hazard Ratio, 1.03; 95% Confidence Interval, 0.91 to 1.15), with no differences observed in subgroups such as within the primary-prevention cohort, and at different statin intensities. Serious adverse events occurred at similar rates across the two groups. Pemafibrate was associated with higher rates of adverse renal events and venous thromboembolism and a lower rate of non-alcoholic fatty liver disease. Overall, these results showed that in patients with type 2 diabetes, hypertriglyceridemia, low HDL cholesterol, and well-controlled LDL cholesterol, pemafibrate alone did not reduce cardiovascular risks despite having intended effects on lipid biomarkers.
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