Although elevated triglyceride levels are associated with an increased risk of myocardial infarction (MI), ischemic stroke, and all-cause mortality,¹ previous trials have failed to demonstrate a significant clinical benefit from the use of triglyceride lowering therapies. However, a prespecified subgroup analysis from the ACCORD trial suggested that fibrates, in combination with statins, may decrease the risk of nonfatal MI, nonfatal stroke, or death from cardiovascular (CV) causes in patients with type 2 diabetes mellitus (T2DM) with high triglyceride and low high-density lipoprotein cholesterol (HDL-C) levels.²

Accordingly, the trial studied the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, in patients with T2DM, hypertriglyceridemia between 200 to 399 mg/dL, and an HDL-C of 40 mg/dL or lower.³ A total of 10,497 participants were randomized to either pemafibrate 0.2mg twice a day or placebo. Patients were also required to be on statin therapy or have a well-controlled low-density lipoprotein cholesterol (LDL-C) level. The primary endpoint of the study was major adverse CV events (MACE) including MI, ischemic stroke, unstable angina resulting in unplanned coronary revascularization, or CV death. After a median follow-up period of 3.4 years, the study found no significant difference in MACE (hazard ratio [HR] 1.03 [0.91-1.15], p=0.67) despite a 26% lower fasting triglyceride level in the pemafibrate group compared to placebo. Furthermore, there was no significant difference in serious adverse events between groups, although pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism.

In this multinational, double-blinded randomized controlled trial, there was no significant difference in CV outcomes with pemafibrate compared to placebo, despite a 26% reduction in triglyceride levels. Notably, pemafibrate was associated with an increase in LDL-C, which is consistent with the known mechanism of PPARα modulators. It is possible that alternative therapies that enhance clearance of triglycerides without raising LDL-C levels may have a CV benefit. Additionally, investigators found a lower incidence of hepatic adverse events with pemafibrate, including nonalcoholic fatty liver disease, which may warrant further study.

References

1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
2. Ginsber HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2018;362:1563-75.
3. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923-34.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: AHA Annual Scientific Sessions, AHA22, Primary Prevention, Secondary Prevention, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peroxisome Proliferator-Activated Receptors, Fibric Acids, Triglycerides, Diabetes Mellitus, Type 2, Non-alcoholic Fatty Liver Disease, Ischemic Stroke, Follow-Up Studies, Hypertriglyceridemia, Hyperlipidemias, Angina, Unstable, Thromboembolism, Lipoproteins, Infarction

< Back to Listings