The Fibrates Story — A Tepid End to a PROMINENT Drug

This editorial analyzes the PROMINENT trial, which evaluated pemafibrate a selective PPARα modulator for cardiovascular risk reduction in patients with type 2 diabetes and atherogenic dyslipidemia. Involving 10,497 participants with elevated triglycerides (200–499 mg/dL) and low HDL cholesterol (≤40 mg/dL), the trial compared pemafibrate against placebo in a predominantly statin-treated population. Although pemafibrate lowered triglycerides by 26.2% and raised HDL by 5.1%, it did not reduce the composite endpoint of myocardial infarction, stroke, revascularization, or cardiovascular death. Notably, apolipoprotein B levels were not meaningfully reduced, undermining the efficacy of triglyceride-lowering in the presence of high-intensity statins. The editorial suggests that increased LDL conversion from remnant lipoproteins may offset benefits, and stresses that net reductions in apolipoprotein B-containing particles are crucial for risk mitigation. Comparisons with REDUCE-IT and STRENGTH trials underscore that lowering triglycerides alone may not suffice. Future therapies must enhance remnant particle clearance. Broader participant representation and rigorous confirmation of post hoc findings are advocated. The trial marks a sobering endpoint in fibrate-driven prevention, with relevance for ongoing drug development.

This editorial analyzes the PROMINENT trial, which evaluated pemafibrate a selective PPARα modulator for cardiovascular risk reduction in patients with type 2 diabetes and atherogenic dyslipidemia. Involving 10,497 participants with elevated triglycerides (200–499 mg/dL) and low HDL cholesterol (≤40 mg/dL), the trial compared pemafibrate against placebo in a predominantly statin-treated population. Although pemafibrate lowered triglycerides by 26.2% and raised HDL by 5.1%, it did not reduce the composite endpoint of myocardial infarction, stroke, revascularization, or cardiovascular death. Notably, apolipoprotein B levels were not meaningfully reduced, undermining the efficacy of triglyceride-lowering in the presence of high-intensity statins. The editorial suggests that increased LDL conversion from remnant lipoproteins may offset benefits, and stresses that net reductions in apolipoprotein B-containing particles are crucial for risk mitigation. Comparisons with REDUCE-IT and STRENGTH trials underscore that lowering triglycerides alone may not suffice. Future therapies must enhance remnant particle clearance. Broader participant representation and rigorous confirmation of post hoc findings are advocated. The trial marks a sobering endpoint in fibrate-driven prevention, with relevance for ongoing drug development.