Fenofibrate plus statin and ASCVD risk by triglyceride-rich lipoprotein cholesterol in 70,000 patients

Fenofibrate may offer cardiovascular benefit in statin-treated individuals with elevated triglyceride-rich lipoprotein cholesterol (TRL-C), a measure reflecting cholesterol carried in triglyceride-rich lipoproteins, yet its role remains uncertain. We investigated whether fenofibrate added to statin therapy is associated with lower risk of atherosclerotic cardiovascular disease (ASCVD), particularly in individuals with high TRL-C. We analyzed 67,662 statin-treated adults without baseline ASCVD from the Korean National Health Insurance Service cohort. Participants were stratified by median TRL-C (26 mg/dl), and propensity score matching was performed for fenofibrate users and non-users within each stratum. The primary outcome was incident ASCVD, defined as a composite of coronary artery disease, ischemic stroke, and cardiovascular death. Over a mean follow-up of 87 months, fenofibrate use was associated with lower ASCVD risk in individuals with TRL-C ≥ median (adjusted hazard ratio [HR_adj] 0.76; 95% confidence interval [CI] 0.59-0.99) but not in those with TRL-C < median after matching. The association remained consistent in multiple sensitivity analyses and was most pronounced in individuals with the highest TRL-C quartile (P_interaction = 0.04). A significant benefit was also observed in individuals with non-high-density lipoprotein cholesterol (Non-HDL-C) ≥140 mg/dl, with HR_adj of 0.68 (95% CI 0.49-0.94) for non-HDL-C 140-172 mg/dl and 0.68 (95% CI 0.46-0.99) for non-HDL-C 172-199 mg/dl. In this nationwide cohort, fenofibrate use was associated with 24% lower ASCVD risk with elevated TRL-C despite statin therapy. These findings suggest that TRL-C may help identify individuals who derive greater benefit from fenofibrate therapy.