1873-LB: Genetically Determined PPARA Expression Modulates Fenofibrate Response on Lipid Profile—A Pharmacogenetic Trial

• Published in: Diabetes (New York, N.Y.) Vol. 74; no. Supplement_1; p. 1
• Main Authors: MORIERI, MARIO LUCA, GIORDANO, MARTINA, FAGARAZZI, CARLO, BOSCARO, CARLOTTA, MARASSI, MARELLA, IORI, ELISABETTA, AMENDOLAGINE, FRANCESCO IVAN, RODELLA, ANNA, MIGLIOZZI, LUDOVICA, PIPINO, CATERINA, ZAMBON, CARLO FEDERICO, DORIA, ALESSANDRO, ALBIERO, MATTIA, FADINI, GIAN PAOLO
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2025
• Subjects: Apolipoprotein C-III; Apolipoproteins; Creatinine; Diabetes mellitus (non-insulin dependent); Dyslipidemia; Fenofibrate; Gene expression; Genetic variability; Lipids; Low density lipoprotein; Precision medicine; Retinopathy; Statins; Transaminase; Triglycerides
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db25-1873-LB

Introduction and Objective: We showed that genetic variability in the PPARA region influences the effectiveness of the PPAR-α agonist fenofibrate on CVD and diabetic retinopathy (DR) progression, even in subjects without atherogenic dyslipidemia. Evidence suggests that higher genetically determined PPARA expression (Genetic Score (eQtGS) of PPARA retinal expression) may contribute to greater fenofibrate benefit. Here, we tested, in a pharmacogenetic trial, whether PPARA eQtGS influences fenofibrate’s effect on lipid and apolipoprotein profiles in statin-treated subjects with on-target lipid levels. Methods: We enrolled adult patients with type 2 diabetes, stable statin treatment, LDL-C <100 mg/dL, triglycerides <200 mg/dl, HbA1c <8%, and eGFR >60 mL/min, to be randomized to 12 weeks of fenofibrate or placebo. Lipid profile, apolipoproteins, transaminases, creatinine, CPK, and CRP were assessed. The eQtGS was derived from the EyeGEx database. Results: A total of 180 subjects (mean age: 66 years, 23% female, 33% obese, 23% with prior CAD, HbA1c: 6.6%) completed the study. All were on statins, mean LDLc was 62 mg/dl and triglycerides 102 mg/dl. Fenofibrate significantly reduced triglycerides (-20.7 mg/dL) and ApoCIII (-1.56 mg/dL) while increasing LDL-C (+4.62 mg/dL), ApoAII (+8.5 mg/dL), and creatinine (+0.14 mg/dL, all p<0.05). PPARA eQtGS significantly modulated fenofibrate’s effects on total and LDL-C, ApoB (higher PPARA eQtGS being associated with lower levels of LDL-C and ApoB after fenofibrate treatment). A significant positive eQtGS by fenofibrate interaction was found on fenofibrate-induced transaminase elevations. Conclusion: These precision medicine finding supports the concept that genetically determined PPARA expression affects fenofibrate response. Nonetheless the observed differences are unlikely to fully explain the large CVD and DR effect seen in previous studies. Further research is needed to dissect additional mechanisms and tissue-specific eQtGS effects.