Long-Term Fenofibrate Therapy Increases Fibroblast Growth Factor 21 and Retinol-Binding Protein 4 in Subjects with Type 2 Diabetes

Context: Fenofibrate is a peroxisome proliferator-activated receptor (PPAR)-alpha agonist that showed beneficial effects on total cardiovascular risk in patients with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Objective: This study aimed to investigate the long-term effect of fenofibrate therapy on three novel biomarkers of cardiovascular risk, namely adipocyte-fatty acid-binding protein (A-FABP), fibroblast growth factor 21 (FGF21), and retinol-binding protein 4 (RBP4), which are all downstream targets of PPAR-alpha or PPAR-gamma, in patients with type 2 diabetes. Design, Setting, and Patients: A total of 216 patients (108 in the fenofibrate group and 108 in the placebo group) were randomly selected from the FIELD study cohort. A-FABP, FGF21, and RBP4 levels were measured in serum samples at both baseline and the fifth year of the study. Results: Relative to the placebo group, the changes of serum FGF21 and RBP4 levels were 85% (P < 0.001) and 10% (P = 0.032) higher in the fenofibrate group, respectively, over 5 yr. Fenofibrate treatment had no detectable effect on serum A-FABP level (P > 0.05). The effect of fenofibrate treatment on serum FGF21, but not RBP4, remained significant after adjusting for fenofibrate-induced changes in glycosylated hemoglobin, total cholesterol, triglycerides, apolipoprotein A-II, fibrinogen, plasma creatinine, and homocysteine (P = 0.002). Conclusions: Long-term fenofibrate treatment could increase serum FGF21 levels over 5 yr in patients with type 2 diabetes. Additional studies are needed to investigate the potential role of FGF21 in the fenofibrate-mediated reduction of cardiovascular risk. (J Clin Endocrinol Metab 97: 4701-4708, 2012)