Long-term fenofibrate therapy increases fibroblast growth factor 21 and retinol-binding protein 4 in subjects with type 2 diabetes

J Clin Endocrinol Metab. 2012 Dec;97(12):4701-8. doi: 10.1210/jc.2012-2267. Epub 2012 Nov 8.


Context: Fenofibrate is a peroxisome proliferator-activated receptor (PPAR)-α 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-α or PPAR-γ, 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Cardiomyopathies / blood
  • Diabetic Cardiomyopathies / diagnosis
  • Diabetic Cardiomyopathies / etiology
  • Diabetic Cardiomyopathies / metabolism
  • Double-Blind Method
  • Female
  • Fenofibrate / pharmacology
  • Fenofibrate / therapeutic use*
  • Fibroblast Growth Factors / blood*
  • Fibroblast Growth Factors / metabolism
  • Humans
  • Hypolipidemic Agents / pharmacology
  • Hypolipidemic Agents / therapeutic use
  • Male
  • Middle Aged
  • Placebos
  • Retinol-Binding Proteins, Plasma / analysis
  • Retinol-Binding Proteins, Plasma / metabolism*
  • Risk Factors
  • Time Factors
  • Up-Regulation / drug effects


  • Hypolipidemic Agents
  • Placebos
  • RBP4 protein, human
  • Retinol-Binding Proteins, Plasma
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Fenofibrate