Effects of the New Dual PPARα/δ Agonist GFT505 on Lipid and Glucose Homeostasis in Abdominally Obese Patients With Combined Dyslipidemia or Impaired Glucose Metabolism

OBJECTIVE: We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator-activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS: The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS: In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means -16.7% 95% one-sided CI -∞ to -5.3, P = 0.005; S2: -24.8% -∞ to -10.5, P = 0.0003) and increased HDL cholesterol (S1: 7.8% 3.0 to ∞, P = 0.004; S2: 9.3% 1.7 to ∞, P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (-11.0% -∞ to -3.5, P = 0.002). In S2, GFT505 did not reduce 2-h glucose (-0.52 mmol/L -∞ to 0.61, P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (-31.4% -∞ to 12.5, P = 0.001), fasting plasma glucose (-0.37 mmol/L -∞ to -0.10, P = 0.01) and fructosamine (-3.6% -∞ to -0.20, P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: -19.9% -∞ to -12.8, P < 0.0001; S2: -15.1% -∞ to -1.1, P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS: GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome.