Saroglitazar, a PPAR-α/γ Agonist, for Treatment of Nonalcoholic Fatty Liver Disease: A Randomized Controlled Double-Blind Phase 2 Trial

Abstract

Background and Aims Non-alcoholic fatty liver disease (NAFLD) is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a novel dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved nonalcoholic steatohepatitis (NASH) histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. Approach & Results A total of 106 patients with NAFLD/NASH with ALT ≥50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at Week 16. Liver fat content (LFC) was assessed by magnetic resonance imaging-proton density fat fraction. The least squares (LS) mean (SE) percent change from baseline in ALT at Week 16 was -25.5% (5.8), -27.7% (5.9) and -45.8% (5.7) with saroglitazar 1 mg, 2 mg, and 4 mg, respectively versus 3.4% (5.6) in placebo (p<0.001 for all). Compared to placebo, saroglitazar 4 mg improved LFC [4.1%, (5.9) versus -19.7% (5.6)], adiponectin [-0.3 ug/mL (0.3) versus 1.3 ug/mL (0.3)], homeostatic model assessment-insulin resistance [-1.3 (1.8) versus -6.3 (1.7)], and triglycerides [-5.3 mg/dL (10.7) versus -68.7 mg/dL (10.3)] (p<0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (p>0.05). Conclusions Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance and atherogenic dyslipidemia in participants with NAFLD/NASH.