Samer Gawrieh1, Mazen Noureddin2, Nicole Loo3, Rizwana Mohseni4, Vivek Awasty5, Kenneth Cusi6, Kris V Kowdley7, Michelle Lai8, Eugene Schiff9, Deven Parmar10, Pankaj Patel11, Naga Chalasani1. 1. Gastroenterology & Hepatology, Indiana University School of Medicine, Indianapolis, IN. 2. Digestive and Liver Diseases, Cedars Sinai Medical Center, Los Angeles, CA. 3. Hepatobiliary Cancer, Texas Liver Institute, San Antonio, TX. 4. Catalina Research Institute, LLC, Montclair, CA. 5. Internal Medicine, Ohio health Marion General Hospital, Marion, OH. 6. Endocrinology, Diabetes & Metabolism, University of Florida, Gainesville, FL. 7. Liver Institute Northwest, Seattle, WA. 8. Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA. 9. Schiff Center for Liver Diseases, University of Miami School of Medicine, Miami, FL. 10. Zydus Discovery DMCC, Dubai, UAE. 11. Zydus Research Centre, Cadila Healthcare Ltd., Ahmedabad, India.
Abstract
BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved 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 AND RESULTS: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (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 MRI proton density fat fraction. The least-squares mean 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 with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -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 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).
BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved 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 AND RESULTS: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (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 MRI proton density fat fraction. The least-squares mean 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 with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -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 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).
Authors: Julia M Fraile; Soumya Palliyil; Caroline Barelle; Andrew J Porter; Marina Kovaleva Journal: Drug Des Devel Ther Date: 2021-09-22 Impact factor: 4.162