Saroglitazar for non-obese metabolic-dysfunction associated steatotic liver disease (MASLD): An open-label randomised controlled trial

Background and objectives Nearly one-third of individuals with metabolic dysfunction–associated steatotic liver disease (MASLD)/non-alcoholic fatty liver disease (NAFLD) are non-obese, yet evidence for pharmacotherapy in this subgroup remains limited. This study assessed the safety and effectiveness of saroglitazar among non-obese individuals with MASLD/NAFLD. Methods In this open-label randomised controlled trial (RCT), non-obese [body mass index (BMI) <25 kg/m 2 ] adults with NAFLD/MASLD and raised alanine aminotransferase levels (ALT >50 U/L) were allocated in a 1:1 ratio to either saroglitazar (4 mg/day) combined with lifestyle modification (Group A) or lifestyle intervention alone (Group B) for a period of six months. The trial was registered with clinical trial registry (CTRI/2022/09/046081). The primary outcome was the change in controlled attenuation parameter (CAP). Secondary outcomes included changes in anthropometric measures, insulin resistance, glycaemic indices, lipid profile, ALT, fibroscan–aspartate aminotransferase (FAST) score, hepatic steatosis index (HSI), non-invasive fibrosis markers [liver stiffness measurement (LSM), fibrosis-4 (FIB-4), aspartate aminotransferase to platelet ratio index (APRI),], and adverse events. Results Sixty-six participants (33 per group) completed the study. Both groups showed significant reductions in CAP; however, the median change in CAP did not differ between the two groups [24 dB/m (9–48.8) vs. 14 dB/m (−4.5 to 50); P =0.52]. Alterations in BMI and waist circumference were similar between groups. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) [0.68 (0.14–1.69) vs . −0.51 (−1.12 to 0.44); P =0.03], triglycerides [34 (−1.5 to 76.8) vs . −10 (−28.5 to 20.5) mg/dL; P =0.006], and ALT (43.7±36.7 vs . 28.1±21.5 U/L; P =0.04) were significantly improved in the saroglitazar group. Changes in HSI, FAST score, APRI, FIB-4, and liver stiffness were similar between groups. No serious adverse events were observed. Interpretation and conclusions In non-obese NAFLD/MASLD patients, the combination of saroglitazar with lifestyle changes over a period of six months improved insulin resistance, triglycerides, and ALT but did not confer additional benefit over lifestyle intervention alone for non-invasive hepatic steatosis or liver fibrosis markers.