S2654 Semaglutide’s Dose Dependent Effect on MASH Resolution: Updated Meta-Analysis of 5 RCTs With Histologic and Metabolic Improvements

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly growing global health concern. Semaglutide, a GLP-1 receptor agonist, treats MASH comorbidities like obesity and type 2 diabetes. Given MASH's increasing burden and evidence of semaglutide efficacy, this meta-analysis assessed the drug’s utility using a larger patient population from recent trials and compared efficacy at different dosages. Methods: A random effects meta-analysis (Der Simonian-Laird method) was performed using R (v4.3.1) on 5 RCT’s (n = 1,366) which evaluated semaglutide’s efficacy in adults with biopsy-proven MASH. The primary outcomes included MASH resolution without worsening fibrosis and stage-1 fibrosis improvement without worsening MASH. The secondary outcomes included changes in MRI-proton density fat fraction (MRI-PDFF), body weight, and liver enzymes (alanine aminotransferase/aspartate aminotransferase). Another objective was to compare the efficacy across different dosing regimens of semaglutide. Results: Our meta-analysis analyzed 3 RCTs (n = 1,191) from 5 RCTs for the primary endpoint, as 2 studies lacked biopsy confirmed follow-up data. The primary outcome of MASH resolution had an odds ratio (OR) of 4.56 (95% CI: 1.78-11.67). We observed only a trend towards fibrosis improvement (OR 1.56, 95% CI: 0.55–4.41), which was not significant. MASH resolution rates increased with higher doses, from 32.8% in the ESSENCE trial (2.4 mg/week for ≥72 weeks) to 59% in the Newsome trial (0.4 mg/day for 72 weeks), with fibrosis improvement of 37% and 43%, respectively. For secondary outcomes, 5 RCTs showed significant results favoring semaglutide with 50% reduction in MRI-PDFF, 10–13% decrease in body weight, and up to 40%/30% reductions in alanine aminotransferase/aspartate aminotransferase. Conclusion: This meta-analysis showed that semaglutide was statistically better at resolving MASH versus placebo. There was a 26.2% increase in MASH resolution rates at higher doses of semaglutide (0.4 mg daily/2.8 mg weekly) compared to 2.4 mg weekly. The results for fibrosis improvement were not significant, but reductions in MRI-PDFF, body weight, and hepatic enzyme levels were observed. Given good compliance and no increased side effects with higher semaglutide dosage, it appears optimal for long-term use. Future studies are needed on dose-dependent outcomes and therapy duration of semaglutide and other GLP-1 receptor agonists.