Glucagon-like peptide-1 (GLP-1) receptor agonists have now been evaluated in patients with MASH in multiple randomized trials. To better understand the efficacy and safety of these agents in patients with MASH, Tripathi and colleagues conducted a meta-analysis of 6 randomized controlled trials.1 The dataset included a study of liraglutide vs placebo in 14 patients with MASH; a phase 2 trial of semaglutide 2.4 mg once weekly vs placebo in 71 patients with MASH and compensated cirrhosis; the phase 2 SYNERGY-NASH trial of tirzepatide in 190 patients with MASH and stage F2 or F3 fibrosis; the phase 2 NN931-4296 trial of semaglutide vs placebo in 320 patients with MASH and F1 to F3 fibrosis; the phase 2 1404-0043 trial of survodutide vs placebo in 293 patients with MASH and F1 to F3 fibrosis; and the phase 3 ESSENCE trial of semaglutide vs placebo in 1196 patients with MASH and F2 to F3 fibrosis.2-7
GLP-1 receptor agonists have revolutionized the treatment of diabetes and obesity. In this systematic review, the authors analyzed data from 6 randomized controlled trials that included 1273 patients and demonstrated positive effects of GLP-1 receptor agonists on MASH resolution and fibrosis improvement with a good safety profile.
—Naim Alkhouri, MD
A total of 1273 patients, 782 receiving GLP-1 receptor agonists and 491 receiving placebo, met the inclusion criteria. Patients were followed for an average of 57 weeks; the median patient age was 54 years, and 45% were male. Overall, patients receiving GLP-1 receptor agonists were significantly more likely than those receiving placebo to have resolution of MASH (odds ratio [OR], 3.94; 95% CI, 3.06-5.08; P<.0001) (Figure 4). Improvements in fibrosis were also associated with the GLP-1 receptor agonists compared with placebo in 5 of the 6 studies (OR, 1.81; 95% CI, 1.40-2.35; P<.0001). Gastrointestinal AEs, including nausea, vomiting, and diarrhea, occurred at a significantly higher rate in patients receiving GLP-1 receptor agonists than in patients receiving placebo (OR, 14.34; 95% CI, 7.98-25.79) across 3 studies.
Figure 4.
Association of GLP-1 receptor agonists vs placebo with regards to MASH resolution.
GLP-1, glucagon-like peptide-1; MASH, metabolic dysfunction-associated steatohepatitis; M-H, fixed, Mantel-Haenszel fixed-effects method.
Adapted from Tripathi et al. Abstract P3746. Presented at: ACG 2025; October 24-29, 2025; Phoenix, Arizona.1
The meta-analysis demonstrated that GLP-1 receptor agonists compared with placebo significantly enhance improvement of fibrosis in patients with MASH, suggesting that they have a role in mitigating disease progression. The results support the inclusion of GLP-1 receptor agonists into clinical management guidelines, granted that further studies assess their long-term safety and effectiveness.
ABSTRACT SUMMARY Incretin-Based Therapies in MASH: A Meta-Analysis of Hepatic and Metabolic Outcomes.
A meta-analysis of 6 randomized controlled trials of incretin-based therapy in MASH was reported (Abstract P1582). The trials evaluated GLP-1 receptor agonist therapy (semaglutide), dual GLP-1 and glucagon agonists (pemvidu-tide, survodutide, and cotadutide), the GLP-1 + GIP agonist tirzepatide, and the triple agonist retatrutide. All included trials involved a treatment period of 12 or more weeks and assessed liver fat (by MRI-PDFF, liver fat content, or hepatic fat fraction). The analysis found significant reductions in liver fat in patients receiving incretin-based therapies, with results suggesting a dose-response effect. Across all agents tested, the pooled mean reduction in liver fat was 50%, which was a clinically meaningful effect. The greatest reductions, up to 83%, were observed with the triple agonist retatrutide 12 mg, followed by the dual GLP-1/glucagon agonists pemvidutide 1.8 mg (64%) and survodutide 6 mg (60%), followed by the GLP-1/GIP agonist tirzepatide 15 mg (47%). Semaglutide 2.4 mg was associated with a 39% reduction in liver fat, and the dual agonist cotadutide 0.6 mg was associated with a 27% reduction. In most studies, the risk of bias was considered low to moderate, however, there was substantial heterogeneity between studies.
References
- Tripathi R, Gupta S, Jarnes L, Zeidan N, Tao M, Jamorabo D. Efficacy of GLP-1 receptor agonists in MASH resolution and fibrosis reduction: a meta-analysis. Abstract P3746. Presented at: ACG 2025 Annual Scientific Meeting; October 24-29, 2025; Phoenix, Arizona. [Google Scholar]
- Armstrong MJ, Hull D, Guo K et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steato-hepatitis. J Hepatol. 2016;64(2):399–408. doi: 10.1016/j.jhep.2015.08.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Loomba R, Abdelmalek MF, Armstrong MJ et al. NN9931-4492 investigators. Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2023;8(6):511–522. doi: 10.1016/S2468-1253(23)00068-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Loomba R, Hartman ML, Lawitz EJ et al. SYNERGY-NASH Investigators. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299–310. doi: 10.1056/NEJMoa2401943. [DOI] [PubMed] [Google Scholar]
- Newsome PN, Buchholtz K, Cusi K et al. NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113–1124. doi: 10.1056/NEJMoa2028395. [DOI] [PubMed] [Google Scholar]
- Sanyal AJ, Bedossa P, Fraessdorf M et al. 1404-0043 Trial Investigators. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391(4):311–319. doi: 10.1056/NEJMoa2401755. [DOI] [PubMed] [Google Scholar]
- Sanyal AJ, Newsome PN, Kliers I et al. ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089–2099. doi: 10.1056/NEJMoa2413258. [DOI] [PubMed] [Google Scholar]