Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide and liraglutide, improves histologic outcomes in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) without compromising safety, reports a Singapore study.
“These findings highlight the potential of GLP-1RAs as disease-modifying agents for MASH, especially in individuals with metabolic comorbidities,” the investigators said.
The databases of PubMed, Embase, Cochrane CENTRAL, and Scopus were searched from inception to 27 June 2025 for randomized controlled trials comparing GLP-1RAs with placebo in adults with biopsy-proven MASH. The Cochrane Risk of Bias 2.0 tool was used to assess study quality.
The investigators estimated pooled risk ratios (RRs) using a random-effects model. MASH resolution without fibrosis progression was the primary endpoint, while ≥1-stage fibrosis improvement and any adverse events were secondary.
Three RCTs involving a total of 1,172 participants met the eligibility criteria. The use of GLP1-RAs resulted in a greater likelihood of MASH resolution without fibrosis progression (risk ratio [RR], 2.04, 95 percent confidence interval [CI], 1.53‒2.72; I2=19 percent). [Proc Singap Healthc 2026;doi:10.1177/20101058261424018]
“This improvement likely arises from the broad metabolic actions of GLP-1RAs, including significant weight loss, amelioration of insulin resistance, decreased hepatic steatosis, and suppression of pro-inflammatory signalling,” the investigators said. [Cureus 2021;13:e15141; Int J Mol Sci 2025;26:5883; Front Endocrinol 2021;12:769069; Diabetes Res Clin Pract 2020;170:108487]
“Notably, these histologic benefits occurred without a corresponding rise in fibrosis severity, supporting the hypothesis that GLP-1RAs mitigate hepatocellular injury and inflammation—the defining features of active MASH—without inducing fibrotic remodelling,” they added. [Prim Care Diabetes 2024;18:268-276]
Fibrosis regression
Similarly, treatment with GLP1-RAs led to improvements in fibrosis without MASH worsening (RR, 1.53, 95 percent CI, 1.24‒1.89; I2=0 percent).
“The observed regression of fibrosis is likely an indirect effect, arising from reduced hepatic inflammation and correction of underlying metabolic dysfunction, rather than a direct antifibrotic mechanism,” the investigators said. [Hormones (Athens) 2024;23:611-619; Endocr Rev 2023;44:14-32; Front Pharmacol 2025;16:1574385]
“Even so, small improvements in fibrosis confer prognostic advantages, and the reproducibility of this effect across studies enhances the robustness of the evidence,” they added. [Hepatology 2022;75:1235-1246]
In terms of safety, overall adverse events showed a modest increase (RR, 1.08, 95 percent CI, 1.02‒1.14; I2=9 percent), particularly gastrointestinal (GI) symptoms. The most common GI side effects were nausea, vomiting, and diarrhoea.
“Although the incidence of these events was slightly higher in the active treatment arms of two trials, they were generally mild to moderate in severity and seldom resulted in treatment discontinuation,” the investigators said. [N Engl J Med 2025;392:2089-2099; N Engl J Med 2021;384:1113-1124]
Dual benefit
The results of the meta-analysis highlight the potential of GLP1-RAs to act as a dual-benefit agent for MASH patients with metabolic comorbidities such as type 2 diabetes or obesity.
Apart from their hepatic effects, GLP-1RAs also enhance extrahepatic metabolic pathways such as weight regulation, insulin sensitivity, and cardiometabolic risk factors. These pathways are “closely intertwined with MASH pathophysiology,” according to the investigators.
“These systemic benefits may therefore contribute to, and help sustain, favourable liver outcomes,” they said. “Their established ability to reduce cardiovascular risk and promote meaningful weight loss further supports their role as a comprehensive therapeutic option for patients with multisystem metabolic disease.” [N Engl J Med 2023;389:2221-2232]