Divergent effect of diabetes on fibrosis response to semaglutide and resmetirom in noncirrhotic MASH: A meta-analysis of randomized trials.

BACKGROUND: Semaglutide has become an alternative to resmetirom for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH). However, the effect of type 2 diabetes mellitus (T2DM) on fibrosis response to these drugs is unknown. METHODS: Our primary research question asked whether semaglutide or resmetirom treatment leads to fibrosis improvement in diabetic and nondiabetic noncirrhotic MASH. Data sources included MEDLINE, Cochrane Library, EMBASE, meeting abstracts, clinical trial registries, and regulatory authorities' websites through October 10, 2025, coveringrandomized controlled trials (RCTs) evaluating the effect of semaglutide and/or resmetirom on liver histology in noncirrhotic MASH patients. Three reviewers extracted data for study characteristics, outcomes of interest, and risk of bias and summarized the strength of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Main outcome (a ≥1 stage histological fibrosis improvement) was pooled using a risk ratio (RR) and random-effects model. FINDINGS: Eight out of 3,751 identified records, describing three placebo-controlled RCTs with histological endpoints (2,086 noncirrhotic MASH patients, 62% with T2DM, trial duration range 52-72 weeks) were included. In MASH patients with T2DM, semaglutide did not improve fibrosis stage (RR = 1.21, 95% CI 0.94-1.56, p = 0.13; I = 0%, N comparisons = 4, 646 participants), while resmetirom significantly improved fibrosis vs. placebo (RR = 1.99, 95% CI 1.35-2.93, p = 0.0005, 647 participants). In MASH patients without T2DM, semaglutide improved fibrosis stage (RR = 1.72, 95% CI 1.21-2.44, p = 0.002, N comparisons = 4, I = 3%, 474 participants), while resmetirom did not (RR = 1.37, 95% CI 0.83-2.25, p = 0.21, 319 participants). Resmetirom treatment was associated with significant fibrosis reduction regardless of background treatment with glucagon-like peptide-1 receptor agonists. CONCLUSIONS: T2DM modifies fibrosis response to semaglutide and resmetirom in noncirrhotic MASH. FUNDING: This study received no funding.