Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease now targeted by new pharmacotherapies, including the thyroid hormone receptor beta (THR-β) agonist resmetirom, glucagon-like peptide-1 (GLP-1) receptor agonists (semaglutide, liraglutide), and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide. Each acts through distinct metabolic pathways, yet no head-to-head comparisons exist. The aim of this study was to systematically review randomized controlled trials assessing the efficacy and safety of resmetirom, GLP-1 receptor agonists, and dual GIP/GLP-1 receptor agonists in adults with biopsy-confirmed, non-cirrhotic MASH (F2-F3), and to evaluate the certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, seven eligible randomized controlled trials (RCTs) involving 3,796 participants were identified through PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and trial registries (inception to October 2025). The comprehensive methodological protocol was filed in PROSPERO (reg. no. CRD420251230032) before the commencement of data collection. Data were extracted in duplicate; risk of bias was assessed using Cochrane Risk of Bias 2 (RoB 2), and certainty of evidence was graded using GRADE. Due to heterogeneity, the data were synthesized qualitatively. The included studies were RCTs of adults with biopsy-confirmed, non-cirrhotic MASH (F2-F3) treated with resmetirom, GLP-1 receptor agonists, or GIP/GLP-1 receptor agonists, while non-randomized studies and pediatric and cirrhotic populations were excluded. This study is limited by the absence of head-to-head trials comparing the three drug classes, as well as by heterogeneity across the included studies, which precluded meta-analysis. The results showed that all active therapies outperformed placebo on at least one biopsy-anchored endpoint. Resmetirom improved both MASH resolution and fibrosis at 52 weeks, with marked low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) reductions but minimal weight change. Semaglutide achieved dose-dependent histologic and metabolic benefits, culminating in dual-endpoint improvement in the phase 3 ESSENCE trial. Liraglutide improved resolution in a small trial, while tirzepatide achieved both endpoints with large, dose-related weight loss. Non-invasive biomarkers paralleled histology, and adverse events were predominantly mild gastrointestinal effects. GRADE assessments indicated low certainty for between-class differences in histologic outcomes, high certainty favoring incretin therapies for weight reduction, and moderate certainty favoring resmetirom for lipid lowering. In conclusion, resmetirom, semaglutide, and tirzepatide each demonstrate clinically meaningful efficacy and tolerability in non-cirrhotic MASH, with distinct metabolic profiles, resmetirom as a lipid-centric, weight-neutral therapy and incretins as weight-centric, pleiotropic agents. Further direct-comparison trials are warranted to clarify their relative benefits on histology and cardiometabolic outcomes.
