Comparative Efficacy of Resmetirom, GLP-1 Receptor Agonists, and Pioglitazone for Fibrosis Regression and MASH Resolution in Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Narrative Synthesis of Network Meta-Analyses with Implications for Pakistan

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a rapidly growing public health challenge in Pakistan and South Asia due to rising prevalence of obesity, type 2 diabetes, and metabolic syndrome. Pharmacological options beyond lifestyle modification are essential for patients with moderate-to-advanced fibrosis (F2–F3). This systematic review synthesizes comparative efficacy data on resmetirom (thyroid hormone receptor-β agonist), GLP-1 receptor agonists (e.g., semaglutide), and pioglitazone for key histological endpoints: MASH resolution without worsening of fibrosis and fibrosis improvement (≥1 stage) without worsening of MASH. Methods: Following PRISMA guidelines, a systematic search was conducted in PubMed, Embase, PMC, PakMediNet, and Google Scholar from January 2015 to July 2025. Eligible studies included phase 3 randomized controlled trials (RCTs) and network meta-analyses reporting histological outcomes in biopsy-proven MASH. Data on responder rates, relative risks (RR), odds ratios (OR), and surface under the cumulative ranking curve (SUCRA) rankings were extracted from high-quality sources. Random-effects model summaries and heterogeneity assessments (I²) were noted from published network meta-analyses. Pakistan-specific epidemiological and access data were integrated for contextual relevance. Results: Network meta-analyses (29 RCTs, n>9,000) ranked pegozafermin highest for both endpoints, followed by tirzepatide, resmetirom, and semaglutide. In MAESTRO-NASH (n=966, F2–F3), resmetirom 100 mg achieved MASH resolution in 29.9% vs. 9.7% placebo and fibrosis improvement in 25.9% vs. 14.2% placebo. In ESSENCE (interim, n=800 at week 72), semaglutide 2.4 mg achieved MASH resolution in 62.9% vs. 34.3% placebo and fibrosis improvement in 36.8% vs. 22.4% placebo. Pioglitazone showed modest effects (RR 2.29 for resolution). In Pakistan, MASLD prevalence ranges 14–38.9%, with limited access to newer agents. Conclusions: Resmetirom and GLP-1 RAs demonstrate superior histological efficacy compared to pioglitazone. In resource-limited settings like Pakistan, a tiered approach prioritizing affordable therapies, non-invasive monitoring, and local research is recommended to address the growing burden.