Comparative Analysis of Glucagon Receptor Agonists vs. Resmetirom in MASLD and MASH: Network Meta-Analysis of Clinical Trials.

BACKGROUND: MASLD and its progressive form MASH represent a global public health challenge due to their rising prevalence and their possible progression to cirrhosis and HCC. Resmetirom, dual (e.g., cotadutide, survodutide), and triple GRAs (e.g., retarutide) have demonstrated potential efficacy in recent clinical trials. This network meta-analysis evaluates the comparative efficacy and safety of these treatments. METHODS: We systematically searched PubMed, Scopus, ClinicalTrials.gov, and Cochrane Central for randomised controlled trials evaluating these medications versus placebo in adults with MASLD and MASH. The outcomes assessed included changes in ALT, AST, LDL, and HDL levels, changes in MRI-PDFF, safety outcomes (diarrhoea, fatigue, and nausea), serious adverse events, ELF, adiponectin, and MASH resolution with no worsening of fibrosis. Random-effects model and network meta-analysis methods were employed. RESULTS: Six trials met the inclusion criteria. GRAs significantly reduced ALT levels with MD of -22.10, while resmetirom demonstrated the greatest reduction in AST levels with a MD of -13.17. Resmetirom also led to a borderline significant increase in HDL with the most significant reduction in LDL levels. Moreover, GRAs showed a significant effect on MRI-PDFF with a MD of -46.09. Overall, resmetirom showed a more favourable safety profile. In addition, GRAs significantly decreased ELF scores, resmetirom significantly improved MASH resolution without worsening of fibrosis, and both treatments significantly increased adiponectin. CONCLUSION: GRAs superiorly reduce ALT levels, MRI-PDFF, and ELF. Resmetirom significantly reduces AST, HDL, and LDL levels, increases MASH resolution without worsening of fibrosis, and offers a more favourable safety profile. Both GRAs and resmetirom significantly increase adiponectin.