SAT-655 Comparative Analysis of Glucagon Receptor Agonists vs Resmetirom in MASLD and MASH:Network Meta-Analysis of Clinical Trials

Abstract Disclosure: C.R. Andonie: None. A. Abusalameh: None. I. Ismail: None. T. Hodrob: None. H. Ayesh: None. Introduction: Metabolic-Associated Steatotic Liver Disease (MASLD) and its progressive form, Metabolic-Associated Steatohepatitis (MASH), represent a global public health challenge due to their rising prevalence, driven by obesity and insulin resistance. These conditions can lead to advanced liver disease, including cirrhosis and hepatocellular carcinoma, with no FDA- or EMA-approved treatments currently available. Resmetirom, a thyroid hormone receptor-β agonist, and glucagon receptor agonists (GRAs), such as Cotadutide, Retatrutide, and Survodutide, have demonstrated potential efficacy in recent clinical trials. This network meta-analysis evaluates the comparative efficacy and safety of these treatments to address an unmet therapeutic need. Methods: A systematic review of clinical trials was conducted, identifying seven eligible studies involving Resmetirom and GRAs. Outcomes assessed included changes in MRI proton density fat fraction (PDFF), alanine aminotransferase (ALT), and rates of serious adverse events (SAEs). Random-effects models and network meta-analysis methods were employed to estimate mean differences (MDs) and risk ratios (RRs) compared to placebo. Results: For MRI-PDFF, Resmetirom demonstrated a significant reduction versus placebo (MD: -47.59%, 95% CI: [-72.84; -22.35], p = 0.0002), comparable to GRAs (MD: -48.93%, 95% CI: [-96.81; -1.05], p = 0.0015). ALT reductions were also substantial, favoring GRAs (MD: -28.97 U/L, 95% CI: [-42.40; -15.55], p < 0.0001) over Resmetirom (MD: -20.08 U/L, 95% CI: [-31.47; -8.70], p = 0.0005). SAE risk was not significantly elevated for Resmetirom (RR: 1.11, 95% CI: [0.77; 1.59], p = 0.58), but GRAs showed a trend toward higher SAE rates (RR: 2.38, 95% CI: [0.98; 5.82], p = 0.056). Conclusions: Both Resmetirom and GRAs effectively reduce liver fat and ALT levels in MASLD/MASH patients, with Resmetirom offering a favorable safety profile and GRAs demonstrating superior ALT reductions but a potential increase in SAE risk. These findings underscore the promise of both therapeutic classes and highlight the need for further comparative trials to inform treatment decisions. Presentation: Saturday, July 12, 2025