Weight reduction–dependent/–independent effects of survodutide on liver endpoints: Mediation analysis of a phase 2 trial in MASH

BACKGROUND AND AIMS: Survodutide was associated with improvements in liver-related endpoints in a phase 2 trial in MASH (NCT04771273). This post hoc mediation analysis evaluated the proportion of the direct treatment effect versus the indirect effect mediated by weight reduction. APPROACH AND RESULTS: Data were included for participants with fibrosis stages F2-F3 and paired baseline/end-of-treatment biopsy readings; survodutide dose arms were pooled. The causal mediation analysis model included treatment (exposure) and percentage change in body weight (mediator), with baseline body weight, type 2 diabetes status, and fibrosis stage as covariates. Outcomes included histological endpoints and non-invasive tests (NITs) after 48 weeks' treatment. Total, direct (weight reduction-independent), and indirect (weight reduction-dependent) treatment effects were calculated for survodutide versus placebo. This analysis included 170 participants. For histological endpoints, the percentage of the total treatment effect mediated by weight reduction (indirect effect) was estimated at 66.7% for resolution of MASH without worsening of fibrosis, 71.8% for improvement in MASH without worsening of fibrosis, and 36.3% for improvement in fibrosis without worsening of MASH (suggesting a greater direct effect). Similarly, for NITs related to inflammation/fibrosis, <50% of the total effect was mediated by weight reduction [16.5% (AST)-38.6% (Enhanced Liver Fibrosis)]. For steatosis-related endpoints (MRI-proton density fat fraction and FibroScan Controlled Attenuation Parameter), a higher proportion was mediated by weight reduction (58.2% and 77.4%, respectively). CONCLUSIONS: Endpoints related to improvements in inflammation/fibrosis were predominantly weight reduction-independent, suggestive of a potential role of direct glucagon receptor agonism in the liver.