Efficacy and safety of zalfermin co-administered with semaglutide in participants with fibrosis and cirrhosis due to metabolic dysfunction-associated steatohepatitis: a phase 2, dose-ranging, double-blind, randomised controlled trial.

Diagnose MASLD by hepatic steatosis on imaging (or biopsy) plus at least one cardiometabolic criterion and exclusion of competing etiologies (significant alcohol use, other liver disease), then risk-stratify fibrosis using a sequential non-invasive approach: FIB-4 first, followed by a second-line imaging-based test (VCTE, MRE, or ELF) for indeterminate/high-risk FIB-4, with liver biopsy reserved for discordant or unclear cases. Lifestyle modification (≥7-10% weight loss, Mediterranean diet, exercise) remains the foundation for all patients. For adults with MASH and F2-F3 fibrosis identified by non-invasive tests (VCTE 8-15 kPa, MRE 3.1-4.4 kPa, or ELF 9.2-10.5) rather than biopsy, AASLD now gives dedicated, updated practice guidance on both FDA-approved pharmacotherapies: resmetirom (Oct 2024 update) and semaglutide 2.4mg/week subcutaneous (Nov 2025 update, following August 2025 accelerated FDA approval based on ESSENCE trial data: 62.9% vs 34.3% MASH resolution without fibrosis worsening; 36.8% vs 22.4% ≥1-stage fibrosis improvement). Pioglitazone or vitamin E remain options per the 2023 base guidance. Manage cardiometabolic risk with statins for ASCVD reduction plus glycemic and blood-pressure control; for semaglutide specifically, routine hepatic panels are recommended only as clinically indicated (no discontinuations for LFT elevation in ESSENCE), with monitoring for GI adverse effects and rare risks (AKI, gallbladder disease, pancreatitis, thyroid C-cell tumors, retinopathy progression, lean mass loss). HCC surveillance with ultrasound and AFP every 6 months remains indicated only if cirrhosis is present.