EASL-EASD-EASO Guidance for the Use of Resmetirom and Semaglutide as MASH-Targeted Therapy.

Adults with metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are at risk for cardiometabolic complications and major adverse liver-related outcomes (MALO), including cirrhosis, cancer, and liver transplantation. Non-invasive tests (NIT) for hepatic fibrosis, including vibration-controlled transient elastography (VCTE), magnetic resonance elastography (MRE), or enhanced liver fibrosis (ELF) score, can replace liver biopsy to identify high risk for MALO (e.g. VCTE 10-20 kPa, MRE 3.1-5.0 kPa, or ELF 9.8-11.3), in which pharmacotherapy may be considered. Following approval by regulatory agencies, this joint EASL-EASD-EASO guidance provides updated recommendations for the use of resmetirom (80mg/100mg po) and semaglutide (2.4 mg sc weekly) in MASH, covering treatment candidate selection, treatment initiation, monitoring, and discontinuation. Pharmacotherapy is recommended for adults with non-cirrhotic MASH and fibrosis stages 2-3 (based on NITs or biopsy), alongside structured lifestyle intervention and optimized comorbidity management. Therapy selection should be individualized according to preferences, potential risks, and cardio-renal-metabolic profile, including presence of obesity, type 2 diabetes (T2D), cardiovascular, and chronic kidney disease. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), may be preferred in adults with obesity or T2D as well as with established cardiovascular (CV) disease or high CV risk because of its cardiometabolic benefits, whereas resmetirom may be prioritized in individuals without obesity or those already receiving or intolerant to GLP-1RAs. Additional recommendations include structured safety and efficacy monitoring such as nutritional and sarcopenia assessment during semaglutide or use of fibrosis NITs for longitudinal response criteria. Ongoing studies are evaluating long-term effectiveness of both agents to reduce MALO. In adults with MASH cirrhosis, resmetirom or semaglutide appear safe but should not be used as MASH-targeted treatment, until further data establish liver-related benefits.