EASL-EASD-EASO Issue New Guidance on Resmetirom and Semaglutide for MASH
The European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) have issued guidance on the use of resmetirom and semaglutide as targeted therapies for metabolic dysfunction-associated steatohepatitis (MASH). Published in the Journal of Hepatology, the guidance provides recommendations on patient selection, treatment initiation, monitoring, and discontinuation of these therapies.
MASH is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) that can lead to advanced fibrosis, cirrhosis, liver cancer, and other major adverse liver outcomes. The guidance emphasizes that targeted pharmacotherapy should complement, rather than replace, lifestyle intervention and management of associated metabolic conditions.
The expert groups recommend considering pharmacological treatment primarily in adults with non-cirrhotic MASH and fibrosis stage F2–F3. Non-invasive tests (NITs) can help identify patients at increased risk and may reduce the need for liver biopsy. Suggested thresholds include liver stiffness of 10–20 kPa with vibration-controlled transient elastography (VCTE), 3.1–5.0 kPa with magnetic resonance elastography (MRE), or an Enhanced Liver Fibrosis (ELF) score of 9.8–11.3.
The main recommendations from the guidance include:
- Target population: Resmetirom or semaglutide may be considered for adults with non-cirrhotic MASH and significant fibrosis (F2–F3), alongside structured lifestyle intervention and optimal management of cardiometabolic risk factors.
- Individualized treatment selection: The choice between therapies should take into account obesity, type 2 diabetes, cardiovascular disease, chronic kidney disease, other comorbidities, treatment risks and patient preferences.
- When to consider semaglutide: Semaglutide may be particularly suitable for patients with obesity, type 2 diabetes, established cardiovascular disease or high cardiovascular risk, given its established metabolic and cardiovascular benefits.
- When to consider resmetirom: Resmetirom may be prioritized in patients without obesity or in those who are already receiving or cannot tolerate GLP-1 receptor agonists.
- Cirrhosis: Neither resmetirom nor semaglutide should currently be used specifically as MASH-targeted therapy in patients with cirrhosis because sufficient liver-outcome evidence is not yet available. Semaglutide can, however, continue to be prescribed for its approved indications such as type 2 diabetes or weight management.
- Monitoring resmetirom: Patients receiving resmetirom should generally be assessed at 3, 6 and 12 months during the first year, with particular attention to treatment response, safety and liver status.
- Monitoring semaglutide: Semaglutide should be gradually increased at approximately four-week intervals according to tolerability. Monitoring should include weight, glycaemic status, nutritional status and muscle mass, particularly in patients at risk of sarcopenia.
- Assessing treatment response: Changes in non-invasive markers can help evaluate response. Potential indicators include a more than 30% reduction in VCTE liver stiffness, more than 20% reduction in MRE stiffness, more than 30% reduction in MRI-PDFF liver fat, a 0.5-point reduction in ELF score or a 17 U/L reduction in ALT.
The guidance also outlines circumstances in which treatment should be stopped. Resmetirom should be discontinued when hepatotoxicity is suspected, while treatment may need to be interrupted following significant gallbladder-related events. Semaglutide should be stopped in serious complications such as acute pancreatitis, acute kidney injury related to dehydration, severe gastroparesis, significant gallbladder disease, or suspected thyroid C-cell tumours.
Treatment decisions should also be reassessed when there is insufficient improvement. For resmetirom, lack of improvement after about 12 months may prompt consideration of discontinuation, particularly if fibrosis is worsening. With semaglutide, treatment may be continued when cardiometabolic benefits remain substantial, even if liver-related improvement is limited.
The guidance does not currently recommend combining resmetirom and semaglutide as first-line MASH-targeted therapy, as evidence supporting combination treatment remains insufficient.
The expert groups emphasized that randomized trials have not yet definitively established long-term liver-related outcome benefits of these therapies. While semaglutide has demonstrated important cardiometabolic benefits, further evidence is needed to determine whether either therapy can reduce major liver-related clinical outcomes over the long term.
Reference:
European Association for the Study of the Liver (EASL). Electronic address: easloffice@easloffice.eu; European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Guidance for the Use of Resmetirom and Semaglutide as MASH-Targeted Therapy. J Hepatol. 2026 Dec 1:S0168-8278(26)02877-1. doi: 10.1016/j.jhep.2026.08.028. Epub ahead of print. PMID: 42805503.
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