Adults with metabolic dysfunction-associated steatohepatitis (MASH) and stage 2 or 3 fibrosis should be considered for resmetirom or semaglutide along with lifestyle changes, according to new European guidance published in the Journal of Hepatology.
The guidance also recommends using noninvasive tests (NITs) instead of routine liver biopsy to determine who may benefit from treatment. It suggests thresholds for significant or advanced fibrosis of 10 to 20 kPa on vibration-controlled transient elastography (VCTE), confirmed by repeat testing or a second NIT; 3.1 to 5.0 kPa on magnetic resonance elastography (MRE); or an enhanced liver fibrosis (ELF) score of 9.8 to 11.3, ideally confirmed by a second test. The guidance recommends the Fibrosis-4 index (FIB-4) as a first-line screening tool but not as a stand-alone test for treatment eligibility.
The guidance was developed by the European Association for the Study of the Liver, the European Association for the Study of Diabetes, and the European Association for the Study of Obesity after the FDA and the European Medicines Agency provisionally approved both drugs for MASH with significant fibrosis but without cirrhosis.
A multidisciplinary committee chaired by Frank Tacke, MD, PhD, MHBA, director of the department of hepatology and gastroenterology at Charité – Universitätsmedizin Berlin in Germany, drafted the recommendations, which were vetted by an international 45-member Delphi panel that included clinicians, patient representatives, and other stakeholders. All recommendations reached the 75% agreement threshold, with agreement ranging from 86% to 100%.
The committee reviewed the available research and graded the evidence using the Oxford Centre for Evidence-based Medicine system. The recommendations to prioritize semaglutide or resmetirom in specific patient groups were rated as weak, and several others rested on expert opinion.
“Rather than providing separate disease-specific perspectives, the guidance aims to translate the emerging evidence and regulatory approvals into a common, multidisciplinary approach that can be applied in clinical practice across Europe and globally,” Dr. Tacke told GI & Hepatology News.
The guidance recommends considering drug treatment, along with structured lifestyle changes, for patients with MASH and stage 2 or 3 fibrosis who do not have cirrhosis. It prefers NITs for identifying treatment candidates and considers liver biopsy unnecessary for most patients. According to the guidance, two or more concordant NITs increase confidence in the fibrosis stage.
For treatment selection, the guidance recommends considering a patient’s cardiometabolic health, other health conditions, possible adverse effects, how the drug is given, and patient preferences. Because the drugs were tested in separate phase 3 trials with substantially different placebo response rates, their liver effects cannot be directly compared, the authors noted. Prespecified subgroup analyses of each trial showed similar efficacy regardless of fibrosis stage, sex, age, disease activity, type 2 diabetes, or body mass index.
Under the guidance, semaglutide may be prioritized for patients with obesity or overweight with weight-related health conditions, type 2 diabetes with blood sugar outside target range, established cardiovascular disease, or chronic kidney disease with overweight, obesity, or type 2 diabetes. In the ESSENCE trial, participants receiving semaglutide had a median 10.5% reduction in body weight, compared with 2% with placebo, and improved blood sugar control.
According to the guidance, resmetirom may be preferred for patients without obesity or type 2 diabetes, or those already taking or unable to tolerate a glucagon-like peptide-1 (GLP-1) receptor agonist. Potential advantages include oral administration and improvements in unhealthy blood lipid levels. Resmetirom also may be an option for patients with or at high risk for sarcopenia because substantial weight loss with semaglutide can include loss of muscle mass.
In the phase 3 trials, adverse events led to discontinuation in 6.8% of participants receiving resmetirom 100 mg and 1.9% of those receiving 80 mg vs. 2.2% with placebo, and in 2.6% of those receiving semaglutide vs. 3.3% with placebo, according to the guidance. The guidance also notes that resmetirom requires statin dose caps and a dose reduction with clopidogrel, and that gemfibrozil is contraindicated.
Monitoring depends on the treatment. For resmetirom, the guidance suggests follow-up at three, six, and 12 months during the first year to check for adverse effects and liver blood test results. For semaglutide, it recommends increasing the dose every four weeks as tolerated, with monitoring of weight and, in patients with type 2 diabetes, blood sugar.
The guidance also suggests periodic assessment of nutrition, physical activity, and muscle mass or strength in patients taking semaglutide, particularly with rapid weight loss. It recommends NITs to gauge liver response with either drug, assessed at about 12 months for resmetirom and 18 months for semaglutide.
The guidance advises against using either drug to treat MASH in patients with cirrhosis until more data are available, although semaglutide may still be used for its approved diabetes and chronic weight-management indications in patients with compensated MASH cirrhosis. The authors noted that available evidence has not raised particular short-term safety concerns with either drug in these patients but has not established liver-related benefits.
Panel members acknowledged that important questions remain. Long-term randomized trials have not shown whether either drug reduces cirrhosis, liver transplantation, liver-related death, or other major liver outcomes. Evidence also is insufficient to recommend resmetirom and semaglutide together as first-line MASH treatment.
The authors also noted that NIT thresholds will miss a relevant share of patients with stage 2 fibrosis and flag some with milder disease. According to the guidance, outcome data are expected from resmetirom’s MAESTRO-NASH Outcomes trial in compensated cirrhosis in 2027 or 2028 and from part 2 of semaglutide’s ESSENCE trial in 2029. No long-term cardiovascular outcome data are available for resmetirom.
The guidance panel received no financial support. Dr. Tacke reported consulting or lecture honoraria from companies including Madrigal Pharmaceuticals and Novo Nordisk, which market resmetirom and semaglutide, respectively, and research grants to his lab from MSD and Agomab. Most other panel members reported relationships with Novo Nordisk, Madrigal, or both; one reported no conflicts.
Expert insight
Dr. Tacke provided additional perspective on the guidance.
Which patients with MASH are most likely to benefit from resmetirom vs. semaglutide, and what factors should guide that choice in practice?
Dr. Tacke: There is currently no head-to-head trial demonstrating superiority of one treatment over the other, so treatment selection should be individualized according to the patient's clinical profile, preferences, potential risks, tolerability, and cardiometabolic comorbidities.
Semaglutide may be particularly attractive in patients with obesity or type 2 diabetes and in those with established cardiovascular disease or high cardiovascular risk, given its established cardiometabolic benefits. Resmetirom may be particularly appropriate in patients without obesity or in those already receiving, or unable to tolerate, a GLP-1 receptor agonist.
The important message is that there is not one universally preferred treatment for every patient with F2–F3 [stage 2 or 3 fibrosis] MASH. The choice should be integrated into the broader management of metabolic risk factors and lifestyle.
How should physicians use noninvasive fibrosis tests to decide who should start MASH-targeted therapy, and when is a liver biopsy still needed?
Dr. Tacke: One practical message is that non-invasive tests should guide risk stratification and consideration of MASH-targeted therapy. FIB-4 can be used initially, followed by VCTE, MRE or ELF to further characterize fibrosis risk.
The guidance suggests treatment consideration in patients with compatible clinical features and fibrosis risk in the range of VCTE 10–20 kPa, MRE 3.1–5.0 kPa, or ELF 9.8–11.3, in the appropriate clinical context.
Routine liver biopsy is therefore not required for treatment selection in many patients. Biopsy remains useful when NIT results are indeterminate or discordant, when another liver disease is suspected, or when there is uncertainty about the presence of cirrhosis. This provides a more pragmatic pathway to treatment while reducing the need for invasive procedures.
Once treatment begins, how should physicians judge whether it is working, and when should they consider switching or stopping therapy?
Dr. Tacke: Monitoring needs to combine treatment safety, metabolic effects, and longitudinal assessment of liver disease. There is no single validated biomarker that can be used as a definitive treatment-response marker.
Changes in NITs can nevertheless provide supportive evidence of response, such as a relative reduction of >30% in VCTE liver stiffness, >20% in MRE liver stiffness, >30% in MRI-PDFF [magnetic resonance imaging proton density fat fraction] liver fat fraction, or an absolute reduction of 0.5 in ELF or 17 U/L in ALT [alanine aminotransferase].
Treatment response should be assessed at approximately 12 months for resmetirom and 18 months for semaglutide. If fibrosis-related parameters improve, treatment can generally be continued. If disease remains stable without clear improvement, treatment continuation should be individualized in the context of the patient's overall cardiometabolic benefit. Evidence of worsening fibrosis should prompt reassessment of lifestyle factors, alcohol exposure, and metabolic control, and consideration of discontinuation or an alternative treatment, depending on the therapy.