EASL–EASD–EASO 2026: 15 Key Takeaways for Resmetirom and Semaglutide in MASH: Journal of Hepatology | September 2026
MASH pharmacotherapy is now recommended for F2–F3 disease. Adults with non-cirrhotic MASH and significant/advanced fibrosis (F2–F3) should be considered for resmetirom or semaglutide, always alongside lifestyle and cardiometabolic management.
Liver biopsy is no longer routinely required to start treatment. Treatment eligibility can be established using validated fibrosis NITs; biopsy should mainly be reserved for discordant/uncertain cases or suspected alternative liver disease.
Practical NIT treatment thresholds are now proposed. Consider treatment when fibrosis risk is compatible with F2–F3, particularly VCTE 10–20 kPa, MRE 3.1–5.0 kPa, or ELF 9.8–11.3. Borderline/high VCTE should preferably be repeated or supported by another NIT.
FIB-4 is a gatekeeper—not a treatment-selection test. FIB-4 remains useful for first-line risk stratification, but its limited positive predictive value means it should not alone establish eligibility for MASH pharmacotherapy.
Two concordant fibrosis NITs increase diagnostic confidence. When VCTE, MRE, ELF or other specific fibrosis tests agree, clinicians can be more confident about clinically relevant fibrosis and future liver-event risk.
Resmetirom and semaglutide should not be ranked by liver efficacy. There are no head-to-head trials, and differences between their phase III studies prevent valid cross-trial claims of superiority.
Semaglutide is favoured when metabolic disease dominates. Semaglutide 2.4 mg weekly may be preferred with obesity, inadequately controlled T2D, established/high cardiovascular risk, or CKD associated with obesity/T2D, because of its broader cardiometabolic benefits.
Resmetirom is attractive when a liver-directed strategy is needed. Resmetirom 80 or 100 mg orally daily may be prioritised in patients without obesity, those already receiving or intolerant to a GLP-1RA, those with prominent atherogenic dyslipidemia, or patients preferring oral therapy.
Sarcopenia should influence drug selection and monitoring. Semaglutide-related weight loss may include skeletal muscle loss. In patients with pre-existing or high sarcopenia risk, resmetirom may be preferable, while semaglutide requires attention to protein intake, muscle strength and resistance exercise.
Do not use either drug as MASH-targeted treatment in cirrhosis—yet. Resmetirom and semaglutide should not currently be prescribed specifically to treat MASH cirrhosis, because liver-outcome efficacy remains unproven. Semaglutide may still be used in compensated cirrhosis for its established diabetes or obesity indications.
Baseline safety assessment must be drug-specific. Before resmetirom, assess thyroid function, lipid profile, drug interactions and gallbladder disease. Before semaglutide, consider pancreatitis, gastroparesis, gallbladder disease, renal function, diabetic retinopathy, nutritional/sarcopenia risk and MTC/MEN2 history.
Monitoring must assess the liver—not simply weight or ALT. Fibrosis NITs should be repeated longitudinally. Candidate response signals include ≥30% VCTE-LSM reduction, ≥20% MRE reduction, ≥0.5 ELF reduction, ≥30% MRI-PDFF reduction, or ALT reduction ≥17 U/L—but these are supportive markers, not validated stand-alone response criteria.
Failure to improve at 12–18 months does not automatically mean treatment failure. Stable fibrosis without reaching predefined improvement thresholds at 12 months for resmetirom or 18 months for semaglutide may justify continued treatment while optimising metabolic and lifestyle factors.
Worsening fibrosis requires a different approach for the two drugs. With worsening fibrosis after 12 months of resmetirom, discontinuation should be considered. With semaglutide, alternative MASH therapy should be considered, but semaglutide may still be continued when its weight, glycemic, cardiovascular or renal benefits justify treatment.
Do not routinely start resmetirom + semaglutide together. Upfront combination therapy currently lacks evidence and cannot be recommended. However, if a patient already taking a stable GLP-1RA remains eligible for MASH therapy, clinicians may switch to semaglutide 2.4 mg or add resmetirom. Resmetirom has demonstrated efficacy in patients already receiving stable GLP-1RA or SGLT2-inhibitor therapy.
GastroAGI Take-Home Message
The 2026 EASL–EASD–EASO guidance moves MASH into an NIT-guided, phenotype-directed treatment era: identify F2–F3 fibrosis without routinely biopsying, then choose therapy according to the whole patient—not just the liver.
Semaglutide → metabolic phenotype: obesity, T2D, cardiovascular/renal risk.
Resmetirom → liver/lipid phenotype: normal weight, established/intolerant GLP-1RA therapy, atherogenic dyslipidemia or sarcopenia concern.
