Learning objectives
After this module you should be able to:
- Identify adults with at-risk MASH (F2–F3, no cirrhosis) who are candidates for drug treatment, using non-invasive tests.
- Prescribe resmetirom safely: weight-based dose, CYP2C8 and statin interactions, thyroid checks and monitoring.
- Prescribe semaglutide 2.4 mg for MASH, including titration, side effects, contraindications and muscle preservation.
- Compare guideline positions (EASL, AASLD, global, Saudi 2026) on other drugs, and judge response and futility.
Boxed recommendations are paraphrased from the EASL–EASD–EASO 2024 guideline, with its grades: evidence level from 1 (strongest) to 5; recommendation strong, weak or open; consensus is the panel's agreement (strong means at least 95%).
1Who needs drug treatment
Drug treatment for metabolic dysfunction-associated steatotic liver disease (MASLD) targets one group: adults with steatohepatitis (MASH) and moderate to advanced fibrosis, stage F2–F3, without cirrhosis. Both licensed drugs were tested in this group, and both regulatory approvals in the US cover only MASH with F2–F3 [1,2]. People with steatosis alone or F0–F1 fibrosis need lifestyle care and treatment of their metabolic risk factors, not a liver drug.
A biopsy is not needed. The US labels do not require one, and AASLD selects patients by non-invasive tests, preferably liver stiffness [1]. The usual route is the two-step pathway from Module 1: FIB-4 first, then elastography. FIB-4 alone must not be used to rule a patient in or out of treatment [2]. Image-based stiffness measured before treatment also gives a baseline for judging response later [1].
Cirrhosis is excluded for now because no MASH drug has shown benefit at that stage. MAESTRO-NASH and ESSENCE enrolled F1B–F3 and F2–F3 patients respectively, and the long-term outcome phases of both trials are still running, as is an outcome trial of resmetirom in cirrhosis [3,4,5].
No drug aimed at MASH can yet be advised for patients who already have cirrhosis. [5]
| Test | Treat (F2–F3 likely) | Specialist decision | Do not start (cirrhosis likely) |
|---|---|---|---|
| VCTE | 8–15 kPa | 15–20 kPa, after a second test, imaging or platelet count excludes cirrhosis | >20 kPa |
| MRE | 3.1–4.4 kPa | 4.4–5.0 kPa, same checks | >5.0 kPa |
| ELF (bands from the semaglutide update) | 9.2–10.5 | 10.5–11.3 | >11.3 |
The VCTE and ELF ranges roughly match the middle half of trial participants, so about half of biopsy-proven F2–F3 patients fall outside them [1,2]. The global consensus draws the lines differently: VCTE 8 to below 10 kPa needs a second test confirming F2; 10 to below 16 kPa is enough on its own; 16–20 kPa needs a second test excluding cirrhosis; above 20 kPa is a stop [6].
2Lifestyle stays the base
Adults with MASLD and overweight should aim for lasting weight loss through diet and behaviour change: more than 5% to cut liver fat, 7–10% to reduce inflammation and more than 10% to improve fibrosis. [5]
Every guidance document places drugs on top of lifestyle change and control of diabetes, blood pressure and lipids, never instead of them [1,2]. A prescription is a good moment to restate diet, activity and alcohol advice. Patients should also hear that treatment is long term: in the STEP trials, stopping semaglutide reversed the cardiometabolic gains [2].
3Resmetirom
Resmetirom is an oral, liver-directed agonist highly selective for the thyroid hormone receptor β1. Thyroid hormone action in the liver increases lipophagy and mitochondrial biogenesis and suppresses lipogenesis, which lowers liver fat [5].
In MAESTRO-NASH, 966 adults with biopsy-proven MASH (F1B–F3) received 80 mg, 100 mg or placebo daily. At 52 weeks, MASH resolved without fibrosis worsening in 25.9% (80 mg) and 29.9% (100 mg), against 9.7% on placebo. Fibrosis improved by at least one stage in 24.2% and 25.9%, against 14.2%. LDL cholesterol fell by 13.6–16.3% by week 24, and serious adverse events were similar across groups [3]. Weight and glucose control did not change [5].
Where the drug is approved locally, consider resmetirom as a MASH-directed treatment for adults with non-cirrhotic MASH and fibrosis of stage F2 or higher. [5]
If approved locally, resmetirom may be considered in non-cirrhotic MASLD with documented advanced fibrosis, at-risk steatohepatitis with significant fibrosis, or non-invasive results that signal a risk of liver events. [5]
Before starting, AASLD advises against resmetirom in cirrhosis, other active liver disease such as autoimmune hepatitis or primary biliary cholangitis, alcohol above 20 g/day for women or 30 g/day for men, untreated thyroid disease, and symptomatic gallstone disease such as acute cholecystitis. Check TSH at baseline or within the previous 6 months [1].
| Item | Practical rule |
|---|---|
| Dose | 80 mg once daily if <100 kg; 100 mg if ≥100 kg |
| With a moderate CYP2C8 inhibitor (e.g. clopidogrel) | 60 mg if <100 kg; 80 mg if ≥100 kg |
| Statin maximum | Rosuvastatin and simvastatin 20 mg/day; atorvastatin and pravastatin 40 mg/day; recheck lipids and keep CV targets |
| Thyroid | Correct thyroid dysfunction first; if on levothyroxine or known thyroid disease, TSH and free T4 every 3–6 months |
| Liver panel | Baseline, then 3, 6 and 12 months; every 6 months after that is suggested |
| Stop for liver injury | ALT or AST >5× ULN, or ALP >2× ULN, on 2 occasions; or bilirubin >2.5 mg/dL or INR >1.5 with raised enzymes |
Resmetirom is a substrate of CYP2C8 and of the transporters OATP1B1 and OATP1B3, which explains both the clopidogrel and the statin rules [1]. Diarrhoea (24–34%) and nausea (12–22%) are the commonest side effects, usually starting within 12 weeks; diarrhoea lasted more than 4 weeks in about half of those affected. Symptomatic gallstone disease was more frequent, but past biliary colic is not a contraindication. Free T4 fell by 16–21% on average, and 1.8% needed new levothyroxine [1].
Judge response at 12 months with the same test used at baseline. AASLD treats a fall in stiffness of at least 25% on VCTE or 20% on MRE, or normalisation of a raised ALT, as benefit: continue. A similar rise, or a steadily rising ALT, suggests failure: consider stopping. A fall in MRI-PDFF of less than 30% predicted a response rate no better than placebo. In between, decide with the patient; stable fibrosis may still be worthwhile in F3 [1]. The global consensus sets the VCTE threshold at 30%, defines futility as worsening of two concordant tests, and warns against using ALT alone [6].
For patients on resmetirom, there are as yet no data on durability of benefit, prediction of individual response, liver outcomes or long-term safety. [5]
4Semaglutide 2.4 mg
Semaglutide is a once-weekly GLP-1 receptor agonist with a half-life of about 5–7 days. Hepatocytes and stellate cells carry almost no GLP-1 receptors, so its liver benefit is thought to come indirectly, through weight loss, better glucose and lipid control and less systemic inflammation [2].
ESSENCE randomised 1,197 adults with biopsy-proven MASH and F2–F3 fibrosis. In the planned week-72 analysis of the first 800, MASH resolved without fibrosis worsening in 62.9% on semaglutide against 34.3% on placebo, and fibrosis improved without MASH worsening in 36.8% against 22.4%. Weight fell by 10.5% against 2.0% [4]. The US FDA granted accelerated approval for this indication in August 2025; final approval depends on outcome data expected from 2028 [2].
The dose is built up from 0.25 mg to 2.4 mg weekly over 16 weeks [7]. Nausea (36.2% vs 13.2%), diarrhoea (26.9% vs 12.2%), constipation (22.2% vs 8.4%) and vomiting (18.6% vs 5.6%) were the main side effects, mostly mild and short-lived; stopping for adverse events was no more common than with placebo (2.6% vs 3.3%). Advise small, lower-fat meals, stopping eating when full, fluids and fibre. Slow the titration or reduce the dose if symptoms persist [2].
- Contraindicated: personal or family history of medullary thyroid carcinoma or MEN2; severe gastroparesis. Do not start during active suicidal ideation [2].
- Gallbladder: cholelithiasis 1.6% vs 0.7%; a meta-analysis of 76 trials showed a 37% higher risk of biliary disease. Past gallbladder disease calls for caution, not refusal [2].
- Pancreatitis: stop at once if suspected and do not restart after a confirmed episode [2].
- Kidneys and glucose: check creatinine during titration if vomiting or diarrhoea; lower insulin or sulfonylurea doses to avoid hypoglycaemia [2].
- Eyes: in type 2 diabetes, arrange a retinal exam before starting if none in the past 12 months [2].
Liver toxicity was not a problem in ESSENCE: no patient stopped because of raised ALT or AST, so AASLD advises liver tests only when clinically needed. Assess response at 72 weeks. A fall from baseline of at least 30% in VCTE stiffness, 20% in MRE stiffness, at least 0.5 in ELF, or more than 17 U/L (or 20%) in ALT probably reflects benefit; rising ALT or stiffness suggests non-response [2].
GLP-1 receptor agonists are safe in MASH, including compensated cirrhosis, and should be used for type 2 diabetes and obesity because they improve cardiometabolic outcomes. [5]
Without phase III histological proof, GLP-1 receptor agonists cannot yet be advised as MASH-directed treatment. [5]
This last recommendation predates the ESSENCE results, which were published in 2025 [5,4]. Expect EASL to revisit it.
5Choosing between them, or combining
No head-to-head trial exists, and no guideline ranks one drug above the other. AASLD leaves the choice to clinical judgement, weighing liver risk against the burden of other disease [1]. In practice, obesity, type 2 diabetes or established cardiovascular disease point towards semaglutide, which treats these conditions as well; the SELECT trial showed a 1.5% absolute reduction in major cardiovascular events in people with overweight or obesity and established cardiovascular disease [2]. Resmetirom is a reasonable choice for patients who are not overweight, cannot tolerate a GLP-1 drug, or remain at F2–F3 despite one. A need for high-dose statin or clopidogrel, or untreated thyroid disease, weighs against resmetirom [1].
Combination is unstudied. About 14% of MAESTRO-NASH patients were on a stable GLP-1 drug and responded to resmetirom as well as others, so EASL considers it reasonable to use resmetirom by the same criteria in these patients [5,2]. However, the 2.4 mg dose has never been combined with resmetirom in a trial [2].
6Other drugs: what each guideline says
Pioglitazone is safe in non-cirrhotic MASH but, lacking large phase III histological evidence, is not advised as a MASH-directed treatment. [5]
Vitamin E is not advised as a MASH-directed treatment, given weak phase III evidence and possible long-term risks. [5]
SGLT2 inhibitors and metformin lack evidence as MASH-directed treatment, but are safe in MASLD and should be used for diabetes, heart failure and kidney disease. [5]
Statins can be used in chronic liver disease, including compensated cirrhosis, and should be prescribed according to cardiovascular risk. [5]
| Drug | EASL 2024 | AASLD 2023 | Global 2025 | Saudi 2026 |
|---|---|---|---|---|
| Pioglitazone | Safe; not a MASH treatment | Can be considered in MASH with T2D | For T2D, not MASH-targeted | Recommended in T2D with biopsy-proven MASH and advanced fibrosis |
| Vitamin E | Not recommended | Selected people without diabetes | Only selected people without T2D or cirrhosis | Can be considered without T2D; not with T2D or advanced fibrosis |
| SGLT2 inhibitors | For their indications; not MASH-targeted | Steatosis may improve; histology unclear | For T2D, not MASH-targeted | May be considered in T2D for cardiometabolic benefit |
| Metformin | For its indications; not MASH-targeted | Should not be used to treat NASH | Not preferred in T2D with MASLD | Not recommended for MASH |
| Tirzepatide | Promising phase 2 data; no recommendation | Possible benefit (liver fat) | Not named; GLP-1 RAs preferred for T2D and obesity | May be considered for obesity |
| Statins | Use for CV risk, incl. compensated cirrhosis | Safe and recommended for CV risk; not a NASH treatment | Not addressed | Not addressed |
Sources for the table: EASL [5], AASLD [8], global consensus [6] and Saudi consensus [7]. The main split is over pioglitazone and vitamin E: AASLD and the Saudi consensus leave room for both in selected patients, whereas EASL does not endorse either as a MASH treatment. Tirzepatide improved MASH in a phase 2 trial (resolution in 62% at 15 mg against 10% on placebo) but is not licensed for MASH [7].
7Approval status around the world
| Region | Resmetirom | Semaglutide 2.4 mg |
|---|---|---|
| United States (FDA) | Accelerated approval, March 2024 | Accelerated approval, August 2025 |
| European Union | Conditional authorisation, August 2025 | Check current status |
| United Kingdom (MHRA) | Approved, June 2026 | Conditional authorisation, July 2026 |
| Saudi Arabia (SFDA) | Check SFDA | Check SFDA |
Sources: FDA dates from the AASLD updates [1,2]; EU decision [9]; UK decisions, both awaiting NICE appraisal for NHS use [10]. All approvals are provisional on outcome data. Approvals change quickly and differ between countries, so always confirm the current SFDA status and the local label before prescribing for MASH.
8The Saudi 2026 consensus
The Saudi consensus adapts international guidance to local practice. It recommends GLP-1 receptor agonists (semaglutide 2.4 mg weekly or liraglutide 3 mg daily) with lifestyle change for MASLD or MASH with BMI above 27 kg/m², type 2 diabetes, cardiovascular disease or other obesity-related conditions. Tirzepatide for obesity and resmetirom 80–100 mg for MASH with fibrosis may be considered, pending more real-world evidence (moderate level of evidence) [7].
At the time of writing, the consensus stated that the drugs available for MASLD in Saudi Arabia were those licensed for diabetes and obesity, such as GLP-1 agonists, pioglitazone and SGLT2 inhibitors, used off-label for the liver, and that resmetirom was not yet approved locally. It also does not advise metformin, acarbose, DPP-4 inhibitors, ursodeoxycholic acid or insulin as MASH treatment (high level of evidence) [7].
9Clinical case
A 55-year-old man with diabetes and a coronary stent
- Presentation
- Seen in Dammam. Type 2 diabetes on metformin and gliclazide, HbA1c 8.1%. Weight 104 kg, BMI 34 kg/m². Coronary stent 1 year ago; takes clopidogrel and atorvastatin 80 mg. No alcohol. AST 38 U/L, ALT 45 U/L, platelets 230 ×10⁹/L, TSH normal. Viral and autoimmune screens negative.
- Staging
- FIB-4 = (55 × 38) ÷ (230 × √45) = 2,090 ÷ (230 × 6.71) = 2,090 ÷ 1,543 = 1.35, which is indeterminate. VCTE with the XL probe: 11.2 kPa, IQR/median 15%, CAP 330 dB/m. This lies within 8–15 kPa, consistent with F2–F3; platelets are normal and imaging shows no signs of cirrhosis.
- Decision
- Both drugs are options on liver grounds. Resmetirom would need 80 mg (≥100 kg plus clopidogrel) and atorvastatin cut to 40 mg, which conflicts with his post-stent lipid target. Semaglutide treats his obesity, diabetes and cardiovascular risk as well. After confirming local availability, semaglutide is started at 0.25 mg weekly and increased over 16 weeks to 2.4 mg. Gliclazide is reduced to avoid hypoglycaemia, a retinal exam is booked and he is advised on protein intake and resistance exercise.
- Week 72
- Weight 93 kg: a loss of 11 kg, or 11 ÷ 104 = 10.6%. VCTE 7.4 kPa: a fall of 3.8 kPa, or 3.8 ÷ 11.2 = 34%. ALT 24 U/L, a fall of 21 U/L. Each change exceeds the AASLD response thresholds (VCTE ≥30%, ALT >17 U/L), so treatment continues.
- Teaching points
- Interactions and comorbidity often decide the drug. Measure stiffness with the same method at baseline and follow-up. A good response does not mean stopping: benefits fade when semaglutide is withdrawn.
10Test yourself
Choose an answer to see the explanation. Nothing is recorded.
1. An 85 kg woman with MASH F2–F3 takes clopidogrel. What resmetirom dose does AASLD advise?
Below 100 kg the usual dose is 80 mg; a moderate CYP2C8 inhibitor such as clopidogrel lowers it to 60 mg.
2. Which statin dose exceeds the AASLD maximum when given with resmetirom?
Rosuvastatin and simvastatin are capped at 20 mg/day, atorvastatin and pravastatin at 40 mg/day.
3. A patient with MASLD has VCTE 23 kPa and platelets 120 ×10⁹/L. What is correct?
VCTE above 20 kPa suggests cirrhosis, which is outside both licences. GLP-1 drugs may still be used for diabetes or obesity.
4. Which finding is a contraindication to semaglutide?
A personal or family history of medullary thyroid carcinoma or MEN2 is a contraindication. Gallstones call for caution, not avoidance.
5. After 12 months of resmetirom, how does the global consensus define a clinically significant VCTE change?
The global consensus uses 30%; AASLD uses 25% for VCTE. CAP changes did not predict response.
11Key messages
- Drug treatment is for MASH with F2–F3 fibrosis and no cirrhosis, identified by non-invasive tests; lifestyle change continues alongside.
- Resmetirom: 80 or 100 mg by weight, lower with clopidogrel, statin caps, TSH first, liver tests at 3, 6 and 12 months.
- Semaglutide 2.4 mg: titrate over 16 weeks, manage GI effects, protect muscle, avoid in MTC or MEN2.
- Judge response with the same stiffness test: AASLD uses 25% (resmetirom) or 30% (semaglutide) on VCTE; the global consensus uses 30%.
- Guidelines disagree on pioglitazone and vitamin E; approvals differ by country, so check SFDA status before prescribing.
References
- Chen VL, et al. Resmetirom therapy for MASLD: October 2024 updates to AASLD Practice Guidance. Hepatology 2025;81(1):312–20. doi:10.1097/HEP.0000000000001112
- Bansal MB, et al. Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD Practice Guidance. Hepatology 2026;83(5):1326–40. doi:10.1097/HEP.0000000000001608
- Harrison SA, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis (MAESTRO-NASH). N Engl J Med 2024;390:497–509. doi:10.1056/NEJMoa2309000
- Sanyal AJ, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis (ESSENCE). N Engl J Med 2025;392:2089–99. doi:10.1056/NEJMoa2413258
- EASL–EASD–EASO Clinical Practice Guidelines on the management of MASLD. J Hepatol 2024;81:492–542. doi:10.1016/j.jhep.2024.04.031
- Younossi ZM, et al. Global consensus recommendations for MASLD and MASH. Gastroenterology 2025;169(5):1017–32. doi:10.1053/j.gastro.2025.02.044
- Abaalkhail F, et al. MASLD management in Saudi Arabia: a modified Delphi-based adaptation of international standards. Saudi J Gastroenterol 2026;32(2):104–20. doi:10.4103/sjg.sjg_199_25
- Rinella ME, et al. AASLD Practice Guidance on the clinical assessment and management of NAFLD. Hepatology 2023;77:1797–835. doi:10.1097/HEP.0000000000000323
- Madrigal Pharmaceuticals. European Commission approval of Rezdiffra, 19 August 2025. https://ir.madrigalpharma.com/node/16716
- British Liver Trust. Two MASH treatments receive MHRA approval, 2026. https://britishlivertrust.org.uk/new-hope-for-people-living-with-mash-as-two-treatments-receive-mhra-approval/
How to cite this module
Desoky M. Choosing drug treatment for MASH. Metabolic Liver Academy, version 1.0. Updated 2026-10-03. Available from: https://drmahmouddesoky.github.io/metabolic-liver-academy/modules/drug-treatment.html
For education only. This module summarises published evidence and guidelines; it does not replace clinical judgement, full guidelines or local drug labels. It is not accredited for CME credit. Disclaimer.