Key facts
- What it is: MASH is the inflammatory, progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD); the previous names were NASH and NAFLD.
- Main drivers: obesity, type 2 diabetes, insulin resistance and the metabolic syndrome.
- Why it matters: untreated MASH can progress to fibrosis, cirrhosis and liver failure, and raises cardiovascular risk.
- Semaglutide (phase 3, ESSENCE): steatohepatitis resolved in 62.9% vs 34.3% on placebo at week 72 (interim analysis; PMID 40305708).
- Retatrutide (phase 2a): liver fat fell about 81–82% at the higher doses vs +0.3% on placebo (PMID 38858523).
- Tesamorelin (HIV NAFLD): hepatic fat fell about 37% relative to baseline vs placebo (PMID 31611038).
- Approval status: resmetirom (a non-peptide thyroid-receptor drug) is the first approved MASH medicine; the GLP-1-based drugs here are not yet approved for MASH.
What is MASH?
MASH — metabolic dysfunction-associated steatohepatitis — is the inflammatory, progressive form of fatty liver disease. Fat builds up inside liver cells, and in MASH that fat is accompanied by inflammation and cell injury that, over years, can scar the liver (fibrosis) and eventually cause cirrhosis.
The naming has changed recently, which causes a lot of confusion. What used to be called non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) was renamed in a 2023 international consensus. The umbrella term is now metabolic dysfunction-associated steatotic liver disease (MASLD), and the inflammatory subtype within it is MASH. The change was deliberate: instead of defining the disease by what it is not ("non-alcoholic"), the new names centre it on the metabolic dysfunction that actually drives it. For most purposes NASH and MASH refer to the same condition.
Why obesity and metabolic disease drive it
MASH is a metabolic disease that happens to show up in the liver. Its strongest risk factors are obesity, type 2 diabetes, insulin resistance and the broader metabolic syndrome — the same cluster that raises cardiovascular risk. When the body is chronically overloaded with energy and insulin signalling is impaired, the liver stores excess fat; in susceptible people that fat provokes inflammation and injury rather than sitting inertly.
That shared metabolic root is exactly why weight-loss and glucose-lowering drugs became MASH candidates. If losing a meaningful amount of body weight and improving insulin sensitivity can reverse some of the drivers, the liver may follow. The GLP-1 class of weight-loss drugs produces both effects, so testing them in fatty liver disease was a natural step. The results below show how far that logic has actually been validated in trials — and where it stops.
Semaglutide: the phase 3 MASH result
The most advanced evidence comes from semaglutide, a GLP-1 receptor agonist. The phase 3 ESSENCE trial enrolled 1,197 patients with biopsy-defined MASH and fibrosis stage 2 or 3, randomly assigned 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo (PMID 40305708). A planned interim analysis at week 72, covering the first 800 patients, reported two co-primary histology endpoints.
| ESSENCE interim endpoint (week 72) | Semaglutide 2.4 mg | Placebo |
|---|---|---|
| Resolution of steatohepatitis without worsening of fibrosis | 62.9% | 34.3% |
| Reduction in fibrosis without worsening of steatohepatitis | 36.8% | 22.4% |
| Combined resolution and fibrosis improvement | 32.7% | 16.1% |
| Mean change in body weight | −10.5% | −2.0% |
Both differences were statistically significant. Gastrointestinal side effects were more common with semaglutide, consistent with the known profile of the class. Two things are worth holding in mind: this is an interim read of an ongoing trial (the full study runs to 240 weeks), and improving liver histology in a trial is not the same thing as a regulatory approval for the MASH indication — see the approval section below.
Retatrutide: liver-fat findings
Retatrutide is an investigational triple agonist that acts on the GIP, GLP-1 and glucagon receptors. The glucagon-receptor arm is of particular interest for the liver, because glucagon signalling influences hepatic fat handling. In a phase 2a substudy of 98 participants with MASLD and at least 10% liver fat, retatrutide produced large reductions in liver fat measured by imaging (PMID 38858523).
| Retatrutide phase 2a (24 weeks) | Mean relative change in liver fat | Reached normal liver fat (<5%) |
|---|---|---|
| 1 mg | −42.9% | 27% |
| 4 mg | −57.0% | 52% |
| 8 mg | −81.4% | 79% |
| 12 mg | −82.4% | 86% |
| Placebo | +0.3% | 0% |
These are striking numbers, but they need to be read at the right altitude. This was an early-phase (2a) study using imaging to measure liver fat, not a biopsy-based histology trial of the kind semaglutide has completed, and it was a substudy nested inside a larger obesity programme. Liver-fat reduction is a promising signal, not proof of long-term histological benefit, and retatrutide remains investigational.
Tesamorelin: liver fat in HIV
Tesamorelin sits apart from the GLP-1 drugs: it is a growth-hormone-releasing-hormone analogue, approved to reduce excess abdominal fat in people with HIV-associated lipodystrophy. Because that population has a high burden of fatty liver, tesamorelin was tested directly for its effect on the liver. In a randomized, double-blind trial of 61 people living with HIV and fatty liver, participants received tesamorelin 2 mg daily or placebo for 12 months (PMID 31611038).
Tesamorelin reduced hepatic fat fraction by roughly 37% relative to baseline compared with placebo, and 35% of the tesamorelin group reached a hepatic fat fraction below 5% versus 4% on placebo. Fasting glucose and HbA1c were not significantly different between the groups at 12 months. The main tolerability issue was localized injection-site reactions. This is the clearest randomized evidence that a non-GLP-1 metabolic peptide can lower liver fat, but it was studied specifically in people with HIV, and tesamorelin is not approved for MASH. Our tesamorelin research summary covers the molecule in more detail.
Approval status: read this carefully
This is the part most easily garbled, so it is worth stating plainly:
- The first approved MASH drug is not a peptide. In 2024 the US FDA approved resmetirom (Rezdiffra), a thyroid hormone receptor-beta agonist, for MASH with moderate to advanced fibrosis, alongside diet and exercise. It is an oral small molecule, not a GLP-1 or peptide drug.
- Semaglutide is not approved for MASH. It is approved for type 2 diabetes and for chronic weight management, and its phase 3 MASH trial is ongoing. Strong interim histology data is not the same as an approved indication.
- Retatrutide is investigational. It is not approved for any use at the time of writing; its liver-fat data comes from early-phase studies.
- Tesamorelin is approved only for HIV-associated excess abdominal fat. Its liver-fat trial was exploratory in that specific population and does not constitute a MASH approval.
The honest summary is that the metabolic drugs discussed here have produced genuinely encouraging liver results, but the regulatory landscape for MASH is early and moving. Whether any of them is appropriate for a given person is a clinical decision, not something to infer from a trial headline.
Frequently asked questions
What is MASH, and how is it different from NASH?
MASH stands for metabolic dysfunction-associated steatohepatitis. It is the same disease that used to be called NASH (non-alcoholic steatohepatitis); a 2023 international consensus renamed the fatty-liver spectrum around the metabolic drivers of the condition rather than defining it by what it is not. MASH is the inflammatory form, in which fat in the liver is accompanied by inflammation and cell injury that can progress to scarring (fibrosis) and cirrhosis.
Is there an approved drug for MASH?
Yes. In 2024 the US Food and Drug Administration approved resmetirom (Rezdiffra), a thyroid hormone receptor-beta agonist, as the first medicine indicated specifically for MASH with moderate to advanced fibrosis, alongside diet and exercise. Resmetirom is not a peptide or a GLP-1 drug. The GLP-1-based medicines discussed on this page are not, at the time of writing, approved for treating MASH itself.
Did semaglutide work for MASH in its phase 3 trial?
In the phase 3 ESSENCE trial, a planned week-72 interim analysis of the first 800 patients found that resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the semaglutide 2.4 mg group versus 34.3% on placebo, and reduction in liver fibrosis without worsening of steatohepatitis in 36.8% versus 22.4%. The trial is ongoing, and these histology results are not the same as an approval for the MASH indication.
How much did retatrutide reduce liver fat?
In a phase 2a substudy of 98 participants with MASLD and at least 10% liver fat, the mean relative reduction in liver fat at 24 weeks was 81.4% at the 8 mg dose and 82.4% at 12 mg, versus a 0.3% increase on placebo. Normal liver fat (under 5%) was reached by 79% and 86% of participants at those doses. This is an early-phase imaging outcome, not a histology trial and not an approval.
What did the tesamorelin liver-fat study show?
In a randomized trial of 61 people living with HIV and fatty liver, once-daily tesamorelin reduced hepatic fat fraction by about 37% relative to baseline compared with placebo over 12 months, and 35% of the tesamorelin group reached a hepatic fat fraction below 5% versus 4% on placebo. Tesamorelin is a growth-hormone-releasing-hormone analogue approved for HIV-associated excess abdominal fat, not for MASH.
Can GLP-1 drugs cure fatty liver disease?
No study to date describes a cure. The trials show that GLP-1 and related metabolic drugs can reduce liver fat and, for semaglutide, improve MASH histology in a large share of treated patients, but not everyone responds and benefits are measured while treatment continues. MASH management centres on the underlying metabolic drivers, and treatment decisions belong with a clinician. This page is educational and not medical advice.
Sources
This summary traces to peer-reviewed publications and their trial registrations:
- Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis (ESSENCE) — New England Journal of Medicine, 2025; PubMed 40305708. Registered as NCT04822181.
- Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial — Nature Medicine, 2024; PubMed 38858523. Registered as NCT04881760.
- Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial — Lancet HIV, 2019; PubMed 31611038. Registered as NCT02196831.
- Condition reference record: metabolic dysfunction-associated steatotic liver disease (MASLD).