"Fatty liver" is a search term for a spectrum. At one end is fat in the liver and nothing else; at the other, cirrhosis. One GLP-1 medicine is approved for one band of it: Wegovy injection, for MASH with F2–F3 fibrosis and no cirrhosis. This page reads the biopsy trials behind that approval and behind the two unapproved drugs furthest along — tirzepatide and survodutide — and the one trial in cirrhosis, which did not work. Everything is from the published trial abstracts, the FDA record and ClinicalTrials.gov, read on 28 September 2026.
The list of approved GLP-1 uses beyond weight — heart, kidney, sleep apnoea and liver — is on GLP-1 benefits. This page is the liver in depth.
The words: MASLD, MASH and the fibrosis stages
The names changed in 2023, which is why older articles say NAFLD and NASH.
| Term | What it means | Covered by the Wegovy label? |
|---|---|---|
| MASLD (formerly NAFLD) | Fat in the liver linked to metabolic risk (weight, blood sugar, blood pressure, lipids) | Only the subset below |
| MASH (formerly NASH) | MASLD with inflammation and liver-cell injury on biopsy | Yes, if fibrosis is F2–F3 |
| F0–F1 | No or mild fibrosis | No |
| F2–F3 | Moderate to advanced fibrosis | Yes |
| F4 | Cirrhosis | No — and see the cirrhosis trial below |
Every result on this page is a biopsy result: a pathologist scores a sliver of liver before and after treatment. That matters because the trials measure two separate things — whether the inflammation (the "SH" in MASH) resolves, and whether the scarring (fibrosis) goes down a stage — and a drug can do one without the other.
The approved drug: Wegovy and ESSENCE
The FDA's Drugs@FDA record lists the efficacy supplement for Wegovy (NDA 215256, supplement 24) as approved on 15 August 2025. The evidence is ESSENCE (NCT04822181): 1,197 patients with biopsy-confirmed MASH and F2–F3 fibrosis, randomised 2:1 to semaglutide 2.4 mg weekly or placebo for 240 weeks. The approval rests on a planned interim look at the first 800 patients at week 72 (NEJM 2025;392:2089–2099).
| Week 72 | Semaglutide 2.4 mg (534) | Placebo (266) | Difference |
|---|---|---|---|
| Steatohepatitis resolved, fibrosis not worse | 62.9% | 34.3% | 28.7 points |
| Fibrosis improved ≥1 stage, steatohepatitis not worse | 36.8% | 22.4% | 14.4 points |
| Both at once | 32.7% | 16.1% | 16.5 points |
| Body weight | −10.5% | −2.0% | −8.5 points |
Two things in that table are easy to miss. The fibrosis effect is about half the size of the inflammation effect, and fibrosis is what predicts liver outcomes. And a third of the placebo group saw their steatohepatitis resolve — a placebo rate much higher than in the other trials on this page, discussed below.
The label's Wegovy MASH population was older and more diabetic than its weight-loss population: median age 57, 57% female, and the adverse-reaction section records fractures in 4.4% on Wegovy in the MASH trial. The second half of ESSENCE runs to week 240 with cirrhosis-free survival as its primary outcome (registry primary completion April 2029). That is the confirmatory evidence the accelerated approval waits on.
The one that failed: semaglutide in cirrhosis
Before ESSENCE, Novo ran a phase 2 trial of the same 2.4 mg dose in 71 people with MASH and compensated cirrhosis (F4, no decompensation; NCT03987451, Lancet Gastroenterol Hepatol 2023). After 48 weeks:
- Fibrosis improved by at least one stage in 5 of 47 (11%) on semaglutide against 7 of 24 (29%) on placebo — the drug arm did numerically worse, and the difference was not statistically significant (p = 0.087).
- MASH resolution did not differ either.
- There were no decompensating events or deaths; nausea affected 45% against 17%.
This is why the label stops at F3. It is also the result most "GLP-1 reverses fatty liver" coverage leaves out. A 2026 phase 2 trial of zalfermin with semaglutide in F2–F4c patients (698 people, NCT05016882) found semaglutide alone improved fibrosis in 30% against 16% on placebo, a nominal result, while the combinations did not beat placebo significantly (Lancet Gastroenterol Hepatol 2026).
The earlier signal: the 2021 phase 2
The first semaglutide MASH trial used daily injections of 0.1, 0.2 or 0.4 mg for 72 weeks in 320 people (NCT02970942, NEJM 2021;384:1113–1124). At 0.4 mg, NASH resolved in 59% against 17% on placebo, but fibrosis improved in 43% against 33% — not significant (p = 0.48). Neoplasms were reported in 15% across the semaglutide groups against 8% on placebo, with no organ pattern. The inflammation result held up in ESSENCE; the fibrosis question needed a larger trial to answer.
The unapproved candidates
Tirzepatide — SYNERGY-NASH (phase 2, NCT04166773, NEJM 2024;391:299–310). 190 people with F2–F3 fibrosis, 52 weeks, 5, 10 or 15 mg weekly against placebo.
| Week 52 | Placebo | 5 mg | 10 mg | 15 mg |
|---|---|---|---|---|
| MASH resolved, fibrosis not worse | 10% | 44% | 56% | 62% |
| Fibrosis improved ≥1 stage | 30% | 55% | 51% | 51% |
Only 157 of the 190 had an evaluable week-52 biopsy; missing values were imputed. The fibrosis effect did not rise with dose.
Survodutide (phase 2, NCT04771273, NEJM 2024;391:311–319), a GLP-1 plus glucagon agonist from Boehringer Ingelheim. 293 people with F1–F3 fibrosis, 48 weeks.
| Week 48 | Placebo | 2.4 mg | 4.8 mg | 6.0 mg |
|---|---|---|---|---|
| MASH improved, fibrosis not worse | 14% | 47% | 62% | 43% |
| Liver fat down ≥30% | 14% | 63% | 67% | 57% |
| Fibrosis improved ≥1 stage | 22% | 34% | 36% | 34% |
Nausea affected 66% on survodutide against 23% on placebo, and vomiting 41% against 4%. How survodutide and retatrutide compare on liver fat is set out in our comparison of the two glucagon drugs.
Why the placebo column is the most important number here
Laying the placebo arms side by side is not something any of the papers do, and it changes how the drug arms read:
| Trial | Population | Placebo: MASH resolved/improved | Placebo: fibrosis ≥1 stage better |
|---|---|---|---|
| Semaglutide phase 2 (2021) | F1–F3, 72 wk | 17% | 33% |
| SYNERGY-NASH, tirzepatide (2024) | F2–F3, 52 wk | 10% | 30% |
| Survodutide phase 2 (2024) | F1–F3, 48 wk | 14% | 22% |
| ESSENCE, semaglutide (2025) | F2–F3, 72 wk | 34% | 22% |
| Semaglutide cirrhosis (2023) | F4, 48 wk | — | 29% |
| Zalfermin + semaglutide (2026) | F2–F4c, 52 wk | — | 16% |
The placebo rate for MASH resolution varies more than threefold, from 10% to 34%. Biopsy scoring has known variability, the trials used different durations and definitions ("resolution" in some, "improvement" in survodutide's), and people in trials lose some weight on placebo. The consequence is practical: tirzepatide's 62% and semaglutide's 62.9% are not the same result, because one sits on a 10% placebo and the other on 34%. Only a head-to-head biopsy trial could say which drug does more for the liver, and none is registered.
The same caution applies to fibrosis: one in five to one in three people on placebo improved by a stage in every trial. Liver-fat percentages from scans are a different measure again and should not be read as biopsy outcomes.
What is being tested now
On 28 September 2026 ClinicalTrials.gov listed:
| Trial | Drug | People | What it measures | Primary completion |
|---|---|---|---|---|
| ESSENCE part 2 (NCT04822181) | semaglutide | 1,197 | cirrhosis-free survival, 240 wk | April 2029 |
| Lilly master protocol (NCT07165028) | tirzepatide, retatrutide | 4,500 | time to major adverse liver outcomes | August 2030 |
| LIVERAGE (NCT06632444) | survodutide | 1,800 | MASH F2–F3 | December 2031 |
| LIVERAGE-Cirrhosis (NCT06632457) | survodutide | 1,590 | compensated cirrhosis | June 2029 |
| PERFORMA (NCT07795164) | pemvidutide | 1,800 | MASH | December 2028 |
The Lilly protocol is the notable design: its primary outcome is not a biopsy score but liver events — the question the accelerated approval leaves open.
What is not established
- Whether any GLP-1 medicine prevents cirrhosis, liver failure or liver death. No outcome trial has reported.
- Whether the liver benefit is more than the weight loss. The trials do not separate the two.
- Anything for simple fatty liver without MASH, or for F0–F1. No approval covers these; most people with "fatty liver" on an ultrasound are in this group.
- Cirrhosis. The one completed GLP-1 trial in F4 was negative.
This page reports trial and regulatory records; it is not advice about treating a liver condition. Diagnosing MASH requires a clinician, and usually a biopsy or validated non-invasive tests. How these drugs work in general is on how GLP-1 works; the class-wide safety record is on GLP-1 side effects.
Sources
- Sanyal AJ, Newsome PN et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. N Engl J Med 2025;392(21):2089–2099. doi:10.1056/NEJMoa2413258 (PMID 40305708).
- Loomba R et al. Tirzepatide for MASH with liver fibrosis. N Engl J Med 2024;391(4):299–310. doi:10.1056/NEJMoa2401943 (PMID 38856224).
- Sanyal AJ, Bedossa P et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med 2024;391(4):311–319. doi:10.1056/NEJMoa2401755 (PMID 38847460).
- Newsome PN et al. A placebo-controlled trial of subcutaneous semaglutide in NASH. N Engl J Med 2021;384(12):1113–1124. doi:10.1056/NEJMoa2028395 (PMID 33185364).
- Loomba R et al. Semaglutide 2.4 mg once weekly in NASH-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol 2023 (PMID 36934740).
- Zalfermin co-administered with semaglutide in MASH fibrosis and cirrhosis, phase 2. Lancet Gastroenterol Hepatol 2026 (PMID 42456707).
- FDA, Drugs@FDA via openFDA, NDA 215256 (Wegovy), supplement 24, efficacy, approved 2025-08-15; WEGOVY label, Novo Nordisk, effective 2026-06-18 (DailyMed setid ee06186f-2aa3-4990-a760-757579d8f77b), sections 1, 6.1, 14.4.
- ClinicalTrials.gov API v2, queried 28 September 2026: NCT04822181, NCT07165028, NCT06632444, NCT06632457, NCT07795164.
- Review: A new era in the treatment of MASLD: clinical breakthroughs and challenges. Front Pharmacol 2026 (PMID 42741482).