MASH is diagnosed by biopsy, which makes its trials small, slow and unusually honest — you either see the tissue change or you do not. The sequence below starts with 52 people on liraglutide in 2016, moves through the dose-finding work that made semaglutide look promising, and arrives at two readouts that matter commercially as well as clinically: tirzepatide's phase 2 and semaglutide's phase 3. Running alongside is a separate bet — that adding glucagon agonism to a GLP-1 burns liver fat faster — which survodutide, retatrutide and pemvidutide are each testing in different combinations. One trial here failed, and it is the most informative on the list.
Ranked papers
#1SYNERGY-NASH
Loomba R, Hartman ML, Lawitz EJ, et al. · N Engl J Med · 2024
What it measured: Liver inflammation resolved on biopsy at one year, with scarring no worse
190 patients with biopsy-proven MASH at stage F2 or F3, given one of three doses or a placebo over 52 weeks. Resolution without fibrosis worsening reached 44%, 56% and 62% against 10% on placebo, with 10 to 15% weight loss. It is the strongest randomized dataset for a dual agonist in this disease and the basis of the phase 3 program now running. ⚠ Still phase 2, and 52 weeks is short for a disease measured in decades.
PMID 38856224 ↗NCT04166773 ↗DOI 10.1056/NEJMoa2401943 ↗
#2ESSENCE
Sanyal AJ, Newsome PN, Kliers I, et al. · N Engl J Med · 2025
What it measured: Two biopsy measures at 72 weeks: inflammation resolving, and scarring improving
The phase 3 result, in 800 biopsy-confirmed patients with F2 or F3 fibrosis. At 72 weeks, 62.9% on semaglutide had resolution without fibrosis worsening against 34.3% on placebo, and 36.8% showed fibrosis improvement against 22.4%. Weight fell 10.5% against 2.0%. ★ Note how high the placebo numbers are — a third of untreated patients improved, which is characteristic of biopsy endpoints and a reason to read single-arm claims in this field skeptically. This is expected to produce a MASH indication.
PMID 40305708 ↗NCT04822181 ↗DOI 10.1056/NEJMoa2413258 ↗
#3
Newsome PN, Buchholtz K, Cusi K, et al. · N Engl J Med · 2021
What it measured: Liver inflammation resolved on biopsy at 72 weeks, with scarring no worse
The dose-finding trial that made the phase 3 program possible: 320 patients with biopsy-confirmed disease across three daily doses for 72 weeks, with resolution reaching 59% at the top dose against 17%. ⛔ But it missed its fibrosis endpoint — the drug cleared the inflammation without demonstrably reversing the scarring. That gap is precisely what ESSENCE later closed at a higher weekly dose, and it is why the distinction between resolution and fibrosis improvement is worth keeping straight.
PMID 33185364 ↗NCT02970942 ↗DOI 10.1056/NEJMoa2028395 ↗
#4Survodutide phase 2
Sanyal AJ, Bedossa P, Fraessdorf M, et al. · N Engl J Med · 2024
What it measured: A meaningful drop in the liver-inflammation score at 48 weeks, without more scarring
293 patients on survodutide, which combines glucagon agonism with GLP-1, at three doses for 48 weeks. Improvement without fibrosis worsening hit 47%, 62% and 43% against 14% — and unlike the earlier semaglutide phase 2, the fibrosis endpoint was met. ★ Note the non-monotonic pattern: the highest dose did worse than the middle one, which is a real feature of these data rather than a rounding artifact, and a caution against assuming more is better.
PMID 38847460 ↗NCT04771273 ↗DOI 10.1056/NEJMoa2401755 ↗
#5Retatrutide MASLD phase 2a
Sanyal AJ, Kaplan LM, Frias JP, et al. · Nat Med · 2024
What it measured: How much liver fat disappeared on MRI over 48 weeks
A liver sub-study of retatrutide's obesity trial: 98 adults with at least 10% liver fat on imaging. Across four doses, liver fat fell 51%, 59%, 82% and 86% at 48 weeks against no change on placebo, with 80 to 93% of the high-dose group dropping below the 5% threshold that defines a normal liver. Weight fell up to 22%. ⚠ Measured by scan, not biopsy — so this is fat clearing, not proof that inflammation or scarring resolved.
PMID 38858523 ↗NCT04881760 ↗DOI 10.1038/s41591-024-03018-2 ↗
#6LEAN
Armstrong MJ, Gaunt P, Aithal GP, et al. · Lancet · 2016
What it measured: Liver inflammation resolved on biopsy at 48 weeks, with scarring no worse
Where it began: 52 overweight adults with biopsy-confirmed disease, randomized to liraglutide or placebo for 48 weeks. Resolution occurred in 39% against 9%. ⚠ The confidence interval ran from 1.0 to 17.7, which is another way of saying 52 people is not many. It was never meant to settle anything — it was the proof of concept that justified every larger trial on this list.
PMID 26608256 ↗NCT01237119 ↗DOI 10.1016/S0140-6736(15)00803-X ↗
#7Semaglutide MASH-cirrhosis phase 2
Loomba R, Abdelmalek MF, Armstrong MJ, et al. · Lancet Gastroenterol Hepatol · 2023
What it measured: Liver scarring improving by at least one stage on biopsy, in cirrhosis
★ The most useful failure in this field. 71 patients with cirrhosis from MASH — the advanced end of the disease — on semaglutide or placebo for 48 weeks. The fibrosis endpoint was not merely missed, it ran backwards: 11% improved on the drug against 29% on placebo. Resolution nominally favored semaglutide but did not reach significance. Once scarring reaches cirrhosis, the evidence that these drugs help is absent, and this trial is why every subsequent program recruits patients at F2 and F3 instead.
PMID 36934740 ↗NCT03987451 ↗DOI 10.1016/S2468-1253(23)00068-7 ↗
#8IMPACT
Noureddin M, Harrison SA, Loomba R, et al. · Lancet · 2025
What it measured: Inflammation resolving and scarring improving on biopsy, after only 24 weeks
212 patients on pemvidutide, another GLP-1 and glucagon combination, for just 24 weeks — with resolution at 59% and 52% against 19%. ★ The striking part is the weight: only 4 to 5% lost, far below every other trial here, while the liver histology moved as much. That dissociation is the strongest available argument that glucagon agonism acts on the liver directly rather than working through weight loss.
PMID 41237796 ↗NCT05989711 ↗DOI 10.1016/S0140-6736(25)02114-2 ↗
#9SURPASS-3 MRI
Gastaldelli A, Cusi K, Fernández Landó L, et al. · Lancet Diabetes Endocrinol · 2022
What it measured: How much liver fat disappeared on MRI over a year
An imaging substudy inside a diabetes trial: 502 adults with fatty liver on scan, given tirzepatide or insulin degludec for 52 weeks. Liver fat fell 29 to 47% against 10%, with the top dose removing 8.1 percentage points of it, and visceral fat falling too. This was the first randomized sign that tirzepatide reverses hepatic steatosis, and it is what led to the biopsy program that followed.
PMID 35468325 ↗NCT03882970 ↗DOI 10.1016/S2213-8587(22)00070-5 ↗
#10GLP-1 MASH class meta-analysis
Mantovani A, Morandin R, Fiorio V, et al. · Liver Int · 2025
What it measured: Inflammation and scarring outcomes pooled across the biopsy trials
The 2025 class-level pooling of the biopsy-anchored trials, across GLP-1, GIP combinations and glucagon combinations. Odds of MASH resolution came out three to four times placebo. ★ The important line is the split: fibrosis improvement reached significance in patients without cirrhosis and did not in those with it — the same boundary the cirrhosis trial above ran into, now confirmed across the whole literature.
PMID 40736113 ↗DOI 10.1111/liv.70256 ↗
About this list
We curate ranked, citation-anchored PubMed paper lists for the most-searched questions in obesity medicine. Every citation on this page was checked against PubMed on 2026-08-16. Each paper card links directly to PubMed and to ClinicalTrials.gov where applicable.
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