Top 10 PubMed Studies on GLP-1 Agonists for MASH and MASLD (2026)

SYNERGY-NASH randomized 190 biopsy-confirmed MASH patients with stage F2 or F3 fibrosis to tirzepatide 5, 10, or 15 mg weekly or placebo for 52 weeks. The primary endpoint — MASH resolution without worsening of fibrosis — was achieved in 44%, 56%, and 62% of tirzepatide arms versus 10% on placebo (p<0.001 for all doses). Mean body weight dropped 10-15%. SYNERGY-NASH is the highest-quality randomized phase 2 dataset for a GIP/GLP-1 dual agonist in MASH and anchors the ongoing phase 3 SYNERGY-NASH-3 program.

PMID 38856224 ↗NCT04166773 ↗DOI 10.1056/NEJMoa2401943 ↗

ESSENCE is the pivotal phase 3 trial of semaglutide 2.4 mg weekly in 800 biopsy-confirmed MASH patients with F2 or F3 fibrosis. The interim 72-week histology readout showed MASH resolution without worsening of fibrosis in 62.9% on semaglutide vs 34.3% on placebo, and improvement in fibrosis without worsening of MASH in 36.8% vs 22.4% (both p<0.001). Body weight fell 10.5% vs 2.0%. ESSENCE is expected to drive an FDA MASH indication for semaglutide and reshape the standard of care alongside resmetirom (Rezdiffra).

PMID 40305708 ↗NCT04822181 ↗DOI 10.1056/NEJMoa2413258 ↗

This was the phase 2 dose-finding biopsy trial that established semaglutide's MASH activity and seeded the ESSENCE phase 3 program. 320 patients with biopsy-confirmed NASH (F1-F3 fibrosis) were randomized to semaglutide 0.1, 0.2, or 0.4 mg daily or placebo for 72 weeks. NASH resolution without worsening of fibrosis occurred in 40%, 36%, and 59% of semaglutide arms versus 17% on placebo (p<0.001 for 0.4 mg). However the trial missed its fibrosis-improvement endpoint — a finding the larger ESSENCE trial later overcame at the weekly 2.4 mg dose.

PMID 33185364 ↗NCT02970942 ↗DOI 10.1056/NEJMoa2028395 ↗

This phase 2 trial randomized 293 biopsy-confirmed MASH patients with F1-F3 fibrosis to weekly survodutide (a dual glucagon/GLP-1 receptor agonist from Boehringer Ingelheim) at 2.4, 4.8, or 6.0 mg or placebo for 48 weeks. MASH improvement without worsening of fibrosis occurred in 47%, 62%, and 43% of survodutide arms versus 14% on placebo. A pre-specified fibrosis-improvement endpoint was also met. The trial established that adding glucagon agonism to GLP-1 can match the histologic benefit of tirzepatide-class drugs and supported phase 3 advancement.

PMID 38847460 ↗NCT04771273 ↗DOI 10.1056/NEJMoa2401755 ↗

This MASLD sub-study of the retatrutide phase 2 obesity trial enrolled 98 adults with MRI-PDFF-confirmed steatotic liver disease (baseline liver fat ≥10%). Retatrutide 1, 4, 8, and 12 mg weekly produced 51%, 59%, 82%, and 86% relative reductions in liver fat at 48 weeks versus 0% on placebo. 80-93% of high-dose participants achieved liver fat normalization (<5%). Body weight dropped up to 22%. Although biopsy outcomes were not measured, retatrutide's triple GIP/GLP-1/glucagon mechanism produced the largest liver-fat reductions ever recorded in a randomized GLP-1-class trial.

PMID 38858523 ↗NCT04881760 ↗DOI 10.1038/s41591-024-03018-2 ↗

LEAN was the first randomized biopsy trial of a GLP-1 receptor agonist in NASH. 52 overweight adults with biopsy-confirmed NASH were randomized to liraglutide 1.8 mg daily or placebo for 48 weeks. NASH resolution without worsening of fibrosis occurred in 39% on liraglutide vs 9% on placebo (relative risk 4.3, 95% CI 1.0-17.7, p=0.019). Fibrosis progression was also reduced. LEAN established the proof-of-concept that prompted the larger phase 2 and phase 3 trials in semaglutide, tirzepatide, survodutide, and retatrutide that followed.

PMID 26608256 ↗NCT01237119 ↗DOI 10.1016/S0140-6736(15)00803-X ↗

This phase 2 trial extended the semaglutide NASH program into the higher-risk compensated-cirrhosis population. 71 adults with biopsy-confirmed NASH-related cirrhosis (F4) were randomized to semaglutide 2.4 mg weekly or placebo for 48 weeks. The primary fibrosis-improvement endpoint was NOT met: 11% on semaglutide vs 29% on placebo improved fibrosis by ≥1 stage (p=0.087 in the wrong direction). NASH resolution favored semaglutide (34% vs 21%) but was not statistically significant. The neutral cirrhosis result tempered enthusiasm for GLP-1 monotherapy in advanced fibrosis and underscored the importance of the pre-cirrhotic F2/F3 patient selection in ESSENCE.

PMID 36934740 ↗NCT03987451 ↗DOI 10.1016/S2468-1253(23)00068-7 ↗

IMPACT was a multicentre phase 2b trial of pemvidutide (a balanced GLP-1/glucagon dual agonist from Altimmune) in 212 biopsy-confirmed MASH patients with F2 or F3 fibrosis randomized to weekly pemvidutide 1.2 or 1.8 mg or placebo for 24 weeks. MASH resolution without worsening of fibrosis occurred in 59% (1.2 mg) and 52% (1.8 mg) versus 19% on placebo (p<0.001) — among the fastest histologic responses recorded in the class. Body-weight loss was 4-5%, notably modest given the histologic benefit, suggesting direct hepatic effects of glucagon-receptor agonism.

PMID 41237796 ↗NCT05989711 ↗DOI 10.1016/S0140-6736(25)02114-2 ↗

This MRI substudy of the SURPASS-3 type-2-diabetes trial randomized 502 T2D adults with MRI-PDFF ≥6% (defining MASLD) to tirzepatide 5, 10, or 15 mg weekly or insulin degludec for 52 weeks. Tirzepatide produced 29-47% relative liver-fat reductions versus 10% on degludec; the high-dose absolute liver-fat reduction was 8.1 percentage points. Volume of abdominal visceral and subcutaneous adipose tissue also fell. SURPASS-3 MRI was the earliest randomized signal that tirzepatide reverses hepatic steatosis and seeded the SYNERGY-NASH biopsy program.

PMID 35468325 ↗NCT03882970 ↗DOI 10.1016/S2213-8587(22)00070-5 ↗

This 2025 class-level meta-analysis pooled randomized biopsy-anchored MASH trials of GLP-1, GLP-1/GIP, and GLP-1/glucagon agonists (including LEAN, the Newsome 2020 phase 2, SYNERGY-NASH, survodutide phase 2, and the semaglutide cirrhosis trial). Across pooled active-arm participants, MASH resolution odds were 3-4 times higher than placebo and the pooled effect on ≥1-stage fibrosis improvement reached statistical significance in the non-cirrhotic strata but not in cirrhosis. The meta-analysis quantifies the incretin class effect in MASH and benchmarks newer combinations against the LEAN-to-ESSENCE evidence arc.

PMID 40736113 ↗DOI 10.1111/liv.70256 ↗