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Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. PMID 40305708

One-paragraph summary

ESSENCE randomised 1,197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 240 weeks. This report is the planned interim analysis at week 72 in the first 800 patients (534 semaglutide, 266 placebo). Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% versus 34.3% (estimated difference 28.7 percentage points, 95% CI 21.1–36.2, p<0.001), and reduction in liver fibrosis without worsening of steatohepatitis in 36.8% versus 22.4% (difference 14.4 points, 7.5–21.3, p<0.001). Combined resolution plus fibrosis reduction occurred in 32.7% versus 16.1% (difference 16.5 points, 10.2–22.8, p<0.001). Mean body-weight change was −10.5% versus −2.0% (difference −8.5 points, −9.6 to −7.4, p<0.001). Mean changes in bodily pain scores did not differ. Gastrointestinal adverse events were more common with semaglutide. The Wegovy formulation received accelerated FDA approval in August 2025 for MASH with F2–F3 fibrosis.

Key findings

Endpoint at week 72 Semaglutide 2.4 mg Placebo Difference (95% CI)
MASH resolution, no worsening of fibrosis 62.9% 34.3% 28.7 (21.1–36.2)
Fibrosis reduction, no worsening of MASH 36.8% 22.4% 14.4 (7.5–21.3)
Both 32.7% 16.1% 16.5 (10.2–22.8)
Body-weight change −10.5% −2.0% −8.5 (−9.6 to −7.4)
  • The weight loss delivered pharmacologically (−10.5%) is at the threshold at which lifestyle-induced weight loss produced 90% NASH resolution in an observational subgroup (Vilar-Gomez 2015, PMID 25865049).
  • The phase 2 trial of semaglutide had missed fibrosis improvement (43% vs 33%, p=0.48; Newsome 2021, PMID 33185364); the phase 3 hit it.

Limitations

  • Interim analysis of 800 of 1,197 patients at week 72 of a 240-week trial; both endpoints are histological surrogates and the outcome phase runs to 2029.
  • The placebo arm resolved steatohepatitis in 34.3% — the highest placebo response in the field, against 9.7% in MAESTRO-NASH. Cross-trial comparison of the two approved drugs is therefore not possible from published data.
  • Cirrhosis excluded. A phase 2 trial of the same drug in compensated NASH cirrhosis found no fibrosis benefit (11% vs 29%, OR 0.28, 95% CI 0.06–1.24; Loomba 2023, PMID 36934740).
  • Bodily pain scores, the only patient-reported measure adjusted for in the multiple-testing plan, did not differ.
  • Class risks require monitoring: acute kidney injury from dehydration, gallbladder disease, pancreatitis, thyroid C-cell tumours, retinopathy progression and lean-mass loss (Bansal 2026, PMID 41201884). An unexplained neoplasm imbalance in the phase 2 trial (15% vs 8%) has not been formally resolved.

Why it matters

It made a drug already prescribed to millions for obesity and diabetes into the second approved MASH therapy, changing the practical question from "is there a treatment?" to "which treatment, for whom, and in what order". AASLD issued implementable guidance within months, specifying non-invasive selection thresholds (VCTE 8–15 kPa, MRE 3.1–4.4 kPa, ELF 9.2–10.5), a grey zone requiring cirrhosis exclusion, and the explicit statement that combination with resmetirom has not been studied (PMID 41201884). It also sharpened the field's central methodological problem: two drugs approved on the same endpoints in trials whose placebo arms differ by a factor of 3.5 cannot be ranked, and the Eli Lilly master protocol testing tirzepatide and retatrutide under one design (NCT07165028, n=4,500) is the field's first structural response.

Cited by wiki pages

  • glp1-and-incretin-therapy.md
  • clinical-trials-landscape.md
  • resmetirom-and-thyromimetics.md
  • bariatric-and-metabolic-surgery.md
  • overview.md