Semaglutide improved MASH liver disease in a phase 3 trial at 72 weeks

The GLP-1 drugs made their name in diabetes and obesity, but their reach keeps extending. One of the most consequential new fronts is the liver — specifically metabolic dysfunction-associated steatohepatitis, or MASH, a progressive fatty-liver disease with few approved treatments. A large phase 3 trial has now reported that semaglutide improved the liver histology that defines it.

The New England Journal of Medicine published on April 30, 2025 an interim analysis from ESSENCE, an ongoing phase 3, multicentre, randomised, double-blind, placebo-controlled trial of once-weekly subcutaneous semaglutide 2.4 mg in patients with MASH [s1].

What the trial is testing

ESSENCE assigned 1,197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 — moderate to advanced liver scarring — in a 2:1 ratio to semaglutide 2.4 mg or placebo, for a planned 240 weeks [s1]. The results published here are from a prespecified interim analysis conducted at week 72 in the first 800 patients, which the trial calls part 1 [s1]. The two primary endpoints for part 1 were resolution of steatohepatitis without worsening of liver fibrosis, and reduction in liver fibrosis without worsening of steatohepatitis — both measured on biopsy, the demanding standard for this disease [s1].

That the endpoints are histologic matters. Many earlier fatty-liver drug programmes leaned on liver fat or blood markers; ESSENCE asked whether the tissue itself improved under the microscope.

The results

On the first primary endpoint, resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group — an estimated difference of 28.7 percentage points (95% confidence interval, 21.1 to 36.2; P<0.001) [s1].

On the second, a reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the semaglutide group and 22.4% of the placebo group, an estimated difference of 14.4 percentage points (95% CI, 7.5 to 21.3; P<0.001) [s1].

A combined outcome — resolution of steatohepatitis and reduction in fibrosis together — was reached by 32.7% on semaglutide versus 16.1% on placebo, a difference of 16.5 percentage points (95% CI, 10.2 to 22.8; P<0.001) [s1]. That combined measure is the more demanding bar, because it counts only the patients who improved on both fronts at once; roughly a third of the semaglutide group cleared it, against a sixth on placebo [s1].

Weight fell as expected: the mean change in body weight was −10.5% with semaglutide and −2.0% with placebo, an estimated difference of −8.5 percentage points (95% CI, −9.6 to −7.4; P<0.001) [s1].

What the numbers do and don't establish

The fibrosis result deserves particular attention, because scarring is what drives MASH toward cirrhosis and liver failure. A 36.8%-versus-22.4% improvement is real but leaves most patients in each group without measured fibrosis improvement, and the placebo response — a fifth of patients improving on no drug — is a reminder of how much biopsy-scored endpoints fluctuate [s1].

Several of the limitations here are structural, not incidental:

This is an interim look at an unfinished trial. The analysis covers 800 of 1,197 patients at week 72 of a planned 240-week study [s1]. Longer follow-up is where the questions that matter most — progression to cirrhosis, liver-related events, survival — will be answered, and none of those are reported here.

Histology endpoints are surrogates. Improved biopsy scores are strongly associated with better long-term outcomes, but the trial has not yet shown that they translate into fewer hard clinical events in this population [s1].

One symptom endpoint was flat. Mean changes in bodily pain scores did not differ significantly between the groups [s1].

Side effects tracked the drug class. Gastrointestinal adverse events were more common in the semaglutide group [s1], the familiar trade-off that accompanies this class wherever it is used.

The funder makes the drug. ESSENCE was funded by Novo Nordisk [s1].

What it means

An accompanying editorial in the same journal placed the finding in the context of a field that has struggled to convert metabolic drugs into proven liver treatments [s2]. The honest reading of part 1 is that semaglutide improved the histologic hallmarks of MASH over 72 weeks in a large randomised trial — a genuine step — while the outcomes that ultimately justify treating a slow disease remain to be reported. The trial is registered on ClinicalTrials.gov as NCT04822181 [s1].

This article describes interim trial results, including a dose and adverse events, for informational purposes only. It is not medical advice and not a recommendation about any medication.

Sources

• [s1] Sanyal AJ, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. New England Journal of Medicine, published online 2025-04-30.
• [s2] Semaglutide for Metabolic Dysfunction-Associated Steatohepatitis. Editorial, New England Journal of Medicine, published online 2025-06-04.