Semaglutide Therapy Improves Liver Histology in MASH

Medscape

12-05-2025

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.
The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.
Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.
A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. 'That study, however, did not show improvement in liver fibrosis, which this study has done,' study co-lead Philip Newsome, PhD, professor in the Department of Immunology and Immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in Birmingham, England, told Medscape Medical News .
'The results aligned with expectations in that that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.'
Study Details
From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine in Richmond, Virginia, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.
All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.
Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).
In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.
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 (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).
A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001).
In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001).
The mean change in body weight was −10.5% with semaglutide and −2.0% with placebo (estimated difference, −8.5 percentage points; 95% CI, −9.6 to −7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms.
The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit.
Gastrointestinal adverse events were more common in the semaglutide group.
Commenting on the study from a nonparticipant's perspective, Naga P. Chalasani, MD, professor of gastroenterology and hepatology at Indiana University School of Medicine in Indianapolis, said results from the ESSENCE trial were 'long awaited and they certainly advance the field of MASH clinical trials substantially.'
Furthermore, he added, the results are well aligned with those of a phase 2B trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.'
'The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,' Chalasani said. 'More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.'
He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. 'But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.'
According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. 'Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?'
This study was supported by Novo Nordisk, the manufacturer of Wegovy.
Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim.
Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk.