Semaglutide 2.4 mg Improves Liver Health in Patients with MASH, Even at Low Levels of Weight Loss

Results from a post hoc analysis of the ESSENCE phase 3 trial presented at The Liver Meeting® 2025 of the American Association for the Study of Liver Diseases (AASLD) suggest that semaglutide 2.4 mg (Wegovy^®) may improve liver injury in adults with metabolic dysfunction-associated steatohepatitis (MASH) and moderate-to-advanced liver scarring, even in patients who achieved minimal weight loss.¹

The findings, presented by Novo Nordisk, showed that semaglutide 2.4 mg was associated with reductions in steatohepatitis across weight loss thresholds (≤2%, ≤5%, ≤7%, and >7%). “These data suggest that the effects of semaglutide 2.4 mg in this study may not be solely dependent on weight loss and provide important insights into the clinical effects of semaglutide 2.4 mg in people living with MASH,” Philip Newsome, MBChB, PhD, co-chief investigator and director, Roger Williams Institute of Liver Studies, King’s College Hospital and King’s College London, said in a press release.²

"These data add new layers to our understanding of MASH, which is often accompanied by other systemic conditions, including cardiometabolic disorders," Newsome added.²

The analysis evaluated the first 800 randomized participants at 72 weeks using histological and noninvasive test (NIT)–based endpoints. Steatohepatitis-related NITs improved in all semaglutide 2.4 mg groups, with the greatest treatment effect observed in alanine aminotransferase (ALT) levels among patients who lost ≤7% of body weight. In this subgroup, the mean absolute change in ALT from baseline to week 72 favored semaglutide versus placebo (estimated treatment ratio [ETR] 0.75; 95% CI, 0.68–0.82), according to the press release.¹

For histological outcomes, semaglutide 2.4 mg was associated with resolution of liver injury at all weight loss thresholds. Among participants with ≤2% weight loss, 48.4% of those receiving semaglutide achieved resolution of liver injury compared with 25.8% of those on placebo (estimated difference in responder proportions [EDP] 21.7; 95% CI, 4.9–38.4). Improvements in liver scarring also trended in favor of semaglutide across all groups; in the ≤2% weight loss subgroup, improvement occurred in 27.2% of the semaglutide group versus 18.3% of the placebo group (EDP 8.3; 95% CI, –6.1 to 22.9).¹

“MASH impacts over 250 million people worldwide and can progress to irreversible liver scarring and liver failure,” Martin Holst Lange, chief scientific officer and executive vice president of research and development at Novo Nordisk, said in a press release. “Today's results suggest that even at low levels of weight loss, people with MASH receiving semaglutide 2.4 mg had greater improvements in liver health parameters than those receiving placebo.”²

A secondary analysis of the same 800 participants assessed treatment response across race (Asian vs non-Asian), ethnicity (Hispanic or Latino vs non-Hispanic or Latino), gender, and age (<45, 45–64, and ≥65 years). Efficacy for the combined endpoint of liver injury resolution and fibrosis improvement, as well as for NITs related to fibrosis, was observed with semaglutide 2.4 mg compared with placebo across all sex and race groups and certain ethnicity subgroups. These findings were consistent across all age categories.³

The exploratory analyses are hypothesis-generating, and investigators noted that additional research is needed to determine the clinical significance of the results. The ESSENCE trial will continue into part 2, with completion and full readout expected in 2029, Novo Nordisk noted in the press release.²

References:

1. Newsome PN, Armstrong MJ, Bakulin I, et al. Weight-dependent and independent effects of semaglutide in participants with MASH: secondary analysis of the phase 3 ESSENCE trial. Presented at the American Association for the Study of Liver Diseases (AASLD) 2025 annual meeting. 10 November 2025, Washington, DC, US.
2. Novo Nordisk's Wegovy® (semaglutide 2.4 mg) was associated with liver health-related benefits not solely based on weight loss in adult patients with MASH with liver scarring, according to a new post hoc analysis. News release. Novo Nordisk. November 10, 2025. Accessed November 12, 2025. https://novonordisk.mediaroom.com/2025-11-10-Novo-Nordisks-Wegovy-R-semaglutide-2-4-mg-was-associated-with-liver-health-related-benefits-not-solely-based-on-weight-loss-in-adult-patients-with-MASH-with-liver-scarring,-according-to-a-new-post-hoc-analysis
3. Rinella ME, Abdelmalek MF, Bugianesi E, et al. Efficacy response in subgroups of participants in ESSENCE demonstrate that semaglutide is effective in improving liver fibrosis across a diverse population. [Abstract details]. American Association for the Study of Liver Diseases (AASLD) 2025 annual meeting. 10 November 2025, Washington, DC, US.