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

Novo Nordisk presented data at the 76th annual American Association for the Study of Liver Diseases (AASLD) meeting, The Liver Meeting® 2025, in Washington, D.C., evaluating the effects of semaglutide 2.4 mg in people with metabolic dysfunction-associated steatohepatitis (MASH) and moderate- to-advanced liver scarring (fibrosis). Results from a post hoc analysis of the ESSENCE phase 3 trial showed semaglutide 2.4 mg was associated with reduction in liver injury (steatohepatitis) in adults with MASH even at low levels of weight loss.

“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,” said Professor Philip Newsome, MBChB, PhD, co-chief investigator and director of Roger Williams Institute of Liver Studies, King’s College Hospital and King’s College London. “These data add new layers to our understanding of MASH, which is often accompanied by other systemic conditions, including cardiometabolic disorders.”
This post hoc analysis of the ESSENCE trial evaluated the first 800 randomized patients at 72 weeks. Histological and non-invasive testing (NIT)–related treatment responses were evaluated according to specific weight loss thresholds (≤2%, ≤5%, ≤7%, >7%).

Steatohepatitis-related NITs improved in all groups receiving semaglutide 2.4 mg, with the greatest treatment effect observed for alanine aminotransaminase (ALT) in patients with weight loss of ≤7%. In this subgroup, patients receiving semaglutide 2.4 mg showed a greater mean absolute change in ALT from baseline to Week 72 when compared to those receiving placebo (ETR* 0.75, 95% CI 0.68, 0.82).

For histological endpoints, semaglutide 2.4 mg, when compared to placebo, was associated with resolution in liver injury across a spectrum of weight loss thresholds, including low levels of weight loss (≤2%). In this subgroup, 48.4% of patients receiving semaglutide 2.4 mg showed improvement in the resolution of the liver injury endpoint compared to 25.8% of patients receiving placebo (EDP* 21.7, 95% CI 4.9, 38.4). Results from the improvement in liver scarring endpoint trended to favor semaglutide 2.4 mg across weight thresholds when compared to placebo, with an improvement in liver scarring observed in 27.2% of patients receiving semaglutide 2.4 mg versus in 18.3% of those receiving placebo within the ≤2% subgroup (EDP* 8.3, 95% CI -6.1, 22.9).

“MASH impacts over 250 million people worldwide and can progress to irreversible liver scarring and liver failure,” said Martin Holst Lange, chief scientific officer and executive vice president of Research & Development at Novo Nordisk. “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.”

An additional secondary analysis of ESSENCE looked at the first 800 randomized patients by race (Asian vs. non-Asian), ethnicity (Hispanic or Latino vs. non-Hispanic or Latino), gender (male vs. female), and age (<45, ≥45-64, and ≥65 years). Results showed efficacy for the combined endpoint of resolution of liver injury and improvement in liver scarring and for liver scarring- related NITs with semaglutide 2.4 mg vs. placebo for all gender, race, and certain ethnicity subgroups. These results for semaglutide 2.4 mg were observed across all age subgroups.

Exploratory secondary analyses are hypothesis generating, and further work investigating the clinical validity of these results would be of value.

Part 2 of the ESSENCE trial will continue with expected readout in 2029.