New Data Show Semaglutide’s Liver Benefits Not Exclusively Tied to Weight Loss

Data presented at The Liver Meeting 2025, the annual assembly of the American Association for the Study of Liver Diseases (AASLD), indicate that semaglutide (Wegovy) 2.4 mg injection may offer therapeutic benefits for metabolic dysfunction–associated steatohepatitis (MASH) that are not exclusively tied to major weight reduction. These new insights stem from secondary analyses of the phase 3 ESSENCE trial (NCT04822181).^1,2

“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, director of Roger Williams Institute of Liver Studies at King’s College Hospital and King’s College London, England, said in a news release.¹ “These data add new layers to our understanding of MASH, which is often accompanied by other systemic conditions, including cardiometabolic disorders.”

Recent FDA Approval of Semaglutide for MASH

The new findings build upon the recent FDA approval of semaglutide 2.4 mg, which is currently the first and only glucagon-like peptide-1 (GLP-1) receptor agonist authorized to treat adults diagnosed with MASH who have moderate to advanced liver fibrosis, provided they do not have cirrhosis of the liver. The drug should be used in conjunction with a reduced-calorie diet and increased physical activity.³

The initial approval was supported by data from part 1 of the ESSENCE trial, a randomized, multicenter, double-blind study. In this phase, patients received once-weekly subcutaneous semaglutide 2.4 mg or placebo, in addition to standard care. The study will last approximately 5 years, with 21 clinic visits and 9 phone calls throughout the study. Patients who had other chronic liver diseases were not included, and women who were pregnant, breast-feeding, or planned to become pregnant were excluded from the study.²

At week 72, investigators reported that steatohepatitis resolution without worsening fibrosis was achieved in 62.9% of patients in the semaglutide group, substantially higher than the 34.3% reported in the placebo group. Furthermore, a reduction in liver fibrosis without worsening steatohepatitis was seen in 36.8% of semaglutide patients compared to 22.4% of placebo patients. The mean change in body weight recorded was −10.5% in the semaglutide group and −2.0% in the placebo group.¹

Efficacy Decoupled from Significant Weight Loss

The secondary analyses evaluated the first 800 randomized patients at 72 weeks by examining histological and noninvasive testing (NIT)–related responses based on specific weight loss thresholds. The key finding was that semaglutide 2.4 mg was associated with resolution in liver injury across a spectrum of weight loss thresholds, suggesting benefits that are not solely dependent on weight loss.¹

Specifically, in the subgroup of patients who achieved only low levels of weight loss (≤2%), semaglutide demonstrated notable efficacy. Within this low weight loss group, 48.4% of patients receiving semaglutide 2.4 mg showed improvement in the resolution of the liver injury endpoint, a greater rate than the 25.8% observed in patients receiving the placebo. Improvement in liver scarring also favored semaglutide 2.4 mg across weight thresholds when compared to placebo. For those who lost ≤2% of body weight, improvement in liver scarring was observed in 27.2% of semaglutide patients versus 18.3% of placebo patients.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 news release.¹ “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.”

Additionally, the analysis showed improvements in steatohepatitis-related NITs, such as alanine aminotransaminase (ALT), in all groups receiving semaglutide 2.4 mg, with the greatest treatment effect observed in patients with weight loss of 7% or less. An additional secondary analysis further confirmed the drug's broad effectiveness, showing that efficacy—measured by the combined end point of resolution of liver injury and improvement in liver scarring—was observed across all age subgroups, genders, races, and certain ethnicity subgroups.¹

The ongoing part 2 of the ESSENCE trial will continue to evaluate the long-term objective of lowering the risk of liver-related clinical events at 240 weeks, with results expected in 2029.¹

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REFERENCES

1. 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 13, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916455

2. Research study on whether semaglutide works in people with non-alcoholic steatohepatitis (NASH) (ESSENCE). ClinicalTrials.gov identification: NCT04822181. Updated October 31, 2025. Accessed November 13, 2025. https://clinicaltrials.gov/study/NCT04822181

3. Gallagher A. FDA approves semaglutide to treat MASH with moderate to advanced fibrosis. Drug Topics. August 18, 2025. Accessed November 13, 2025. https://www.drugtopics.com/view/fda-approves-semaglutide-to-treat-mash-with-moderate-to-advanced-fibrosis