Secondary analyses from the ESSENCE phase 3 trial show semaglutide 2.4 mg improved liver injury markers independent of weight loss

Published: Thu 4 Dec 2025, 9:05 AM

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Novo Nordisk's Wegovy® (semaglutide 2.4 mg) was associated with liver health–related benefits not solely driven by weight loss in adult patients with metabolic dysfunction-associated steatohepatitis (MASH) with liver scarring.

Secondary analyses of the ESSENCE trial were presented at the American Association for the Study of Liver Diseases (AASLD), The Liver Meeting® 2025.

Novo Nordisk shared new data from the 76th annual AASLD meeting in Washington, D.C., evaluating the effects of semaglutide 2.4 mg in adults with MASH and moderate-to-advanced liver fibrosis. Post hoc results from the ESSENCE phase 3 trial showed that semaglutide 2.4 mg was associated with reductions in liver injury (steatohepatitis) 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 the Roger Williams Institute of Liver Studies at King's College Hospital and King's College London.“These findings add new layers to our understanding of MASH, which is often accompanied by other systemic conditions, including cardiometabolic disorders.”

This post hoc analysis evaluated the first 800 randomized patients at 72 weeks. Histological and non-invasive testing (NIT) responses were assessed based on weight-loss thresholds (≤2%, ≤5%, ≤7%, >7%). Steatohepatitis-related NITs improved across all groups receiving semaglutide 2.4 mg, with the strongest effect seen in alanine aminotransaminase (ALT) among patients with ≤7% weight loss. In this subgroup, patients on semaglutide 2.4 mg showed a greater mean absolute change in ALT from baseline to Week 72 compared with placebo (ETR* 0.75, 95% CI 0.68, 0.82).

Dr. Farooq Khan, Consultant Hepatologist, Gastroenterologist & Interventional Endoscopist at King's College Hospital Dubai, said: "Liver disease associated with cardiometabolic health is a significant problem in GCC including UAE. The emerging data from the landmark ESSENCE trial presented in AASLD 2025 suggest benefits in liver disease improvement beyond just weight loss, reflecting wider impact on liver-related outcomes. It gives new hope and opportunity; in the presence of emerging effective treatments, it's imperative to develop local and national framework to stratify liver disease in earlier stages to prevent liver related morbidity and transplantation."

For histological endpoints, semaglutide 2.4 mg was associated with resolution of liver injury across a spectrum of weight-loss categories, including ≤2%. In this subgroup, 48.4% of patients receiving semaglutide 2.4 mg showed improvement in liver injury versus 25.8% on placebo (EDP* 21.7, 95% CI 4.9, 38.4). Improvement in liver scarring also trended in favor of semaglutide 2.4 mg: 27.2% vs. 18.3% on placebo in the ≤2% subgroup (EDP* 8.3, 95% CI –6.1, 22.9).

“MASH impacts more than 250 million people globally and can progress to irreversible scarring and liver failure,” said Martin Holst Lange, chief scientific officer and executive vice president of research and development at Novo Nordisk.“Today's results suggest that even with minimal weight loss, people receiving semaglutide 2.4 mg experienced greater improvements in liver health parameters compared to placebo.”

Another secondary analysis examined outcomes by race (Asian vs. non-Asian), ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), gender, and age groups (<45, ≥45–64, ≥65). Results showed efficacy for the combined endpoint (resolution of liver injury plus improvement in liver scarring) and for liver scarring–related NITs across gender, race, and certain ethnicity groups. Benefits were observed across all age subgroups.

These exploratory secondary analyses are hypothesis-generating, and further research is needed to confirm clinical significance. Part 2 of the ESSENCE trial is ongoing, with data expected in 2029.

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