Interim findings from the Phase 3 ESSENCE trial (NCT04822181) published in the New England Journal of Medicine show that weekly treatment with semaglutide 2.4 mg significantly resolves metabolic dysfunction–associated steatohepatitis (MASH) and reduces liver fibrosis. At 72 weeks, semaglutide induced histological resolution of steatohepatitis in 62.9% of patients compared with 34.3% for placebo (P<0.001). 

The ongoing ESSENCE trial, funded by Novo Nordisk, is a randomized, double-blind, placebo-controlled study involving 1,197 adults with biopsy-confirmed MASH and stage 2 or 3 fibrosis. Participants were randomized 2:1 to receive semaglutide 2.4 mg or placebo weekly for 240 weeks. 

Key interim results from 800 participants at 72 weeks demonstrated substantial efficacy: 

• Resolution of steatohepatitis without fibrosis worsening (P<0.001): 62.9% (semaglutide) vs. 34.3% (placebo). 
• Improvement in fibrosis stage without worsening steatohepatitis (P<0.001): 36.8% (semaglutide) vs. 22.4% (placebo). 
• Combined resolution of steatohepatitis and fibrosis improvement achieved in 32.7% with semaglutide versus 16.1% with placebo (P<0.001). 
• Significant mean body weight reduction (10.5%) in the semaglutide group compared to placebo (2.0%, P<0.001). 

Semaglutide treatment was associated with gastrointestinal side effects consistent with its known safety profile from previous obesity and diabetes trials. 

These findings highlight semaglutide’s potential as a groundbreaking treatment for MASH, addressing an unmet clinical need. "It’s been a long journey, and it’s great to report the first GLP-1 receptor agonist demonstrating efficacy in a phase 3 trial for MASH," noted Dr. Philip Newsome, lead author from King's College London. Principal investigator Dr. Arun Sanyal of VCU emphasized, "These initial data show semaglutide slowed MASH progression and reversed existing liver damage. The ESSENCE data may represent key findings for patients in the treatment of MASH, which is estimated to affect about one in 20 adults in the U.S.” Part 2 of the ESSENCE trial continues until week 240, evaluating long-term clinical outcomes such as progression to cirrhosis, liver failure, or hepatocellular carcinoma. These outcomes will determine whether semaglutide’s benefits in liver histology translate into meaningful clinical improvements, shaping the future management of MASH. 

References 

1. ClinicalTrials.gov Identifier: NCT04822181. Link: https://clinicaltrials.gov/study/NCT04822181 (Accessed on May 2, 2025) 
2. Sanyal AJ, Newsome PN, Kliers I,et al. ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025. doi: 10.1056/NEJMoa2413258. Epub ahead of print. PMID: 40305708. 
3. Medscape Cardiology. ‘Watershed Moment’: Semaglutide Shown to Be Effective in MASH’ Link: https://www.medscape.com/viewarticle/watershed-moment-semaglutide-shown-be-effective-mash-2024a1000l8i?&icd=login_success_email_match_fpf (Accessed on May 2, 2025) 
4. Virginia Commonwealth University: School of Medicine. New research suggests diabetes, weight loss drug has potential to improve liver health. Link: https://liverinstitute.medschool.vcu.edu/news/diabetes/ (Accessed on May 2, 2025)