Semaglutide administered once-weekly at a dose of 2.4 mg resulted in significant improvements in liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced fibrosis. Semaglutide treatment also led to substantial weight loss, according to results from a prespecified interim analysis of the ESSENCE trial at week 72 published April 30, 2025 in the New England Journal of Medicine.¹

In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, 1197 patients with biopsy-confirmed MASH and stage 2 or 3 liver fibrosis were randomly assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for a total of 240 weeks in a 2:1 ratio. The co-primary endpoints for part 1 of the study were resolution of steatohepatitis without worsening of fibrosis, and improvement in liver fibrosis without worsening of steatohepatitis.

At Week 72, resolution of steatohepatitis without worsening of fibrosis was achieved in nearly 63% of patients receiving semaglutide with no worsening of liver fibrosis, compared to 34.3% in the placebo group, yielding an estimated difference of 28.7 percentage points (p<0.001). Improvement in liver fibrosis without worsening of steatohepatitis was observed in 36.8% of patients treated with semaglutide with no worsening of steatohepatitis compared to 22.4% in the placebo group, resulting in an estimated difference of 14.4 percentage points (p<0.001).

Combined resolution of steatohepatitis and improvement in liver fibrosis, a confirmatory secondary endpoint, was achieved in 32.7% of patients receiving semaglutide compared to 16.1% in the placebo group. This corresponded to an estimated difference of 16.5 percentage points (p<0.001).

Semaglutide treatment led to a significantly greater reduction in body weight compared to placebo, with a mean decrease of 10.5% versus 2.0%, respectively (estimated difference, -8.5 percentage points; p<0.001). However, there was no significant difference between the groups in mean changes in bodily pain scores.

Gastrointestinal adverse events occurred more frequently in patients treated with semaglutide. These included nausea (36.3% vs 13.2%), diarrhea (26.9% vs 12.2%), constipation (22.3% vs 8.4%), and vomiting (18.6% vs 5.6%).

This trial, based on data from the first 800 participants, demonstrates that once-weekly semaglutide significantly improved the major histological elements, which may reduce disease progression to cirrhosis and end-stage liver disease. The associated weight loss also contributes to the improvement of MASLD. These findings therefore support the potential role of semaglutide as an effective therapeutic option for MASH, which addresses both hepatic pathology as well as metabolic risk factors.

Reference

1.   Arun J Sanyal, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025 Apr 30. doi: 10.1056/NEJMoa2413258.