Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis

The ESSENCE trial was the first phase 3, randomized, double-blind, placebo-controlled study to evaluate weekly semaglutide 2.4 mg in metabolic dysfunction-associated steatohepatitis (MASH) — formerly NASH — with moderate to advanced fibrosis (stages F2 or F3). 1,197 patients with biopsy-confirmed MASH were randomized to semaglutide or placebo, with planned duration of 240 weeks and a pre-specified interim analysis at week 72 with the first 800 patients.

The two primary endpoints were histological, assessed by paired central biopsy review:

• Resolution of steatohepatitis without worsening of fibrosis: 62.9% with semaglutide vs. 34.3% with placebo (estimated difference +28.7 percentage points; P<0.001)
• Improvement of fibrosis >=1 stage without worsening steatohepatitis: 36.8% with semaglutide vs. 22.4% with placebo (difference +14.4 points; P<0.001)
• Resolution of steatohepatitis AND improvement of fibrosis: 32.7% vs. 16.1% (confirmatory secondary endpoint)
• Weight loss: -10.5% with semaglutide vs. -2.0% with placebo

Cardiometabolic benefits were broad: significant improvements in HbA1c, liver transaminases (ALT/AST), blood pressure, and lipid profile. Gastrointestinal events were more frequent with semaglutide, mainly during dose escalation; the overall safety profile was consistent with the drug's prior long-term experience.

ESSENCE was transformative: semaglutide became the first GLP-1 agonist with demonstrated histological efficacy in MASH, leading to FDA approval in August 2025 for this indication. Previously, only resmetirom (THR-β agonist) had approval. The demonstration that semaglutide can reverse hepatic fibrosis establishes a new paradigm in MASH treatment, a condition whose prevalence rises in parallel with global obesity.