Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.

Summary

In a 72-week interim analysis of a phase 3 RCT in biopsy-proven MASH with stage F2–F3 fibrosis, semaglutide 2.4 mg weekly significantly increased steatohepatitis resolution and fibrosis improvement versus placebo and produced substantial weight loss. Gastrointestinal adverse events were more frequent with semaglutide.

Key Findings

• Steatohepatitis resolution without fibrosis worsening: 62.9% with semaglutide vs 34.3% with placebo (difference 28.7 pp; P<0.001).
• Fibrosis improvement without steatohepatitis worsening: 36.8% vs 22.4% (difference 14.4 pp; P<0.001).
• Combined resolution and fibrosis improvement: 32.7% vs 16.1% (P<0.001).
• Mean body weight change: −10.5% with semaglutide vs −2.0% with placebo.
• Gastrointestinal adverse events were more frequent with semaglutide.

Clinical Implications

For patients with MASH and fibrosis F2–F3, semaglutide 2.4 mg weekly can be considered to achieve NASH resolution and potential fibrosis benefit alongside weight loss, while monitoring gastrointestinal tolerability. Long-term outcomes (240 weeks) and regulatory approvals will guide adoption.

Limitations

• Interim analysis at 72 weeks; long-term clinical outcomes (e.g., decompensation, mortality) are pending.
• Fibrosis improvement effect size was modest; GI adverse events may limit tolerability in some patients.

Future Directions

Await 240-week outcomes for clinical endpoints and durability; evaluate combination regimens (e.g., GLP-1RA plus antifibrotics) and real-world effectiveness across fibrosis stages.