Phase 3 Trial Shows Semaglutide Improves Histologic Outcomes in MASH with Fibrosis
Interim results from a phase 3 randomized controlled trial published in The New England Journal of Medicine indicate that once-weekly subcutaneous semaglutide (2.4 mg) significantly improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced fibrosis.
These data offer early evidence that semaglutide may be an effective therapeutic option in this high-risk population.
The ongoing trial enrolled 1197 patients with biopsy-confirmed MASH and fibrosis stage 2 or 3, randomized 2:1 to receive semaglutide or placebo for 240 weeks. The current report presents outcomes from a planned interim analysis at 72 weeks in the first 800 participants. The primary endpoint of the study was resolution of steatohepatitis resolution without worsening of fibrosis.
“Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group,” the authors reported, with a statistically significant difference of 28.7 percentage points (95% CI, 21.1 to 36.2; P<0.001).
Semaglutide also demonstrated benefit on the second primary endpoint—reduction in liver fibrosis without worsening of steatohepatitis—achieved in 36.8% of semaglutide-treated patients versus 22.4% of those receiving placebo (difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001).
Secondary endpoints further supported the treatment effect. Combined resolution of steatohepatitis and reduction in fibrosis occurred in 32.7% of patients with semaglutide versus 16.1% of placebo patients (difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). In addition, semaglutide was associated with a mean weight reduction of 10.5%, compared to 2.0% in the placebo group (difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001).
“Once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results,” the authors concluded. Notably, there was no significant difference in bodily pain scores between groups. Gastrointestinal adverse events were more frequently observed in the semaglutide group but were not further detailed.
For gastroenterologists managing MASH, these findings support semaglutide’s potential to address both hepatic histology and metabolic risk factors in patients with fibrosis, marking a promising step toward effective pharmacologic therapy in a disease with limited treatment options.
Reference
Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258
