Semaglutide Significantly Improves Steatohepatitis, Fibrosis in Phase III MASH Trial

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Weekly semaglutide was found to significantly improve steatohepatitis and fibrosis while enhancing metabolic markers and noninvasive liver health measures in patients with metabolic dysfunction–associated steatohepatitis (MASH), according to results of a planned interim analysis of the Phase III ESSENCE trial (NCT04822181) published by The New England Journal of Medicine.^1,2 The authors noted that these findings indicate semaglutide not only targets hepatic pathology, but also treats the underlying metabolic dysfunction that drives disease progression, reinforcing its potential as a comprehensive therapy for MASH.

“Building on encouraging data from the phase 2 study, our current trial shows improvement in two areas of disease activity: steatohepatitis and fibrosis stage,” the study authors wrote. “On the basis of biologic characteristics of MASH, resolution of steatohepatitis is expected to reduce fibrogenesis—and the reduction in fibrosis stage is particularly relevant because higher stages are associated with poorer outcomes.”¹

Semaglutide, a glucagon-like peptide-1 receptor agonist, was initially approved in June 2021 for chronic weight management in those with obesity or overweight and at least one weight-related condition, including high blood pressure, type 2 diabetes, or high cholesterol, in addition to diet and increased exercise.3 Semaglutide has also been approved by the FDA in both long-acting injectable (Wegovy and Ozempic) and daily oral tablet (Rybelsus) formulations.

Wegovy is indicated for weight loss and weight maintenance in patients aged 12 years and older with obesity; and for reducing major cardiovascular event (MACE) risks in adults with type 2 diabetes with known heart disease. Ozempic is indicated to treat type 2 diabetes in adults to help control blood sugar levels along with diet and exercise; for reducing MACE risks in adults with type 2 diabetes with known heart disease; and to lower the risk of kidney function decline, kidney failure, and death due to cardiovascular disease in adults with chronic kidney disease and type 2 diabetes. Rybelsus is indicated to help control blood sugar levels in adults with type 2 diabetes.

Trial Design

The ongoing, multicenter, randomized, double-blind, placebo-controlled trial enrolled patients with biopsy-defined MASH and fibrosis stage 2 or 3. A total of 1197 patients were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks.

The planned interim analysis of part one of the trial was conducted at week 72 with results for the first 800 patients. The primary endpoints for this portion of the trial were resolution of steatohepatitis without worsening liver fibrosis and decrease in liver fibrosis without worsening of steatohepatitis.

Results show that 62.9% of 534 patients administered semaglutide achieved resolution of steatohepatitis without worsening of fibrosis compared to 34.3% of 266 patients in the placebo cohort (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). Among these patients, 36.8% of the semaglutide cohort achieved a decrease in liver fibrosis without worsening of steatohepatitis compared to 22.4% in the placebo cohort (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Further, 32.7% of patients in the semaglutide cohort achieved combined resolution of steatohepatitis and liver fibrosis compared to 16.1% of patients in the placebo cohort (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001).

Mean body weight reduction was −10.5% in the semaglutide cohort compared to −2.0% in the placebo cohort (estimated difference, −8.5 percentage points; 95% CI, −9.6 to −7.4; P<0.001). Body pain scores were similar among both cohorts, but patients in the semaglutide cohort experienced a higher rate of gastrointestinal adverse effects.

“[Metabolic dysfunction–associated steatotic liver disease] (which includes MASH) is closely linked to obesity, type 2 diabetes, and cardiovascular and kidney disease, with the burden of end-stage liver disease from this condition on the rise worldwide,” the study authors concluded. “In part 1 of our trial, patients who received a weekly dose of 2.4 mg of semaglutide had better results regarding steatohepatitis and fibrosis than those who received placebo. Patients in the semaglutide group also had more weight loss. Although formal hypothesis tests were not planned or conducted, semaglutide appeared to be associated with improvements in glucometabolic factors and noninvasive markers of liver health.”¹

References

1. Sanyal A., et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. N Engl J Med 2025; DOI: 10.1056/NEJMoa2413258.

2. Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH) (ESSENCE). ClinicalTrials.gov. Updated April 27, 2025. Accessed May 1, 2025. https://clinicaltrials.gov/study/NCT04822181

3. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. News release. June 4, 2021. Accessed May 1, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014