Study Demonstrates Semaglutide Improves Liver Histologic Results in Patients With MASH

Author(s):

Gillian McGovern, Associate Editor

Key Takeaways

Semaglutide significantly improved liver histology in MASH patients, with higher rates of steatohepatitis resolution and fibrosis reduction compared to placebo.
The phase 3 ESSENCE trial involved 1197 patients, with significant findings at week 72 for semaglutide's efficacy in liver health improvement.
Adverse events were more frequent in the semaglutide group, with gastrointestinal issues being the most common, though serious adverse events were similar between groups.
Semaglutide's potential approval could provide a novel treatment option for MASH, addressing both liver disease and underlying metabolic dysfunction.

About 62.9% of patients with metabolic dysfunction–associated steatohepatitis (MASH) receiving semaglutide experienced resolution of steatohepatitis without worsening of fibrosis.

In patients with metabolic dysfunction–associated steatohepatitis (MASH), once-weekly semaglutide (Ozempic, Wegovy; Novo Nordisk) at a dose of 2.4 mg improved liver histologic results compared with placebo. Despite these improvements, there were not significantly different mean changes in bodily pain scores between the semaglutide and placebo groups.^1,2

Image credit: Rasi | stock.adobe.com

Currently, semaglutide is FDA-approved for multiple indications, including the treatment of type 2 diabetes (T2D); the reduction in risk of major cardiovascular events in adults with T2D and known heart disease; and the reduction in risk of worsening kidney disease, kidney failure, and death due to cardiovascular disease in adults with T2D and chronic kidney disease (Ozempic). It is also approved for weight management in adults with a body mass index (BMI) of 30 or higher or with at least 1 weight-related condition (eg, hypertension, high cholesterol), as well as the reduction of risk in adults with obesity or overweight who have established cardiovascular disease (Wegovy).^1,3

The authors wrote that, in a previous phase 2 trial, the GLP-1 receptor agonist resulted in a higher percentage of steatohepatitis resolution without worsening of fibrosis (59%) when compared with placebo (17%; P < .001). Additionally, because resmetirom (Rezdiffra; Madrigal Pharmaceuticals, Inc.) is the only GLP-1 receptor agonist with an FDA accelerated approval for the treatment of MASH with stage 2 or 3 liver fibrosis, there is an unmet need for additional treatment options. Patients with MASH are also at a higher risk for adverse liver outcomes and cardiovascular disease. For these reasons, the investigators conducted a trial to assess the efficacy and safety of semaglutide when used in this patient population.^1,2,4

ESSENCE (NCT04822181)² is an ongoing multicenter, randomized, double-blind, placebo-controlled phase 3 trial evaluating the effects of semaglutide in patients with biopsy-defined MASH and fibrosis stage 2 or 3. A total of 1197 patients were randomly assigned to receive either once-weekly subcutaneous semaglutide (2.4 mg) or placebo for a 240-week duration. This current analysis involves 800 patients and was conducted at week 72 (part 1). This part’s primary end points were resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.^1,2

The findings demonstrated that the resolution of steatohepatitis without worsening of fibrosis occurred in approximately 62.9% (n = 534) of patients in the semaglutide group and in 34.3% (n = 266) of patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI [21.1 to 36.2]; P < .001). Additionally, a reduction in liver fibrosis without worsening of steatohepatitis was reported in about 36.8% and 22.4% of patients in the semaglutide and placebo groups, respectively (estimated difference, 14.4 percentage points; 95% CI [7.5 to 21.3]; P < .001).¹

About the Trial

Trial Name: Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH) (ESSENCE)

ClinicalTrials.gov ID: NCT04822181

Sponsor: Novo Nordisk A/S

Completion Date (Estimated): April 25, 2029

"The results from this landmark study across 37 countries provide strong evidence that semaglutide can help patients with MASH by not only improving liver health, but also addressing the underlying metabolic issues that contribute to the disease," Arun Sanyal, professor of medicine at Virginia Commonwealth University, said in a news release. "If approved, this could offer an additional therapeutic option for patients with MASH and fibrosis.”⁴

Further, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in approximately 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI [10.2 to 22.8]; P < .001). The mean change in body weight was about −10.5% with semaglutide and −2.0% with placebo (estimated difference, −8.5 percentage points; [95% CI −9.6 to −7.4]; P < .001); however, the investigators wrote that mean changes in bodily pain scores did not differ significantly between the 2 groups.¹

Generally, adverse events (AEs) were more frequently reported by patients receiving semaglutide (86.3%) than those receiving placebo (79.7%). In each group, 13.4% of patients had a serious AE. Gastrointestinal adverse events were observed to be more common in the semaglutide group. Other common AEs included nausea, diarrhea, constipation, and vomiting. There were similar incidences of acute pancreatitis between the 2 groups, the authors wrote. A total of 9 patients died during part 1’s duration, of which 3 were receiving semaglutide and 6 placebo.¹

"By treating both liver disease and its metabolic causes, semaglutide offers a promising new approach for millions of patients," Sanyal said.⁴

REFERENCES

1. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. New Eng J Med. 2025, April 30. doi:10.1056/NEJMoa2413258

2. Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH) (ESSENCE). ClinicalTrials.gov identifier: NCT04822181. Updated April 27, 2025. Accessed May 5, 2025. https://clinicaltrials.gov/study/NCT04822181

3. Halpern L. FDA Approves Semaglutide to Reduce Kidney Disease, Cardiovascular Death Risk in Adults With Type 2 Diabetes, Chronic Kidney Disease. Pharmacy Times. January 28, 2025. Accessed May 5, 2025. https://www.pharmacytimes.com/view/fda-approves-semaglutide-to-reduce-kidney-disease-cardiovascular-death-risk-in-adults-with-type-2-diabetes-chronic-kidney-disease

4. Science Alert. Landmark Study Finds Semaglutide Effectively Treats Serious Liver Disease. News release. May 2, 2025. Accessed May 5, 2025. https://www.sciencealert.com/landmark-study-finds-semaglutide-effectively-treats-serious-liver-disease