Semaglutide resolved liver inflammation in most MASH patients in phase 3 trial

The New England Journal of Medicine published the first part of the ESSENCE trial online on April 30, 2025, reporting that once-weekly semaglutide at a dose of 2.4 mg resolved steatohepatitis in most adults with metabolic dysfunction–associated steatohepatitis (MASH) and stage 2 or 3 liver fibrosis ^[1]. The results appeared in the journal's June 5, 2025 issue ^[1].

ESSENCE is an ongoing phase 3, randomized, double-blind, placebo-controlled trial. It enrolled 1,197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 and assigned them in a 2:1 ratio to semaglutide or placebo for 240 weeks ^[1]. The published paper reports a planned interim analysis at week 72 covering the first 800 patients, conducted at 253 clinical sites across 37 countries ^[1][2]. Patients were 18 or older ^[2].

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and 34.3% of the 266 patients in the placebo group, an estimated difference of 28.7 percentage points (95% CI, 21.1 to 36.2; P<0.001) ^[1]. A reduction in liver fibrosis without worsening of steatohepatitis occurred in 36.8% versus 22.4% (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001) ^[1]. The combined outcome — both resolution of steatohepatitis and fibrosis reduction — occurred in 32.7% versus 16.1% (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001) ^[1].

Mean body weight fell 10.5% with semaglutide and 2.0% with placebo ^[1]. Gastrointestinal adverse events were more common in the semaglutide group ^[1]. A summary of the trial from the American College of Gastroenterology reports that any adverse event occurred in 86.3% of semaglutide patients and 79.7% of placebo patients, and that 2.6% of semaglutide patients and 3.3% of placebo patients stopped treatment because of adverse events, with no new safety signals identified ^[2]. Mean changes in bodily pain scores did not differ significantly between the two groups ^[1].

The study has limits. It is still running, so full long-term clinical outcomes are not yet available ^[2]. The gastroenterology summary notes that the trial had a small representation of Black patients and a small number of lean patients, so the findings may not be generalizable to those groups ^[2].

Why it matters for patients

People with MASH and stage 2 or 3 fibrosis have a form of liver disease closely linked to metabolic conditions, and the trial tested semaglutide in exactly that group ^[2]. According to the American College of Gastroenterology's review, this was the first time semaglutide showed improvement in fibrosis as well as MASH activity, an earlier phase 2 trial having shown MASH resolution alone ^[2].

The same review reports that on August 15, 2025, the FDA approved semaglutide for adults with MASH and moderate to advanced fibrosis, making it the second approved drug for this population, after resmetirom in March 2024 ^[2]. Before those approvals, treatment centered on lifestyle interventions ^[2]. Semaglutide is already a known treatment for type 2 diabetes and obesity, and many people with MASH or MASLD are already taking semaglutide or another GLP-1 receptor agonist ^[2].

What has not been established is whether these biopsy findings translate into fewer long-term problems such as cirrhosis complications or death. That question is not answered by part 1 of the trial.

What happens next

The trial is scheduled to continue for 240 weeks, and part 2 is expected to report cirrhosis-free survival ^[1][2]. Whether semaglutide helps people who already have cirrhosis has not been established, and the review calls for longer-term studies in that group ^[2]. Research into combining GLP-1 receptor agonists with other MASH therapies is also described as an open question ^[2].