ESSENCE published: semaglutide resolves MASH in most treated patients
A 72-week analysis of the phase 3 ESSENCE trial found 62.9% of adults on weekly 2.4 mg semaglutide had their liver inflammation resolve versus 34.3% on placebo, with fibrosis improving in 36.8% versus 22.4% [1].
The New England Journal of Medicine published the first part of the ESSENCE trial on April 30, 2025, showing that once-weekly injectable semaglutide at 2.4 mg improved liver biopsy findings in adults with metabolic dysfunction–associated steatohepatitis (MASH) and moderate to advanced scarring [1].
ESSENCE is an ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1,197 patients with biopsy-confirmed MASH and fibrosis stage 2 or 3, assigned 2-to-1 to semaglutide 2.4 mg weekly or placebo for 240 weeks [1]. The paper reports a planned interim analysis at week 72 in the first 800 patients, called part 1 [1]. The trial ran at 253 clinical sites in 37 countries and was funded by Novo Nordisk [2].
What the trial measured
Part 1 had two primary endpoints, both based on liver biopsies read centrally. The first was resolution of steatohepatitis without worsening of fibrosis; the second was a reduction in fibrosis — at least a one-stage drop on the NASH CRN scale — without worsening of steatohepatitis [2].
Both were met. Steatohepatitis resolved without worsening fibrosis in 62.9% of the 534 patients taking semaglutide versus 34.3% of the 266 on placebo, an estimated difference of 28.7 percentage points (95% CI, 21.1 to 36.2; P<0.001) [1]. Fibrosis improved without worsening steatohepatitis in 36.8% versus 22.4%, a difference of 14.4 percentage points (95% CI, 7.5 to 21.3; P<0.001) [1].
Among secondary results, 32.7% of the semaglutide group achieved both resolution of steatohepatitis and reduced fibrosis, versus 16.1% on placebo (difference 16.5 percentage points; 95% CI, 10.2 to 22.8) [1]. Mean body-weight change was −10.5% with semaglutide and −2.0% with placebo, a difference of 8.5 percentage points [1]. One prespecified secondary endpoint did not show a difference: mean changes in bodily pain scores were similar between groups [1].
On safety, gastrointestinal side effects such as nausea and diarrhea were more common with semaglutide, and no new safety signals were identified [2]. Any adverse event was reported in 86.3% of the semaglutide group and 79.7% of the placebo group, while adverse events leading to stopping treatment were 2.6% with semaglutide and 3.3% with placebo [2].
One notable feature of these results is the high placebo response — about a third of placebo patients also had steatohepatitis resolve [1] — which is why the trial's randomized, blinded design matters for interpreting the size of the drug effect.
Why it matters for patients
MASH is a form of fatty liver disease in which fat, inflammation and scarring build up in the liver, and it is closely tied to metabolic problems like obesity and type 2 diabetes [2]. Until recently there were very few approved drug options. In a commentary for the American College of Gastroenterology, Stanford hepatologist Paul Y. Kwo wrote that ESSENCE was the first trial to show semaglutide improving fibrosis, not just MASH activity, unlike the earlier phase 2 study [2]. He noted the drug addresses "both the liver disease and its underlying causes" [2].
There are limits. The study is still running, and long-term clinical outcomes — whether people avoid cirrhosis, liver failure or death — are not yet available [2]. Kwo also flagged that the trial had small representation of Black patients and few lean patients, so results may not generalize to those groups [2]. The data reported here apply to adults with stage 2 or 3 fibrosis; ESSENCE did not test people with cirrhosis [1][2].
What happens next
Part 2 of ESSENCE will follow patients through 240 weeks and report longer-term outcomes, including cirrhosis-free survival [2]. Kwo's commentary states that on August 15, 2025, the FDA approved semaglutide for adults with moderate to advanced fibrosis, making it the second approved MASH therapy after resmetirom, cleared in March 2024 for the same population [2]. The sources do not detail coverage, pricing or which brand-name product carries the MASH indication, so those specifics are not yet known from this reporting.
The full article appeared in print in the June 5, 2025 issue and was updated online on May 19, 2025 [1].
Sources
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