CATEGORY: GUT & DIGESTIVE HEALTH
In adults whose fatty liver disease had progressed to inflammation and scarring, weekly semaglutide injections resolved the liver inflammation in 62.9% of patients over 72 weeks, compared with 34.3% of those given a placebo—and measurable liver scarring improved in 36.8% of patients on the drug versus 22.4% on placebo.1 The results come from a planned interim analysis of ESSENCE, an ongoing phase 3 trial, and they arrive in a disease that had no approved drug treatment at all until 2024.
When a Fatty Liver Starts Scarring Itself
The condition in the trial is metabolic dysfunction-associated steatohepatitis, or MASH—until recently called NASH. It is what doctors call fatty liver disease once the fat that has accumulated inside liver cells begins to inflame the organ and replace healthy tissue with scar tissue, a process called fibrosis—the liver’s version of the scarring you can see on skin. Scar tissue accumulates in a liver much the way limescale builds up inside a kettle: the organ keeps working, but each added layer leaves it stiffer and less able to do its job, and the end stage of that process is cirrhosis, where the damage becomes largely permanent. Doctors grade the scarring in stages from 0 (none) to 4 (cirrhosis); everyone in this trial was at stage 2 or 3.
Two Biopsies, Seventy-Two Weeks Apart
ESSENCE is a randomized trial: 1,197 adults with MASH confirmed by biopsy were assigned by chance to once-weekly semaglutide 2.4 mg or an identical-looking placebo injection, with neither patients nor their doctors knowing who received which. The findings reported here are a planned interim look at the first 800 patients—534 on semaglutide, 266 on placebo—after 72 weeks; the full trial continues out to 240 weeks. The headline outcomes were determined the direct way: each patient had a second liver biopsy—a thin needle sample of liver tissue examined under a microscope—read against the biopsy taken at the start, so the trial measured the state of the liver itself rather than blood markers or symptoms.
What Improved on the Drug—and What Didn’t
Both of the trial’s primary goals were met. Beyond the headline figures, 32.7% of patients on semaglutide achieved both things at once—the inflammation resolved and the scarring lessened—compared with 16.1% on placebo. Patients on the drug also lost 10.5% of their body weight on average, versus 2.0% with placebo. Not everything moved: one prespecified secondary outcome, bodily pain scores, did not differ significantly between the groups. The main downside was familiar from semaglutide’s other uses—stomach-related side effects such as nausea were more common on the drug.1
A Second Drug Is Pulling in the Same Direction
This trial does not stand alone. In 2024, a phase 3 randomized trial of resmetirom—a once-daily pill that works through an entirely different route, and the first drug approved in the United States for MASH—reported the same pattern in 966 patients over 52 weeks: liver inflammation resolved in 25.9% to 29.9% of patients on the drug versus 9.7% on placebo, and scarring improved by at least one stage in about a quarter versus 14.2%.2 Two large randomized trials, two unrelated drug mechanisms, one direction of change: a liver disease long described in medical journals as having no treatment now has two that have been shown to improve the organ itself. Whether these biopsy improvements go on to mean fewer cases of cirrhosis and liver failure is exactly what the continuing years of the semaglutide trial are designed to answer.
Key Takeaways
- In a phase 3 interim analysis, weekly semaglutide resolved MASH liver inflammation in 62.9% of patients versus 34.3% on placebo, and improved liver scarring in 36.8% versus 22.4%, over 72 weeks.
- The outcome was measured directly, by comparing liver biopsies taken before and after treatment—not by blood tests or symptoms.
- A different drug, resmetirom, produced the same pattern in a separate randomized trial, so the finding does not rest on a single study or a single drug mechanism.
- The trial is ongoing: whether these tissue-level improvements translate into fewer cases of cirrhosis and liver failure is still being followed.
References
- Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. The New England Journal of Medicine. 2025;392(21):2089–2099. link
- Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. The New England Journal of Medicine. 2024;390(6):497–509. link