Michael Monostra , 2025-05-01 12:50:00
Key takeaways:
- More than half of adults with MASH receiving semaglutide had resolution of steatohepatitis at 72 weeks.
- A reduction in liver fibrosis stage was observed among 36.8% of the semaglutide group.
Once-weekly semaglutide 2.4 mg significantly reduced steatohepatitis and liver fibrosis symptoms among adults with metabolic dysfunction-associated steatohepatitis and moderate or advanced liver fibrosis, researchers reported.
In findings from part one of the ESSENCE phase 3 trial published in The New England Journal of Medicine, semaglutide 2.4 mg (Wegovy, Novo Nordisk) conferred greater improvements in multiple liver endpoints compared with placebo. In addition to greater improvements in steatohepatitis and liver fibrosis, researchers also observed greater weight loss, reduced insulin resistance and improvement in noninvasive liver markers with the GLP-1 medication.
A higher proportion of adults receiving semaglutide in the ESSENCE trial had improvements in steatohepatitis and liver fibrosis than those receiving placebo. Image: Adobe Stock
“There is a major unmet need for therapeutics for patients with metabolic dysfunction-associated steatohepatitis (MASH) who have started scarring down their liver, but have not yet progressed to cirrhosis,” Arun J. Sanyal, MD, director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University and professor at the Virginia Commonwealth University School of Medicine, told Healio. “Semaglutide met the criteria for regulatory approval by showing improvement in liver histology, which makes it reasonably likely that it will prevent cirrhosis and related outcomes. Together, with the established benefits of semaglutide for diabetes, obesity and heart disease, this is a major step forward for patients with MASH, who often have obesity and diabetes and are at risk for heart disease as well.”
Arun J. Sanyal
ESSENCE is an ongoing phase 3 randomized controlled trial that enrolled 1,197 adults aged 18 years and older with histologically diagnosed steatohepatitis, stage 2 or 3 liver fibrosis and a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher. Participants were randomly assigned 2:1 to once-weekly semaglutide or placebo plus standard of care for 72 weeks. Liver biopsies were conducted at baseline and 72 weeks. Three pairs of pathologists reviewed liver histological slides to determine fibrosis stage and NAFLD activity score. The trial’s primary endpoint in part one was resolution of steatohepatitis with no worsening of liver fibrosis, and reduction of liver fibrosis with no worsening of steatohepatitis.
Liver benefits with semaglutide
Data were reported for the first 800 participants enrolled in the trial (mean age, 56 years), of whom 534 received semaglutide and 266 received placebo. Of the study group, 55.9% had type 2 diabetes. Mean BMI was 34.6 kg/m2 at baseline. Stage 3 fibrosis was prevalent in 68.8% of the participants at the beginning of the study.
Of the participants, 62.9% achieved a resolution of steatohepatitis at 72 weeks with semaglutide compared with 34.3% of the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2; P < .001). Reduction in liver fibrosis was observed among 36.8% of those receiving semaglutide compared with 22.4% of those receiving placebo (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3; P < .001). A resolution of steatohepatitis plus reduction in fibrosis symptoms occurred in 32.7% of the semaglutide group vs. 16.1% of those receiving placebo (P < .001).
The semaglutide group achieved a weight loss of 10.5% at 72 weeks compared with 2% for adults receiving placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4; P < .001). There was no significant difference between the two groups in change in bodily pain score as self-reported on the SF-36.
Enhanced liver fibrosis score as indicated through noninvasive testing declined by 0.5 or more points in 55.8% of the semaglutide group and 25.5% of the placebo group. A decrease in liver stiffness of 30% or more occurred in 52% of those receiving semaglutide and 30.3% of those receiving placebo.
Among adults with type 2 diabetes, those receiving semaglutide had a slightly greater decrease in insulin resistance than the placebo group.
Safety profile
Adverse events were reported in 86.3% of the semaglutide group and 79.7% of the placebo group. Serious adverse events occurred in 13.4% of adults in each group. Most adverse events were gastrointestinal related, with nausea, diarrhea, constipation and vomiting being the most common among semaglutide recipients. Of the participants, 2.6% receiving semaglutide and 3.3% receiving placebo discontinued the trial due to an adverse event.
Sanyal said the findings revealed semaglutide can be beneficial for adults with liver disease in addition to other cardiometabolic disorders that the medication has already been approved for.
“While we have focused on patients with significant scarring of the liver in the past, given these beneficial effects on the liver, those with early liver disease who are getting this drug for obesity and diabetes may have less progression to more advanced stages and ultimately reduced burden of disease,” Sanyal said.
The ESSENCE trial is ongoing, with more data to be released in part two of the study, which will examine endpoints of cirrhosis-free survival.
Sanyal said more studies are also needed in adults with diabetes or obesity with early-stage metabolic dysfunction-associated steatotic liver disease as well as among adults who did not respond to combination therapies for MASH.
For more information:
Arun J. Sanyal, MD, can be reached at liverinstitute@vcuhealth.org.
Sources/Disclosures
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Disclosures:
The study was funded by Novo Nordisk. Sanyal reports consulting for 89Bio, Abbott Laboratories, Akero, Aligos, Alynlam, Amgen, AstraZeneca, Avant Sante, Biocellvia, Boehringer Ingelheim, Boston Pharmaceuticals, Corcept Therapeutics, Eli Lilly, Genentech, Gilead, GlaxoSmithKline, Histoindex, Intercept, Inventiva, Madrigal, Median Technologies, Myovant Sciences, NGM Biopharmaceuticals, Northsea Novo Nordisk, Path AI, Pfizer, Poxel, Regeneron, Roche, Rubio Laboratories, Salix Pharmaceuticals, Satellite Bio, Siemens, Surrozen, Takeda Pharmaceuticals, Target Pharma Solutions, Terns, Variant and Zydus Pharmaceuticals; receiving grant funding from Boehringer Ingelheim, Echosens, Eli Lilly, Intercept, Mallinckrodt LLC, Merck, Perspectum, Pfizer, Salix Pharmaceuticals and Zydus Pharmaceuticals; serving on a data and safety monitoring board for Bard Peripheral Vascular Inc., NGM Biopharmaceuticals and Sequana; and holding equity in Durect, Exhalenz, Genfit, Hemoshear, Inversago, Northsea and Tiziana. Please see the study for all other authors’ relevant financial disclosures.
