Semaglutide may help improve liver scarring in some people with advanced metabolic dysfunction-associated steatohepatitis, or MASH, according to results from a large international clinical trial.
The finding, published in The Lancet Gastroenterology & Hepatology, is promising because the trial included people with moderate to advanced fibrosis, including compensated cirrhosis, an early stage of cirrhosis in which the liver can still perform most of its essential functions. But the study does not show that semaglutide prevents liver failure, transplantation or death, and larger trials are needed to confirm the result.
The phase 2 trial included about 700 adults with biopsy-confirmed MASH and moderate to advanced liver fibrosis. It was funded by Novo Nordisk, which manufactures semaglutide and the experimental drug zalfermin tested in the study. Four authors were Novo Nordisk employees and stockholders, and one held a patent related to zalfermin. Novo Nordisk also funded medical writing support for the publication.
MASH is a progressive form of fatty liver disease in which excess fat is accompanied by inflammation and liver cell injury. Over time, repeated injury can lead to fibrosis, cirrhosis and, in some cases, liver failure or liver cancer.
The trial was designed primarily to test whether zalfermin, an experimental medication intended to improve metabolism, would work better when combined with semaglutide than the comparison treatment. That combination did not produce a superior result.
Semaglutide alone, however, was associated with a statistically significant improvement in liver fibrosis without worsening the underlying liver inflammation. The researchers reported that the effect was also seen among some participants with compensated cirrhosis.
“This is the first clinical trial to demonstrate that semaglutide may improve liver fibrosis in patients with advanced MASH, including those with compensated cirrhosis,” senior author Dr. Rohit Loomba of the University of California San Diego said.
The result matters because fibrosis is more closely tied to long-term liver outcomes than liver fat alone. Earlier studies of metabolic treatments have often shown reductions in liver fat, body weight or liver enzyme levels without clearly demonstrating improvement in scar tissue.
Still, an improvement in fibrosis on a biopsy is a surrogate outcome. It does not establish that treatment will reduce hospitalizations, liver failure, transplantation or mortality.
Liver biopsy also has limitations. A biopsy samples only a small portion of the liver, and fibrosis can be unevenly distributed. Two samples taken from different areas may not always show the same stage of disease.
The researchers also examined blood tests and imaging measures intended to estimate liver damage without a biopsy. Those measures appeared to reflect treatment-related changes more clearly than the biopsy results.
That could eventually make it easier to monitor patients without repeatedly performing an invasive procedure. But noninvasive tests remain indirect measures and cannot yet replace clinical outcomes showing that patients live longer or avoid serious liver complications.
Semaglutide belongs to a class of medications that mimic GLP-1, a hormone involved in appetite, blood sugar regulation and digestion. It is widely used for type 2 diabetes and chronic weight management.
Weight loss and improved insulin sensitivity may partly explain why GLP-1 medications could benefit people with MASH. Excess liver fat, insulin resistance and inflammation are closely connected in the disease. Semaglutide may also influence liver-related pathways beyond weight loss, though this study was not designed to establish the exact mechanism.
The findings do not mean semaglutide is appropriate for everyone with fatty liver disease. MASH ranges from relatively early inflammation to advanced cirrhosis, and treatment decisions depend on disease severity, other health conditions, medication risks and access to care.
The trial also cannot show whether semaglutide would outperform other emerging MASH treatments or whether combining it with a different drug would produce a greater benefit.
Researchers said larger clinical trials focused specifically on people with cirrhosis are needed. Longer follow-up will also be necessary to determine whether fibrosis improvement lasts and translates into fewer major liver-related events.
“These findings strengthen the need to continue studying semaglutide and other metabolic therapies in advanced liver disease,” Loomba said.
The commercial relationships surrounding the research are extensive. Loomba has served as a consultant to Novo Nordisk and numerous other pharmaceutical companies, and his institution has received industry research grants. Several other investigators reported consulting, speaking or research relationships with companies developing treatments for obesity, diabetes and liver disease.
Those relationships do not invalidate the trial, but they make independent confirmation especially important.
For now, the study provides encouraging evidence that semaglutide may affect advanced liver scarring, not merely body weight or liver fat. It does not yet establish that the medication can reverse cirrhosis or prevent the most serious consequences of MASH.
The study was funded by Novo Nordisk. Four authors were employees and stockholders of the company, and one held a patent related to zalfermin. Novo Nordisk also funded medical writing support provided by OPEN Health Communications.
Senior author Rohit Loomba reported consulting relationships with Novo Nordisk and numerous other pharmaceutical and biotechnology companies. His institution has received research grants from several drug manufacturers, and he is a co-founder of LipoNexus. Other investigators reported extensive consulting, speaking and research relationships with companies developing treatments for metabolic and liver diseases.
Loomba also receives research support from the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. Other authors reported support from Australian government research programs and academic institutions.