Semaglutide produces NASH resolution without worsening fibrosis
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Patients treated with subcutaneous semaglutide experienced better resolution of non-alcoholic steatohepatitis without worsening fibrosis, according to the results of a placebo-controlled study presented at The Liver Meeting Digital Experience.
In his presentation, Phillip N. Newsome, PhD, from the Birmingham Biomedical Research Centre in the United Kingdom, said a glucagon-like peptide-1 analog, like semaglutide (Novo Nordisk), can impact appetite suppression, gastric emptying and glycemic control.
“Semaglutide is the latest example of long-lasting GLP-1 analogs with a half-life of 165 hours and which is licensed in the management of patients with diabetes,” he said. “In this study, it is being tested for its efficacy in patients with NASH.”
Researchers recruited 320 patients with biopsy-confirmed NASH to investigate the effects of semaglutide. Patients had fibrosis stage F1 (28%), F2 (23%) or F3 (49%), a NAFLD activity score (NAS) of at least 4 and a BMI of more than 25 kg/m2.
Investigators randomly assigned patients to receive either 0.1, 0.2 or 0.4 mg of subcutaneous semaglutide or placebo once daily for 72 weeks. The primary outcome, tested in patients with F2 or F3 (n = 230), was resolution of NASH with no worsening of fibrosis. Researchers also assessed improvement in fibrosis with no worsening of NASH as a confirmatory secondary endpoint.
A greater proportion of patients in all three semaglutide dose groups achieved the primary endpoint (40.4%, 35.6% and 58.9%) compared with placebo (17.2%). There was no significant difference between the treatment groups and the placebo group in the secondary endpoint of fibrosis improvement.
However, Newsome said a pre-specified analysis of changes in fibrosis stage over treatment showed that there was a dose-dependent difference between patients who received semaglutide compared with placebo. Among patients who received placebo, 18.8% of patients experienced a worsening in liver fibrosis, compared with just 4.9% in the 0.4 mg semaglutide group.
Investigators also observed dose-dependent improvements in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and fibrosis biomarkers, as well as better induction of weight loss among patients who received semaglutide.
“Fewer patients had progression of fibrosis, and there were significant improvements in fibrosis biomarkers,” Newsome said. “In addition, there were improvements in multiple metabolic characteristics, and the safety profile was very much consistent with that seen in patients treated with semaglutide with type 2 diabetes.”
Perspective
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Jamile' Wakim Fleming, MD, FACG, FAASLD
NASH represents an advanced form of fatty liver and is characterized by inflammation and fibrosis that can lead to cirrhosis, liver failure and liver cancer. Obesity is on the rise reaching about 35% to 40% of the general population worldwide, and about 75% of overweight people have fatty liver. Preventing and reducing fatty liver and regression of fibrosis and cirrhosis are becoming an essential step in the management of fatty liver disease and its consequences. Trials are being conducted to address fatty liver disease.
Semaglutide is a GLP-1 agonist and is being used to induce weight loss and improve glycemic control and cardiovascular complications in type 2 diabetes. In a randomized double blind placebo controlled study conducted by Newsome et al. on 320 people, using semaglutide at 3 different doses of 0.1, 0.2 or 0.4 mg a day subcutaneously, the researchers found that at 0.4 mg semaglutide was superior to placebo in resolving NASH in 59% of patients compared with 17% of patients in the placebo group, without worsening fibrosis, when patients were followed over 72 weeks. This finding is very encouraging, and it met the primary aim of the study, but it did not totally meet the secondary aim which was resolving fibrosis at least by one stage. Regression of fibrosis and cirrhosis is an essential factor in limiting the progression to liver failure, cancer and death. The short duration of the trial and the interobserver variability in interpreting the pathology findings are some of the limitations in this trial. Long-term studies that will show regression of fibrosis without the burden of side effects of medications used are needed.
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Newsome PN, et al. Abstract 0010. Presented at: The Liver Meeting Digital Experience; Nov. 13-16, 2020.
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