麻豆传媒

More patients who received subcutaneous semaglutide (Ozempic), the glucagon-like peptide-1 (GLP-1) receptor agonist, saw resolution of their nonalcoholic steatohepatitis (NASH), with no worsening of fibrosis, versus patients who received placebo in a randomized trial.

While the proportion of patients with NASH resolution was higher among those who received semaglutide at several dose levels versus placebo, the highest dose (0.4 mg) showed the greatest difference (59% vs 17%, P<0.001), reported Philip Newsome, PhD, of the University of Birmingham in England, and colleagues.

However, there was no difference in improvement in fibrosis stage between the two groups (43% in the 0.4-mg group vs 33% in placebo group, P=0.48).

Findings from this phase II trial were presented at TLMdX, the virtual American Association for the Study of Liver Diseases (AASLD) meeting, and published in the .

Semaglutide is approved to treat type 2 diabetes, as it increases insulin secretion, which boosts sugar metabolism. The researchers noted it is being studied for use in weight management, and that it has a mechanism of action similar to liraglutide, another GLP-1 receptor agonist, but with "more pronounced metabolic effects."

Prior research found that semaglutide induced weight loss and improved glycemic control in patients with obesity and type 2 diabetes, in addition to reducing cardiovascular risks among patients with type 2 diabetes at high risk. In addition, semaglutide reduced markers of inflammation and levels of alanine aminotransferase, said the study authors.

Newsome and colleagues conducted the phase II trial from January 2017 to September 2018, with a 7 week follow-up period, at 143 centers in 16 countries. Patients were mostly adults 18-75, with or without type 2 diabetes, and a BMI of greater than 25. They had biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. The primary endpoint was resolution of NASH, defined as no more than mild residual inflammatory cells, no hepatocyte ballooning, and no worsening of liver fibrosis after 72 weeks.

Patients were randomized to receive either 0.1, 0.2, or 0.4 mg of subcutaneous semaglutide or corresponding placebo daily.

Overall, 320 patients were randomized -- 80 to the 0.1-mg semaglutide group, 78 to the 0.2-mg group, 82 to the 0.4-mg group, and 80 to placebo. Patients' mean age was 55, 61% were women, 78% were white, and 62% had type 2 diabetes. Mean BMI was about 36, and about half had stage F3 fibrosis. Mean activity score for nonalcoholic fatty liver disease was about 5.

The researchers noted the lack of significant difference between groups with respect to improvement of at least one fibrosis stage, characterizing it as "unexpected," but added that the temporal association between NASH resolution, weight loss, and improvement in fibrosis stage "is not fully understood."

"It is possible that the current trial was not of sufficient duration for improvements in fibrosis stage to become apparent, especially since most patients had advanced fibrosis," they wrote, further speculating about a lack of statistical power for this secondary endpoint.

Examining safety, gastrointestinal disorders were the most common adverse events, with substantially higher proportions of patients in the 0.4-mg semaglutide group versus patients in the placebo group reporting nausea (42% vs 11%, respectively), constipation (22% vs 12%), decreased appetite (22% vs 5%), and vomiting (15% vs 2%). More serious adverse events were reported across semaglutide groups (15-19%) compared with placebo (10%), but the authors noted no apparent dose-dependent relationship.

Hepatic events were similar across groups, with gallbladder disorders occurring in a higher percentage of semaglutide patients. There were no cases of acute pancreatitis, and severe hypoglycemic episodes were rare. Malignant neoplasms were reported in three patients in the semaglutide groups (vs none in the placebo group), though observed events of benign, malignant, and unspecified neoplasms (which were not adjudicated) were 15% in the semaglutide groups and 8% in the placebo group. However, "no pattern of occurrence in specific organs was observed," the authors wrote.

They also said cardiovascular events were adjudicated, and occurred in three patients in the semaglutide groups, but no conclusions can be drawn, since the trial was not powered to evaluate cardiovascular outcomes.

One possible limitation to the trial was the lack of long-term clinical outcomes.

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