Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, was associated with resolution of nonalcoholic steatohepatitis (NASH) but no significant improvement in liver fibrosis, according to a recent industry-funded phase 2 trial.
The 72-week trial included 320 patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Participants were randomized to placebo or once-daily subcutaneous semaglutide at three different doses. The primary end point was resolution of NASH with no worsening of fibrosis, and a confirmatory secondary end point (for which only patients with F2 or F3 fibrosis at baseline were analyzed) was an improvement of at least one fibrosis stage with no worsening of NASH. The trial was sponsored by Novo Nordisk, and results were published by the New England Journal of Medicine on Nov. 13.
The primary end point occurred in 40% of the 80 patients on 0.1 mg of semaglutide, 36% of the 78 patients on 0.2 mg, and 59% of the 82 patients on 0.4 mg, compared to 17% of the 80 patients on placebo (P<0.001 for 0.4 mg vs. placebo). The secondary end point of fibrosis improvement was not significantly improved with the drug (43% in the 0.4-mg group vs. 33% on placebo; P=0.48). The mean percentage of weight loss was 13% in the 0.4-mg semaglutide group and 1% in the placebo group. Nausea, constipation, and vomiting were more common with 0.4 mg of semaglutide than with placebo (nausea, 42% vs. 11%; constipation, 22% vs. 12%; vomiting, 15% vs. 2%). Neoplasms (benign, malignant, or unspecified) were reported in 15% of patients on semaglutide versus 8% of those on placebo; they were malignant in three patients on the drug and in no patients on placebo.
“The fact that the percentage of patients who had an improvement in fibrosis stage was not significantly higher with semaglutide than with placebo—despite a greater benefit with respect to NASH resolution and dose-dependent weight loss—was unexpected, given that previous studies have suggested that resolution of NASH and improvements in activity scores for the components of nonalcoholic fatty liver disease are associated with regression of fibrosis,” the authors said.
They noted that the trial might not have been long enough or sufficiently powered for differences in fibrosis to become apparent. The mechanisms of action of GLP-1 receptor agonists on NASH outcomes are also not yet clearly understood, the authors said. They observed that the safety profile of semaglutide in this study was similar to that seen when the drug is used for type 2 diabetes, its current FDA-approved indication.