Liver and Bile
Lancet Gastroenterol Hepatol. 2023;8(6):511–22
Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: A randomized, placebo-controlled phase 2 trial
Background: Patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis are at high risk of liver-related and all-cause morbidity and mortality. The authors investigated the efficacy and safety of the glucagon-like peptide-1 analogue semaglutide in patients with NASH and compensated cirrhosis.
Methods: This double-blind, placebo-controlled phase 2 trial enrolled patients from 38 centers in Europe and the USA. Adults with biopsy-confirmed NASH-related cirrhosis and body-mass index (BMI) ≥ 27 kg/m2 were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2.4 mg or visually matching placebo. Patients were randomly allocated via an interactive web response system, stratified by presence or absence of type 2 diabetes. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary end point was the proportion of patients with an improvement in liver fibrosis of ≥ 1 stage without worsening of NASH after 48 weeks, assessed by biopsy in the intention-to-treat population. Safety was assessed in all patients who received at least 1 dose of study drug.
Findings: 71 patients were enrolled between June 18, 2019, and April 22, 2021; 49 patients (69%) were female and 22 (31%) were male. Patients had a mean age of 59.5 years (SD 8.0) and mean BMI of 34.9 kg/m2 (SD 5.9); 53 patients (75%) had diabetes. 47 patients were randomly assigned to the semaglutide group and 24 to the placebo group. After 48 weeks, there was no statistically significant difference between the 2 groups in the proportion of patients with an improvement in liver fibrosis of ≥ 1 stage without worsening of NASH (5/47 patients [11%] in the semaglutide group vs. 7/24 [29%] in the placebo group; odds ratio = 0.28, 95% confidence interval: 0.06–1.24; p = 0.087). There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (p = 0.29). Similar proportions of patients in each group reported adverse events (42 patients [89%] in the semaglutide group vs. 19 [79%] in the placebo group) and serious adverse events (6 [13%] vs. 2 [8%]). The most common adverse events were nausea (21 [45%] vs. 4 [17%]), diarrhea (9 [19%] vs. 2 [8%]), and vomiting (8 [17%] vs. 0). Hepatic and renal function remained stable. There were no decompensating events or deaths.
Interpretation: In patients with non-alcoholic steatohepatitis (NASH) and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo. No new safety concerns were raised.