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New phase 2 trial results suggest semaglutide 2·4 mg once weekly did not improve fibrosis without worsening of NASH in patients with NASH-related compensated cirrhosis.
Once-weekly semaglutide 2.4 mg did not significantly improve fibrosis or achievement of non-alcoholic steatohepatitis (NASH) resolution versus placebo in patients with NASH-related compensated cirrhosis, according to new phase 2 results.1
However, in patients with cirrhosis, the therapy was linked to improvements in cardiometabolic risk parameters, did not lead to new safety concerns, and was considered well-tolerated on the basis of the established profile of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) class.
"Overall, the safety profile of semaglutide seen in this trial was consistent with previous trials in patients with type 2 diabetes, overweight or obesity, and NASH, with mild-to-moderate, transient gastrointestinal effects accounting for most on-treatment adverse events," wrote the investigative team. "We did not observe effects on hepatic or renal function with semaglutide treatment, and there were no decompensating events."
According to the investigative team led by Rohit Loomba, MD, University of California at San Diego, individuals with NASH-related cirrhosis experience a greater risk of liver-related and all-cause morbidity and mortality. There is a large unmet need for effective pharmacotherapies to improve the natural history of the disease, but currently no approved therapies for the treatment of NASH. Previous data has suggested that GLP-1 RAs may have hepatoprotective effects, with semaglutide linked to improved metabolic parameters and NASH resolution.
However, there is no present data on semaglutide in patients with NASH-related cirrhosis. Loomba and colleagues thus investigated the efficacy and safety of semaglutide in patients with NASH and compensated cirrhosis in a double-blind, placebo-controlled phase 2 trial. Patients were enrolled from 38 centers across the United States and Europe.
Eligible adults with biopsy-confirmed NASH-related cirrhosis and body mass index (BMI) of 27 kg/m2 or more were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2.4 mg or visually matching placebo. Randomization was performed centrally using an interactive web response system and stratified for presence or absence of type 2 diabetes (T2D). Patients, investigators, and trial site staff remained blinded to treatment assignment throughout the trial.
The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH after 48 weeks, assessed by biopsy in the intention-to-treat population. Secondary endpoints included the relative change in liver fat content and in liver stiffness, change in NASH resolution on biopsy, and number of treatment-emergent adverse events.
A total of 71 patients were enrolled between June 2019 and April 2021, including 49 female patients (69%) and 22 (31%) male patients. The mean age was 59.5 years, and the mean BMI was 34.9 kg/m2, with 53 patients (75%) having diabetes.
After 48 weeks, data showed no statistically significant difference between the two groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH (5 [11%] of 47 patients in semaglutide group vs. 7 [29%] of 24 in the placebo group; odds ratio [OR], 0.28; 95% confidence interval [CI], 0.06 - 1.24; P = .087).
There was no significant difference between groups in the proportion of patients with improvement in liver fibrosis and no worsening of NASH after 48 weeks (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 patients in the placebo group; odds ratio 0·28 [95% CI 0·06–1·24]; p=0·087).
Additionally, the findings indicated a lack of significant difference between groups in the proportion of patients who achieved NASH resolution (16 [34%] vs. 5 [21%]; OR, 1.97; 95% CI, 0.56 - 7.91; P = .29). At week 48, change in liver stiffness from baseline was not significantly different between groups, but improvement in liver steatosis was significantly greater in the semaglutide group (P = .0042). Investigators noted reduction in liver fat volume and thus total liver volume was significantly greater in the semaglutide group than in the placebo group.
Further, similar proportions of patients in each group reported adverse events (42 [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, diarrhea, and vomiting, which mainly occurred during treatment initiation or dose escalation.
Investigators noted hepatic function remained stable after semaglutide treatment and did not result in decompensating events. Renal function was additionally reported to have remained stable in patients who received semaglutide and decreased slightly with placebo.