Potential or Problematic New Treatment for Nonalcoholic Steatohepatitis

A recent study describes the efficacy and safety of Semaglutide, a glucagon-like peptide-1 receptor agonist for nonalcholic steatohepatitis (NASH): PN Newsome et al. NEJM 2021; 384: 1113-1124. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis

Methods: This was a a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo.

Key findings:

  • The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo).
  • An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48).
  • The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. 
  • Safety: Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group

Clearly this study indicates that there may be safety concerns with semaglutide. In addition to the malignant neoplasms, there were 8 individuals with colonic polyps in the treatment groups and 7 with renal cysts in the treatment group. However, the authors note that in a recent meta-analysis with 55,921 patients, GLP-1 agonists were not associated with an increased risk of malignant neoplasms (Diabetes Obes Metab 2020; 22: 699-704).

Related article: JPH Wilding et al. NEJM 2021; 384: 989-1002. Once-Weekly Semaglutide in Adults with Overweight or Obesity Key finding: The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo. This study indicates potential for GLP-1 Agonist class for pharmacologic treatment of obesity.

My take: The improvement in NASH with semaglutide is encouraging and perhaps improvement in fibrosis will occur with more time. Yet, more time is also needed to determine if this agent is truly safe in this population. In patients receiving other GLP analogues, vigilance for adverse events is needed as well.

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