Clinical Pearls & Morning Reports
To date, there are no approved pharmacotherapies for the treatment of nonalcoholic steatohepatitis (NASH). Newsome et al. conducted a randomized, placebo-controlled, phase 2 trial to investigate the effect of semaglutide on histologic resolution of NASH in patients with biopsy-confirmed NASH and fibrosis. Read the NEJM Original Article here.
Q: What are the pathogenic drivers of NASH?
A: NASH is a severe form of nonalcoholic fatty liver disease that is characterized by the accumulation of fat (steatosis), hepatocyte damage, and inflammation. Increased adiposity, adipose tissue dysfunction, and insulin resistance contribute to increased levels of free fatty acids and carbohydrates, which place excess lipotoxic and metabolic loads on the liver and ultimately lead to hepatic lipid accumulation, cell injury, inflammation, and fibrosis.
Q: Why is semaglutide thought to have promise as a therapy for NASH?
A: The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide has been shown to improve liver-enzyme levels and reduce liver fat and to have a beneficial effect on histologic resolution of NASH. Semaglutide is another GLP-1 receptor agonist, with a mechanism of action that is similar to that of liraglutide but with more pronounced metabolic effects. In previous studies, semaglutide induced weight loss and improved glycemic control in patients with obesity and type 2 diabetes and was associated with reduced cardiovascular risk among patients with type 2 diabetes at high cardiovascular risk. Moreover, semaglutide has been reported to reduce levels of alanine aminotransferase and markers of inflammation.
A: In the trial, patients were randomly assigned to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients. Once-daily subcutaneous treatment with semaglutide at a dose of 0.4 mg was superior to placebo with respect to resolution of NASH without worsening of fibrosis after 72 weeks of treatment, with 59% of the patients in the 0.4-mg group having a response, as compared with 17% of those in the placebo group (odds ratio, 6.87; 95% CI, 2.60 to 17.63; P<0.001). However, semaglutide did not show a significant between-group difference with respect to an improvement of at least one fibrosis stage without worsening of NASH, which occurred in 43% of the patients in the semaglutide 0.4-mg group as compared with 33% in the placebo group (odds ratio, 1.42; 95% CI, 0.62 to 3.28; P=0.48).
A: 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. However, the temporal association among 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 of the patients had advanced fibrosis.