Phase II trial shows potential of antidiabetic drug for NASH

A greater proportion of individuals with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and fibrosis had NASH resolution with subcutaneous semaglutide, a GLP-1* receptor agonist approved for the treatment of type 2 diabetes (T2D), a phase II study has shown.

“To date, there are no approved pharmacotherapies for the treatment of NASH,” said the researchers. “[Our study shows that] among patients with stage F2 or F3 fibrosis, subcutaneous treatment with semaglutide at a dose of 0.4 mg QD was superior to placebo with respect to resolution of NASH, without worsening of fibrosis after 72 weeks of treatment.”

The team sought to explore the effect of semaglutide on histologic resolution of NASH in 320 patients (mean age 55 years, 61 percent female). Of these, 22 percent had F2 fibrosis and 49 percent had F3 fibrosis. Participants were randomized 3:3:3:1:1:1 to receive once-daily SC semaglutide 0.1, 0.2, or 0.4 mg, or corresponding placebo, for 72 weeks, with a 7-week follow-up period. [N Engl J Med 2020;doi:10.1056/NEJMoa2028395]

More than half of participants (59 percent) on semaglutide 0.4 mg had a response, as opposed to only 17 percent of those receiving placebo (odds ratio [OR], 6.87; p<0.001). There were also more patients on semaglutide 0.1 and 0.2 mg (40 percent and 36 percent, respectively) who achieved NASH resolution vs placebo.

Other efficacy findings favoured semaglutide 0.4 mg over placebo – with fewer patients exhibiting fibrosis worsening (5 percent vs 19 percent) and more patients having NAFLD** activity score improvements (83 percent vs 44 percent).

However, no significant difference was seen between semaglutide 0.4 mg and placebo in terms of the fraction of participants with an improvement of at least one fibrosis stage without NASH worsening (43 percent vs 33 percent; OR, 1.42; p=0.48). According to the researchers, this was “unexpected,” in view of evidence linking NASH resolution and NAFLD activity score improvements to regression of fibrosis. [JAMA Netw Open 2019;2:e1912565; Hepatology 2019;70:522-531]

“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,” the researchers explained. “Moreover, outcomes such as the score on the enhanced liver fibrosis test and the degree of liver stiffness are continuous variables … [T]herefore, they may show changes that are not evident from categorical liver-biopsy evaluation. A lack of adequate statistical power for this secondary endpoint may also have contributed to the unanticipated results.”

Semaglutide 0.4 mg was associated with higher incidences of nausea (42 percent vs 11 percent), constipation (22 percent vs 12 percent), reduced appetite (22 percent vs 5 percent), and vomiting (15 percent vs 2 percent) vs placebo. Serious adverse event rates were also higher across all semaglutide arms (15–19 percent) vs placebo (10 percent).

Nonetheless, the safety profile of semaglutide correlates with that seen in T2D patients and with the known effects of GLP-1 receptor agonists. [Lancet 2018;392:637-649; Eur J Endocrinol 2019;181:R211-R234; Diabetes Metab 2019;45:409-418; Diabetes Obes Metab 2018;20:22-33]

Repurposing antidiabetic agents for liver disease?

Insulin resistance is a shared characteristic of T2D and obesity, and is a key pathogenic driver of NASH. [JHEP Rep 2019;1:312-328; Nat Rev Gastroenterol Hepatol 2019;16:377-386] “[The] increased adiposity, adipose tissue dysfunction, and insulin resistance contribute to increased levels of free fatty acids and carbohydrates,” explained the researchers. “[This] places excess lipotoxic and metabolic loads on the liver and ultimately lead to hepatic lipid accumulation, cell injury, inflammation, and fibrosis.”

In one study, liraglutide, another GLP-1 receptor agonist, was associated with NASH resolution and prevention of fibrosis worsening. [Lancet 2016;387:679-690] Another study reflected the ability of semaglutide to reduce ALT*** levels and inflammatory markers. [Aliment Pharmacol Ther 2019;50:193-203]

Together with previous evidence, the current study underpins the potential of an antidiabetic drug for a severe form of NAFLD that is associated with increased morbidity and mortality, with limited treatment options, noted the researchers.