ESPE Yearbook of Paediatric Endocrinology

N Engl J Med 2021; 384:1113–1124. DOI: 10.1056/NEJMoa2028395 https://www.nejm.org/doi/full/10.1056/NEJMoa2028395

The authors report a 72-week, double-blind placebo-controlled trial in 320 adult patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and liver fibrosis (stage F1, F2, or F3). Patients were randomly assigned to once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4 mg or placebo. NASH resolution was significantly higher in patients on 0.1-mg (40%), 0.2-mg (36%) and 0.4-mg (59%), than on placebo (17%). Mean percent weight loss was also much higher on 0.4-mg (13%) than on placebo (1%). However, there was no significant effect on improvement in fibrosis stage (43% on 0.4-mg vs. 33% on placebo; P=0.48).

There are few effective treatments for NASH, other than lifestyle changes to produce weight loss.By contrast, there is increasing evidence for the efficacy of GLP-1 agonists, exenatide, liraglutide, and semaglutide, in treating patients with Type 2 diabetes and/or obesity. They act by increasing beta cell insulin secretion, reducing glucagon secretion and delaying gastric emptying. Possible other mechanisms of GLP-1 agonists include central promotion of satiety and peripheral enhancement of insulin sensitivity in fat, muscle and liver.

This paper shows that semaglutide is clearly effective in treating NASH: odds ratio for NASH resolution (OR)=3.36 in the 0.1 mg group, OR=2.71 in the 0.2 mg group, and OR=6.87 in the 0.4 mg group, compared to placebo. It is unclear whether or not these benefits were dependent on its effects on weight loss, which were also impressive. However, the lack of benefit of semaglutide on liver fibrosis stage may indicate that longer duration of treatment is needed, or that patients should start treatment earlier, before liver fibrosis is apparent or advanced. In this regard, a recent systematic review and meta analysis identified clear benefits of GLP-1 agonists in children and adolescents with Type 2 diabetes or obesity, and importantly these benefits seem to be as large as those in adults (1). Health service funding remains a major barrier to the wider use of GLP-1 agonists in children.

Reference: 1. Chadda KR, et al. GLP-1 agonists for obesity and type 2 diabetes in children: Systematic review and meta-analysis. Obesity Reviews. 2021 Jun;22(6):e13177. doi: 10.1111/obr.13177.