ESPE Yearbook of Paediatric Endocrinology

Nat Rev Endocrinol 2021;17(8):484-95. doi: 10.1038/s41574-021-00507-z

Brief Summary: This article reviews the results of clinical trials for modulators of glucagon-like peptide-1 (GLP1) activity, insulin-sensitizing thiazolidinediones, and inhibitors of the sodium-glucose cotransporter 2 (SGLT2) for the treatment of NAFLD and type 2 diabetes mellitus.

Comment: NAFLD has become the most common chronic liver disease in childhood, due to the growing pandemic of pediatric obesity. The current prevalence of NAFLD in the general pediatric population ranges between 3 and 10%, and is up to 50% of children and adolescents with obesity. NAFLD is closely linked to obesity and tightly interrelated with insulin resistance, the MetS and T2DM. Hepatic fat accumulation represents the hallmark of NAFLD, which may progress from simple steatosis through non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis. The first part of this article reviews the results of anti-diabetic agents in NAFLD, and the second part describes experimental agents that have progressed to clinical trials.

There is currently no licensed drug therapy for NASH or NAFLD. Given the tight link between T2DM and NAFLD, numerous anti-diabetic drugs have been tested as treatments:

• Metformin, the first-line T2DM therapy, has not been shown to have beneficial effects on NASH.• GLP-1 agonists reduce hepatic steatosis and markers of liver damage in genetically induced and diet-induced animal models. Treatment with GLP-1 agonists in individuals with T2DM is effective to reduce hepatic lipid content, liver enzymes and inflammatory markers; the effect is associated with improved HbA1c levels and weight loss. Further, GLP-1 agonists resulted in resolution of NASH with no worsening of fibrosis.• Sitagliptin, a DPP4 inhibitor, failed to improve hepatic lipid content, despite improvement in HbA1c. Therefore, DPP4 inhibitors might not be an effective strategy for treating patients with NAFLD.• SGLT2, a sodium-dependent glucose transporter primarily expressed in the proximal tubule epithelium of the kidney, is responsible for most filtered glucose reabsorption. SGLT2 inhibitors increase urinary excretion of glucose and, in individuals with NAFLD, improve hepatic lipid content, liver enzymes and liver stiffness.

The review also discussed the following experimental treatment agents: PPAR agonists, the farnesoid X receptor (FXR) agonist, thyroid hormone receptor beta agonist, fatty acid synthase (FAS) inhibition, stearoyl-CoA desaturase 1 (SCD1) inhibition, diacylglycerol acyltransferase (DGAT) inhibition, and also FGF19 and FGF21.