Clinicopathological analyses led us to hypothesize that glycemic control and insulin therapy ameliorate or protect against the histological progression of liver fibrosis in patients with nonalcoholic steatohepatitis. To test this hypothesis, we aim to compare the effects of Sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas, which lower glucose levels by decreasing and increasing circulating levels of insulin, respectively, in patients with type 2 diabetes.

Previous clinical trials lacked a control group or histological examination, which precludes meaningful conclusions since the natural course of the disease or tight glycemic control may ameliorate liver pathology in some patients with nonalcoholic fatty liver disease (NAFLD). We investigated the efficacy of the SGLT2 inhibitor tofogliflozin and the sulfonylurea glimepiride in liver pathology in patients with NAFLD and T2D for 48 weeks in an open-label, randomized, parallel study.

Using many metabolic markers (hyperinsulinemic euglycemic clamp study, arginine stimulation test,1H MRS (magnetic resonance spectroscopy), bioelectrical impedance analysis, Holter electrocardiograms, liver and blood cells, and gut microbiota profiling), we may be able to clarify the mechanisms underlying the SGLT2 inhibitor/sulfonylurea-mediated alteration in body weight and whole-body energy metabolism.