Distinct metabolomic signatures of SGLT2 inhibitor vs. sulfonylurea in a paired human liver biopsy study.

This study aimed to elucidate how sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas differentially modulate hepatic metabolism in persons with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). In this 48-week randomized, open-label, parallel-group trial, Japanese participants with type 2 diabetes and biopsy-confirmed MASLD received either tofogliflozin or glimepiride. Paired liver biopsy samples and serum were collected at baseline and after 48 weeks. We performed a post hoc metabolomic analysis to assess hepatic and systemic metabolic shifts and their correlations with histological and clinical parameters. Tofogliflozin treatment significantly increased hepatic glucose 1-phosphate and acetyl-CoA levels, reflecting a metabolic shift toward ketogenesis and gluconeogenesis. Regarding TCA cycle intermediates, tofogliflozin elevated serum citrate but reduced serum succinate; notably, the reduction in succinate correlated with reduction in liver enzyme levels. Furthermore, higher baseline serum succinate predicted superior histological improvements (ballooning and inflammation) in the tofogliflozin group. In contrast, glimepiride specifically reduced hepatic branched-chain amino acids (BCAAs), which was associated with decreased steatosis. Tofogliflozin also elevated serum urea cycle intermediates, suggesting a distinct "aestivation-like" response to hypovolemia. The metabolic signature of SGLT2 inhibitors in the human liver is characterized by starvation-induced glucose production and hypovolemia-induced aestivation-like response. Serum succinate emerged as a potential biomarker associated with MASLD severity and treatment-related improvements under SGLT2 inhibition.