Effects of Empagliflozin Treatment on Glycerol-Derived Hepatic Gluconeogenesis in Adults with Obesity: A Randomized Clinical Trial

Objective: The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 (¹³C)-labeled glycerol. Methods: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived ¹³C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U-¹³C₃]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived ¹³C enrichment studies were repeated, and treatment differences in the mean percentage of ¹³C glycerol enrichment in glucose were compared using mixed linear models. Results: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived ¹³C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerol-derived ¹³C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived ¹³C enrichment was inversely correlated with VAT but was not correlated with weight loss. Conclusions: VAT is associated with endogenous glycerol–derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity.