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.