Empagliflozin Enhances Hepatic Glucose Production and Reduces Total-Body Norepinephrine Turnover Rate: A Randomized Trial

The current study examined the effect of empagliflozin on hepatic glucose production (HGP) and total-body norepinephrine (NE) turnover in individuals with and without type 2 diabetes (T2D). The study randomized 36 individuals with T2D and 36 individuals without T2D to receive in a double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. HGP and NE turnover were measured with [3-3H]glucose and [3H]NE infusion, respectively, at baseline and at day 1 and 12 weeks after starting therapy with empagliflozin or placebo. Empagliflozin increased HGP by 22% in individuals with T2D and by 19% in those without T2D, and the increase in HGP persisted at week 12. Total-body NE turnover significantly decreased in both groups at 1 day after empagliflozin administration, and the decrease in NE turnover persisted for 12 weeks. The decrease in NE turnover strongly and inversely correlated with the increase in HGP at week 12 (r = 0.64, P < 0.001), but not with the increase in HGP on day 1 of empagliflozin administration (r = 0.09, P = ns). These results demonstrate that empagliflozin causes a long-term reduction in NE turnover and that the decrease in NE turnover was strongly correlated with the increase in HGP. Regulation of sympathetic activity by sodium–glucose cotransporter 2 inhibitors (SGLT2i) can explain some of the systemic actions of SGLT2i, but cannot explain the long-term SGLT2i-induced rise in HGP. ARTICLE HIGHLIGHTS Sodium–glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 hours) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate. Empagliflozin caused a decrease in total-body NE turnover at 1 day and at 12 weeks after starting therapy, despite an increase in glucose production, and the magnitude of decrease in NE turnover inversely correlated with the increase in HGP caused by empagliflozin.