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

The aim of the present study is to examine the effect of empagliflozin on hepatic glucose production (HGP) and total-body norepinephrine (NE) turnover in subjects with and without type 2 diabetes (T2DM). 36 subjects with T2DM and 36 individuals without T2DM were randomized to receive in 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-norepinephrine infusion, respectively, at baseline and at day 1 and 12 weeks after starting therapy with empagliflozin or placebo. Empagliflozin increased HGP by 22% and 19% in individuals with T2DM and in subjects without T2DM, respectively, and the increase in HGP persisted at week 12. Total-body NE turnover significantly decreased in both groups at one 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 one of empagliflozin administration (r=0.09, p=ns). These results demonstrate that empagliflozin causes long term reduction in NE turnover and the decrease in NE turnover was strongly correlated with the increase in HGP. Regulation of sympathetic activity by sodium glucose co-transport inhibitors (SGLT2i) can explain some of the systemic actions of SGLT2i, but cannot explain the long-term SGLT2i-induced rise in HGP.