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

Background/Aims: SGLT2 inhibitors cause an increase in hepatic glucose production (HGP) which returns glucose to the systemic circulation and offsets the amount of glucose excreted in the urine by ~50%. The signal which is activated by SGLT2 inhibition and causes the increase in HGP is unknown. We previously have shown that the acute administration of SGLT2 inhibitor is associated with an increase (within 4 hours) in norepinephrine (NE) turnover. The aim of the present study is to examine the long-term effect of SGLT2 inhibition on total body NE turnover.

Methods: 36 T2D and 36 nondiabetic subjects were randomized to receive empagliflozin or matching placebo (2:1 ratio) for 12 weeks. HGP and total-body NE turnover were measured with 3-³H-glucose and ³H-NE infusion before and after therapy with empagliflozin.

Results: Empagliflozin administration (day 1), caused an increase in HGP by 22% and 19% within 4 hours in T2D and nondiabetic individuals, respectively, and the increase in HGP persisted at week 12. Total-body NE turnover significantly decreased in both groups. The placebo-subtracted decrease in NE turnover was -139±35 and -165±71 ng/min (both p<0.05) in T2DM and nondiabetic individuals, respectively, at 24 hours after empagliflozin administration (day 2), and the decrease in NE turnover persisted at week 12 (p<0.01). The decrease in NE turnover strongly and inversely correlated with the increase in HGP at week 12 (r=0.64, p<0.001). However, the decrease in NE turnover at day 2 did not correlate with the increase in HGP on day 1 of empagliflozin administration (r=0.09, p=ns).

Interpretation: The long-term empagliflozin-induced stimulation of HGP cannot be explained by activation of the SNS. However, the inhibition of sympathetic activity by SGLT2i may explain the lack of increase in heart rate consistently observed in cardiovascular outcome trials with SGLT2 inhibitors.