Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial.

Abstract

SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes. The underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24-h energy metabolism and insulin sensitivity in patients with type 2 diabetes. There were 26 patients with type 2 diabetes randomized to a 5-week double-blind, crossover study with a 6- to 8-week washout. Indirect calorimetry was used to measure 24-h energy metabolism and the respiratory exchange ratio (RER), both by whole-room calorimetry and by ventilated hood during a two-step euglycemic-hyperinsulinemic clamp. Results are presented as the differences in least squares mean (95% CI) between treatments. Evaluable patients (<i>n</i> = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m², and HbA_1c of 6.9% (0.7) (51.7 [6.8] mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, whereas fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 [1.39, 3.14] μmol/kg/min, <i>P</i> < 0.0001). Insulin-induced suppression of EGP (-1.71 [-2.75, -0.63] μmol/kg/min, <i>P</i> = 0.0036) and plasma free fatty acids (-21.93% [-39.31, -4.54], <i>P</i> = 0.016) was greater with dapagliflozin. Twenty-four-hour energy expenditure (-0.11 [-0.24, 0.03] MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced the RER during daytime and nighttime, resulting in an increased day-to-nighttime difference in the RER (-0.010 [-0.017, -0.002], <i>P</i> = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (-20.51 [-27.90, -13.12] g/day). Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction, increased fat oxidation, improved hepatic and adipose insulin sensitivity, and improved 24-h energy metabolism.