Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial
Yvo J.M. Op den Kamp, Marlies de Ligt, Bas Dautzenberg, Esther Kornips, Russell Esterline, Matthijs K. C. Hesselink, Joris Hoeks, Vera B. Schrauwen‐Hinderling, Bas Havekes, Jan Oscarsson, Esther Phielix, Patrick Schrauwen
Abstract
OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS Evaluable patients (n = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m2, and HbA1c 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, P < 0.0001). Insulin-induced suppression of EGP (–1.71 [–2.75, –0.63] μmol/kg/min, P = 0.0036) and plasma free fatty acids (–21.93% [–39.31, –4.54], P = 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], P = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (–20.51 [–27.90, –13.12] g/day). CONCLUSIONS 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.