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

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 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, 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.

Trial registration: ClinicalTrials.gov NCT03338855.

Figure 1

Body composition (n = 24) (A), fat mass (n = 24) (B), and IHL (C) content upon placebo (P) and dapagliflozin (D) treatment (n = 22). BW, body weight; FM, fat mass; LBM, lean body mass. Results are in LSM and 95% CI, obtained through a linear mixed model, with the exception of IHL, where a Wilcoxon paired rank sum test was used. *P < 0.05 is considered significantly different.

Figure 2

Urinary glucose excretion (A), EGP (B), fatty acid (FA) oxidation (C), carbohydrate oxidation (D), NOGD (E), plasma NEFA levels (F), plasma glycerol levels (G), plasma insulin levels (H), ΔEGP (I), ΔR_d (J), percentage of NEFA suppression (K), Δsuppression of glycerol plasma levels (L), and ΔRER (M) measured during a two-step EHC upon placebo (P) and dapagliflozin (D) treatment. Results (n = 22) are in LSM and 95% CI, obtained through a linear mixed model. *P < 0.05 is considered significantly different.

Figure 3

Twenty-four-hour energy expenditure (n = 24) (A), glucose excretion daytime (n = 23) (B), glucose excretion nighttime (n = 23) (C), energy balance (n = 24) (D), 24-h RER plot (n = 24) (E), daytime RER (n = 24) (F), nighttime RER (n = 24) (G), and ΔRER between day and night (n = 24) (H). Results are in LSM and 95% CI, obtained through a linear mixed model. *P < 0.05 is considered significantly different.

Figure 4

A: Twenty-four-hour fatty acid oxidation measured during the stay in the respiration chamber after placebo (P) or dapagliflozin (D) treatment. Substrate balance (n = 24) (B), 24-h carbohydrate oxidation (n = 24) (C), 24-h protein oxidation (n = 24) (D), plasma glucose (n = 21) (E), NEFA (n = 23) (F), and β-hydroxybutyrate levels (G) as measured in the respiration chamber (n = 23). Blood draws at 8:30 a.m., 1:00 p.m., and 6:00 p.m. were taken before meals. Results are in LSM and 95% CI, obtained through a linear mixed model. *P < 0.05 is considered significantly different.