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

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posted on 15.04.2021, 18:24 by Yvo J.M. Op den Kamp, Marlies de Ligt, Bas Dautzenberg, Esther Kornips, Russell Esterline, Matthijs K.C. Hesselink, Joris Hoeks J, Vera B. Schrauwen-Hinderling, Bas Havekes, Jan OscarssonJ, Esther Phielix E, Patrick Schrauwen
Background: 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 24h energy metabolism and insulin sensitivity in patients with type 2 diabetes mellitus.

Methods: Twenty-six type 2 diabetes patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. 24h energy metabolism and respiratory exchange ratio (RER) were measured by indirect calorimetry, 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 (LSM) (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, while 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. 24h energy expenditure (-0.11 (-0.24, 0.03) MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced RER during day- and night-time resulting in an increased day to night-time difference in RER (-0.010 (-0.017, -0.002), p=0.016). Dapagliflozin treatment resulted in a negative 24h energy and fat balance (-20.51 (-27.90, -13.12) g/day).

Interpretation: 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 24h energy metabolism.

Funding

The study was funded by AstraZeneca. The study funder was involved in the design of the study, the interpretation of data, and writing the report, and did not impose any restrictions regarding the publication of the report.

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