Metabolic effects of an SGLT2 inhibitor (dapagliflozin) during a period of acute insulin withdrawal and development of ketoacidosis in people with type 1 diabetes.

Abstract

Objective: To determine the effect of SGLT<sub>2</sub> inhibitor dapagliflozin on glucose flux, lipolysis and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. <p> </p> <p>Research Design and Methods: A double-blind placebo controlled crossover study with a 4-week wash out period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the rate of glucose production (Ra), disappearance (Rd) and lipolysis. At isotopic steady state insulin was withdrawn and the study terminated after 600 minutes or earlier if blood glucose reached 18mmol/L, bicarbonate <15mmol/L, venous pH <7.35 or capillary ketones >5.0 mmol/L. </p> <p><br></p><p>Results: At baseline, glucose Ra was significantly higher with dapagliflozin than placebo. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and AUC<sub>0-180min </sub>glucose Rd and AUC<sub>0-180min </sub>β-hydroxybutyrate (BOHB) were significantly higher. There was a small but significantly higher AUC<sub>0-180min </sub>glycerol Ra (measure of lipolysis) with dapagliflozin. Non-esterified fatty acid concentrations were not different between treatments.</p> <p>When divided by BMI>27 and <27kg/m<sup>2</sup>, basal glucose Ra and BOHB, and AUC<sub>0-180min </sub>glycerol Ra were significantly higher in the low BMI group with dapaglifozin versus placebo treatment.</p> <p><br></p><p>Conclusions: During insulin withdrawal the increase in BOHB with dapaglifozin may be partially due to increased lipolysis. However reduced renal excretion, reduced BOHB uptake by peripheral tissues or a metabolic switch to increase ketogenesis within the liver may also play a role. <u></u></p>