LBSUN213 An Investigation Into The Effects Of Dapagliflozin On Ketogenesis In Type 1 Diabetes

BACKGROUND: Treatment with sodium-glucose transporter (SGLT)-2 inhibitors in patients with type 1 diabetes (T1DM) is associated with increased ketogenesis and diabetic ketoacidosis (DKA). The exact relationship between SGLT-2 inhibitors use in T1DM and ketogenesis is not fully understood. PATIENTS AND METHODS: In this single center, randomized, double blind and placebo-controlled trial 70 patients with established T1DM were randomized into placebo, dapagliflozin (SGLT-2 inhibitor) alone, exenatide/Bydureon (short and long-term acting GLP-1 RA, respectively) alone or with dapagliflozin and exenatide/Bydureon (triple therapy) groups in addition to routine insulin treatment (titrated in all groups to reduce risk of hypoglycemia). Patients were tested acutely (single dose before and after 12 weeks of treatment) under extended fasting and insulinopenic conditions (stress conditions) and under basal fasting conditions during 12 weeks treatment period. RESULTS: At end of 12 weeks treatment, glycemic indices improved significantly compared to baseline in the dapagliflozin and Bydureon alone groups and improved significantly compared to placebo in the triple therapy group (HbA1c: -0.9±0.1%, p<0. 001). Weight loss was significant (p<0. 001) in all active treatment groups. Ketones (beta-hydroxybutyrate, BHB) increased significantly in blood (0.21±0. 04 to 1.57±0.21 mM) and urine under acute stress conditions in control group at baseline and at 12 weeks visits. The magnitude of this increase was reduced following a single dose of dapagliflozin or exenatide at baseline visit (average of 1.16±0.17 mM) but was further increased following a single dose in the dapagliflozin receiving groups at 12 weeks visit (average of 1.83±0.28 mM). Under acute testing conditions, single dose of dapagliflozin treatment was associated with reduced urinary BHB clearance at baseline and 12 weeks visits. After 12 weeks of treatment and under basal conditions, ketone levels in blood and urine were not significantly altered following dapagliflozin or Bydureon alone but were significantly higher in the triple therapy group (0.22±0. 04 to 0.42±0. 07 mM in blood). At 12 weeks of treatment, dapagliflozin was associated with increased glucagon and lipolysis (increased FFAs) while Bydureon was associated with decreased glucagon and lipolysis. During the 12 weeks there were no episode of DKA or hypoglycemia (<55mg/dl). CONCLUSIONS: Adjunct therapies treatment in T1DM results in significant improvements in glycemia and HbA1c. Dapagliflozin treatment increases lipolysis and glucagon while reduces urinary excretion of BHB. This may contribute to the increased blood ketone levels following extended treatment with dapagliflozin. However, the magnitude of this increase in ketones is significantly below DKA ketones levels which indicates that other DKA triggering factors play a more significant role. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.