Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes
Status:
Completed
Trial end date:
2020-11-12
Target enrollment:
Participant gender:
Summary
Inhibitors of sodium-dependent glucose-transporter 2 (including dapagliflozin) represent
intensively investigated drugs in the field of diabetes. SGLT-2 inhibition limits glucose
reabsorption in renal tubular cells, hereby increasing the amount of glucose excreted via
urine in the hyperglycemic state. Its mechanisms of action are independent of insulin, the
indispensable standard of care in Type 1 Diabetes (T1D). Several international diabetes
experts highlighted the need for adjunct therapies in T1D.
Subcutaneous application of insulin is non-physiological. Most significant, subcutaneous
insulin substitution does not address the bi-hormonal character of T1D. The loss of
pancreatic beta cells and subsequent endogenous insulin production uncouples alpha cell
derived glucagon secretion from its paracrine suppressor. Consequently, excess glucagon
concentrations occur in the fasting and the postprandial state, which promotes hyperglycemia,
requires higher doses of subcutaneous insulin, and promotes glycaemic variability.
Recent studies on SGLT-2 inhibition in T1D showed better glycemic control compared to
placebo, whereas a higher risk for the development of diabetic ketoacidosis was observed.
Knowledge about the underlying mechanisms is scarce. Studies showed that SGLT-inhibition
increased Glucagon-like-peptide 1 (GLP-1) in T1D, an incretin hormone capable of suppressing
glucagon. On the other side, total concentrations of ketone bodies were higher following
SGLT-2 inhibition, irrespective of ongoing subcutaneous or intravenous insulin substitution.
The present study aims to investigate the effect of SGLT-2 inhibitor dapagliflozin on
hormonal regulators of glucose homeostasis and ketogenesis in T1D. The primary endpoint is
the difference of GLP-1 during oral glucose tolerance test clamps (OGGTc). Secondary
endpoints comprise total ketone body concentrations, free fatty acids, glucagon, and
somatostatin during OGTTc and hyperinsulinemic, euglycemic clamps (HEC) following
dapagliflozin and placebo. The study recruits male and female patients with T1DM in a
randomized, open label, cross-over intervention study.