Exploring the Potential of the SGLT2 Inhibitor Dapagliflozin in Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

Abstract

OBJECTIVEInsulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters. RESEARCH DESIGN AND METHODSA 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-ofconcept study randomly assigned 70 adults with type 1 diabetes (HbA 1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. RESULTSSixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by 221.5 g/24 h (95% CI 253.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: 22.29 mmol/L (95% CI 23.71 to 20.87 [241.3 mg/dL; 95% CI 266.9 to 215.7]) for 24-h daily average blood glucose; 23.77 mmol/L (95% CI 26.09 to 21.45 [263.1 mg/dL; 95% CI 2111.5 to 214.8]) for mean amplitude of glycemic excursion; and 216.2% (95% CI 229.4 to 20.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: 21.13 mmol/L (95% CI 23.63 to 1.37), 20.45 mmol/L (95% CI 24.98 to 4.08), and 1.7% (95% CI 222.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo. CONCLUSIONSThis exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, doserelated reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

“…weight, insulin dose, and the incidence of hypoglycemia with canagliflozin treatment are consistent with the effects reported with other SGLT2 inhibitors added on to insulin therapy in patients with type 1 diabetes (17,18). Dose-related reductions in HbA 1c were seen with canagliflozin across phase 3 studies in patients with type 2 diabetes (10), but no dose response was observed in the current study.…”

“…Several small pilot studies with SGLT2 inhibitors, ranging from 2 to 8 weeks, have been performed in patients with type 1 diabetes (17)(18)(19). These studies have generally shown that treatment with SGLT2 inhibitors provides improved glucose control and reductions in the insulin dose without increasing hypoglycemic events.…”

SGLT2 inhibition and ketoacidosis – should we be concerned?

“…13 From the limited available data, the risk appears to be firstly of euDKA in type 1 diabetes and in the context of pancreatic (β-cell) failure. SGLT2 inhibitors were shown to have beneficial effects on glucose profiles with lower daily insulin doses in type 1 diabetes from short term studies 9,14 ; nevertheless, worries regarding ketosis were noted. 15 Recognised precipitating factors for ketoacidosis were noted in the two patients with type 2 diabetes who developed ketoacidosis: poor nutrition and postoperative stress.…”

Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus

“…30 This new class of drugs has already been shown to reduce glycemic levels in animals and humans with type 1 DM (T1DM), in addition to allowing a reduction in insulin dosage. [31][32][33] These drugs could, thus, be used as an adjuvant therapy in the treatment of DM1, with low risk of hypoglycemia and without weight gain. However, this is not yet an approved therapy for T1DM, and further studies are needed to assess the safety of SGLTi-2 in this group of patients.…”