Combined antidiabetic benefits of exenatide and dapagliflozin in diabetic mice

Abstract

The combined glucose-lowering effect of exenatide and dapagliflozin has not yet been studied. We investigated this combination (single-dose or 4-week dosing) in diabetic ob/ob mice. Vehicle-corrected basal glucose showed greater reduction 1 h following exenatide + dapagliflozin than with exenatide or dapagliflozin alone, and stayed significantly lower for all groups versus vehicle over 3 h. During an oral glucose tolerance test, glucose excursion (30 min post-dose) was significantly lower for exenatide + dapagliflozin versus exenatide or dapagliflozin, or vehicle. Exenatide + dapagliflozin and exenatide, but not dapagliflozin alone, reduced glucose excretion over 24 h versus vehicle. After dosing for 4 weeks, exenatide, dapagliflozin and exenatide + dapagliflozin similarly decreased haemoglobin A1c (HbA1c). Body weight was reduced only with exenatide or exenatide + dapagliflozin. The glomerular filtration rate was similar with exenatide, dapagliflozin and vehicle, and increased with exenatide + dapagliflozin. Optimized combinatorial dosing of these antidiabetic agents may provide additive glucose lowering in type 2 diabetes mellitus.

Keywords: combination; dapagliflozin; diabetes; exenatide; glucagon-like peptide-1; mouse.

© 2013 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Change in plasma glucose (A) and glucose excursion during an oral glucose tolerance test (B), and total 24-h urine glucose (C) and total urine volume (D) in diabetic ob/ob mice after single-dose administration of exenatide (0.03 mg/kg), dapagliflozin (1 mg/kg), exenatide + dapagliflozin combination or combined respective vehicles (vehicle). Data are presented as mean ± s.e.m. *p < 0.05 versus vehicle control, †p < 0.05 versus exenatide, ‡p < 0.05 versus exenatide + dapagliflozin.

Figure 2

Effects of 4-week administration of exenatide (0.03 mg/kg/day), dapagliflozin (1 mg/kg/day), exenatide + dapagliflozin combination or combined respective vehicles (vehicle) on haemoglobin A1c (HbA1c) change from baseline (A), body weight (B) and food intake (C) change from baseline, glomerular filtration rate (GFR) (D), plasma creatinine (E) and total urine volume (F) in diabetic ob/ob mice. Mice were placed in metabolic cages 1 h after the final dapagliflozin dose at week 4, and samples for measurement were then collected over 17 h. Data are presented as mean ± s.e.m. *p < 0.05 versus vehicle control, †p < 0.05 versus exenatide, ‡p < 0.05 versus exenatide + dapagliflozin.