Abstract
AIMS/HYPOTHESIS: In rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes. METHODS: Data from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin + sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin + sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide. RESULTS: In Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min(-1) m(-2) (mmol/l)(-1) with canagliflozin 100 and 300 mg, respectively (p < 0.002, Study 1), and 16 (8) and 10 (9) pmol min(-1) m(-2) (mmol/l)(-1) (p < 0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min(-1) m(-2), respectively; p < 0.05 for both]. CONCLUSIONS/INTERPRETATION: Treatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01081834 (Study 1); NCT01106625 (Study 2); NCT01137812 (Study 3).