Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes

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).

Figures

Fig. 1

Baseline (pretreatment) relationship between insulin secretion and plasma glucose concentrations (Studies 1 to 3). Black circles, untreated (Study 1; n = 193); white circles, metformin + sulfonylurea (Study 2; n = 163); white diamonds, metformin + sulfonylurea (Study 3; n = 234). Values are mean ± SEM and include all patients studied at the baseline visit in each study

Fig. 2

(a–c) Plasma glucose, (d–f) C-peptide and (g–i) insulin concentrations, and (j–l) ISR per plasma glucose values in Study 1. Black circles, baseline; white circles, Week 26. Values are mean ± SEM for placebo (a, d, g, j), canagliflozin 100 mg (b, e, h, k) and canagliflozin 300 mg (c, f, i, l)

Fig. 3

(a–c) Plasma glucose, (d–f) C-peptide and (g–i) insulin concentrations, and (j–l) ISR per plasma glucose values in Study 2. Black circles, baseline; white circles, Week 26. Values are mean ± SEM for placebo (a, d, g, j), canagliflozin 100 mg (b, e, h, k) and canagliflozin 300 mg (c, f, i, l)

Fig. 4

(a, b) Plasma glucose, (c, d) C-peptide and (e, f) insulin concentrations, and (g, h) ISR per plasma glucose in Study 3. Black circles, baseline; white circles, Week 52. Values are mean ± SEM for sitagliptin 100 mg (a, c, e, g) and canagliflozin 300 mg (b, d, f, h)