Canagliflozin, a Sodium Glucose co-transporter 2 (SGLT2) inhibitor, improves indices of β-cell function in patients with type 2 diabetes on metformin plus sulphonylurea

Question: Progressive loss of β-cell function (βCF) is thought to underlie the pathophysiology of type 2 diabetes mellitus (T2DM). Canagliflozin (CANA), an inhibitor of SGLT2, is in development for the treatment of T2DM. In hyperglycaemic, partially pancreatectomised rats, βCF can be restored when normoglycaemia is achieved with SGLT2 inhibitor treatment. In a Phase 3 study, 26 weeks of CANA monotherapy treatment improved glycaemic control and indices of βCF in patients with T2DM inadequately controlled with diet and exercise. To further assess the effects of CANA on βCF, indices of βCF were evaluated in a Phase 3 study of patients with T2DM inadequately controlled with metformin (MET) + sulphonylurea (SU).

Methodology: This 26-week, randomised, double-blind, placebo (PBO)-controlled study evaluated CANA 100 and 300 mg compared with PBO as add-on therapy to MET + SU in patients with T2DM (N = 469; mean baseline characteristics: age = 57 years; HbA_1c= 8.1%; BMI = 33.0 kg/m²; duration of T2DM = 9.6 years). A subset of patients (n = 168) were given a meal tolerance test at baseline and Week 26 and plasma glucose (G) and serum C-peptide (C) were measured at 7 time points over 3 hours. βCF was assessed using the AUC_C/AUC_G ratio and a model-based method relating the insulin secretion rate (ISR; obtained by deconvolution of C) to concomitant G using linear regression. β-cell glucose sensitivity as the slope of ISR vs. G relationship and ISR at 9 mM G were calculated. All changes are reported as PBO-subtracted least squares (LS) mean changes using an ANCOVA model.

Results: At Week 26, CANA 100 and 300 mg significantly reduced HbA_1c from baseline compared with PBO (ΔHbA_1c=-0.71% and -0.92%, respectively; P < 0.001) and were generally well tolerated. The ISR vs. G relationship was unchanged with PBO and was shifted upwards (indicating increased ISR at each PG concentration) with both CANA doses. Mean values of all calculated indices of βCF increased with both CANA doses versus PBO, although some of the changes did not reach statistical significance. Mean AUC_C/AUC_G increased by ˜20% from baseline values of 123 – 132 pM/mM (increases of 27.1 (95% CI =-0.2; 54.4; P= 0.051) and 27.4 (-0.7; 55.6; P= 0.056) for CANA 100 and 300 mg). Mean ISR at 9 mM G increased by ˜50 – 60% from baseline values of 114 – 117 pmol/min/m² (increases of 54.6 (7.7; 101.5; P= 0.02) and 69.2 (19.7; 118.9; P= 0.007) for CANA 100 and 300 mg). Mean β-cell glucose sensitivity increased by ˜20% from baseline values of 31 – 34 pmol·min^-1·m^-2·mM^-1 (increases of 7.6 (-2.6; 17.9; P= 0.14) and 6.7 (-4.1; 17.5; P= 0.22) for CANA 100 and 300 mg).

Conclusions: In T2DM patients (mean T2DM duration of 9.6 years) on background MET + SU, CANA 100 and 300 mg improved glycaemic control and measures of βCF compared with PBO after 26 weeks of treatment.