Effect of canagliflozin treatment on β-cell responsiveness in insulin-dysregulated horses: a 4-week, multi-arm, double-blind, randomized clinical trial

Background: The sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin (CAN) decreases hyperinsulinemia in insulin-dysregulated (ID) horses, but its effects on pancreatic β-cell responsiveness to glucose are unknown. Hypothesis/Objectives: Compare the effects of 2 CAN dosages (0.6 and 1.2 mg/kg) with placebo (PBO) on β-cell responsiveness to IV glucose in ID horses using a graded glucose infusion (GGI) test. Animals: Forty-two privately-owned ID horses. Methods: Randomized, multicenter, double-blind, parallel-group, multi-arm, PBO-controlled study. Horses underwent GGI testing before and after 4 weeks of treatment with PO CAN (0.6 or 1.2 mg/kg) or PBO. Indices of β-cell responsiveness included the slope of insulin vs glucose relationship (ΔI vs ΔG) and the ratio of the incremental areas under the curve for insulin and glucose (iAUCINS/iAUCGLU). Results: Least squares (LS) means ± SEM ΔI vs ΔG values were lower with CAN (0.6 and 1.2 mg/kg) than with PBO (P ≤ .001; 22.0 ± 3.5 and 21.1 ± 3.2 mIU/mmol vs 38.4 ± 3.3 mIU/mmol) with no difference between CAN dosages (P = .96). Geometric LS mean (95% CI) iAUCINS/iAUCGLU values were lower with CAN (0.6 and 1.2 mg/kg) compared with PBO (P ≤ .001; 19.3 [16.5-22.5] and 16.4 [13.9-19.3] mIU/mmol vs 33.1 [28.4-38.7] mIU/mmol). Conclusions and clinical importance: Canagliflozin decreased β-cell responsiveness to IV glucose in ID horses, representing a key mechanism underlying the hyperinsulinemia-decreasing effect of SGLT2 treatment in horses.