Efficacy and safety of canagliflozin in insulin dysregulated horses: a 4-week multi-arm, double-blind, randomized, clinical trial

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are promising drugs for treatment of hyperinsulinemia in insulin-dysregulated (ID) horses. HYPOTHESIS/OBJECTIVES: Compare short-term effects of the SGLT2 inhibitor canagliflozin versus placebo on glucose and insulin responses during an oral sugar test (OST) and a forage-based feed challenge test (FCT), and to assess adverse effects. ANIMALS: Forty-two privately owned severely ID horses. METHODS: Multi-center, randomized, double-blind, placebo-controlled, parallel-group study. Horses were allocated (1:1:1) to receive canagliflozin (0.6 or 1.2 mg/kg PO q24h) or placebo. The study included a 5-day baseline evaluation, a 4-week at-home double-blind treatment period, and a 5-day follow-up evaluation. During each clinical visit, an OST (day 3) and FCT (day 4) were performed to characterize glucose and insulin responses. Adverse effects were recorded. Data are presented as geometric least squares mean (95% CI). RESULTS: Peak insulin concentrations (μIU/mL) during the OST and the FCT were lower after treatment with canagliflozin 0.6 and 1.2 mg/kg compared with placebo (P ≤ .01); OST: 122.0 (96.6-154.0) and 108.6 (85.6-137.8) vs 288.7 (227.1-366.9) and FCT: 78.3 (37.6-162.9) and 54.2 (25.7-114.5) vs 140.3 (68.5-287.3). Canagliflozin caused a dose-dependent increase in triglyceride concentrations (P ≤ .01). Post-treatment triglyceride concentrations were 0.5 (0.4-0.8), 1.3 (0.9-2.0), and 2.9 (1.9-4.4) mmol/L for placebo, 0.6 mg/kg, and 1.2 mg/kg groups, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Canagliflozin effectively decreases hyperinsulinemia in ID horses but induces a dose-dependent increase in triglyceride concentrations.