Vitamin D deficiency increases vulnerability to canagliflozin-induced adverse effects on 1,25-dihydroxyvitamin D and PTH

CONTEXT. Canagliflozin has been reported to increase the risk of bone fracture – possibly mediated by decreasing 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and increasing PTH. OBJECTIVE. To investigate whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective. DESIGN. This study had a paired design comparing individual participants before and after VitD3 supplementation. SETTING. Community-based outpatient. PATIENTS. 11 VitD deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals recruited from the Amish population in Lancaster PA. INTERVENTIONS. Participants underwent two canagliflozin challenge protocols (300 mg daily for five days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50,000 IU once or twice a week depending on BMI for 4–6 weeks) to achieve 25(OH)D ≥ 30 ng/mL. MAIN OUTCOME MEASURES. Two co-primary endpoints were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH)(2)D and PTH. Secondary endpoints included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH. RESULTS. VitD3 supplementation increased mean 25(OH)D from 16.5±1.6 to 44.3±5.5 ng/mL (p=0.0006) and 24,25-dihydroxyvitamin D [24,25(OH)(2)D] from 1.0±0.1 to 4.3±0.6 ng/mL (p=0.0002). Mean 1,25(OH)(2)D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)(2)D (from −31.3%±4.7% to −9.3%±8.3%; p=0.04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; p=0.005). CONCLUSIONS. VitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin’s short-term adverse effects on 1,25(OH)(2)D and PTH.