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)₂D) and increasing parathyroid hormone (PTH). Objective This work investigated whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD₃ supplementation is protective. Methods This community-based, outpatient study had a paired design comparing individual participants before and after VitD₃ supplementation. Eleven VitD-deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals were recruited from the Amish population in Lancaster, Pennsylvania. Participants underwent 2 canagliflozin challenge protocols (300 mg daily for 5 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 body mass index for 4-6 weeks) to achieve 25(OH)D of 30 ng/mL or greater. Two coprimary end points were identified: effects of VitD₃ supplementation on canagliflozin-induced changes in 1,25(OH)₂D and PTH. Secondary end points 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 =.0006) and 24,25-dihydroxyvitamin D (24,25(OH)₂D) from 1.0 ± 0.1 to 4.3 ± 0.6 ng/mL (P =.0002). Mean 1,25(OH)₂D and PTH were unchanged. VitD₃ supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)₂D (from −31.3%±4.7% to −9.3%±8.3%; P =.04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; P =.005). Conclusion 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)₂D and PTH. [ABSTRACT FROM AUTHOR]