Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study
Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study
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DOI：
10.1172/jci.insight.99123
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发表时间：
2018-04-19
期刊：
影响因子：
8
通讯作者：
Taylor, Simeon I.
中科院分区：
文献类型：
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作者：
Blau, Jenny E.;Bauman, Viviana;Taylor, Simeon I.
背景钠-葡萄糖协同转运蛋白-2（SGLT-2）抑制剂是最近批准的2型糖尿病药物，可同时提供血糖疗效和降低心血管风险。已经确定了一些安全性问题，包括治疗后出现的骨折。为了了解总体临床特征，这些安全性问题必须与有吸引力的疗效特征相平衡。我们的研究旨在探讨介导治疗后出现的骨健康不良反应的病理生理机制。我们在接受卡格列净（300 mg/d）或安慰剂治疗5天的住院健康成人（n = 25）中进行了一项单盲随机交叉研究。主要终点是药物诱导的血浆完整成纤维细胞生长因子23（FGF 23）免疫活性AUC在24和72小时之间的变化。卡格列净给药增加了血清磷（+16%）、血浆FGF 23（+20%）和血浆甲状旁腺激素（PTH）（+25%）减去安慰剂的平均水平，同时降低了1，25-二羟维生素D的水平（-10%）。这些药效学反应的幅度存在显著的个体间差异。血浆FGF 23升高与血清磷升高相关，血浆1，25-二羟维生素D降低与血浆FGF 23升高相关。卡格列净诱导血清磷迅速增加，从而引发FGF 23、1，25-二羟基维生素D和PTH的下游变化，可能对骨骼健康产生不良影响。这些药效学数据为未来的研究提供了基础，以阐明对骨骼健康不良反应的病理生理学机制，目的是制定治疗策略，以减轻药物相关的骨折风险。
BACKGROUND. Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health.METHODS. We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours.RESULTS. Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (-10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23.CONCLUSIONS. Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk.