Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study
Jenny E. Blau, Viviana Bauman, Ellen M. Conway, Paolo Piaggi, Mary F. Walter, Elizabeth C. Wright, Shanna Bernstein, Amber B. Courville, Michael T. Collins, Kristina I. Rother, Simeon I. Taylor
Jenny E. Blau, Viviana Bauman, Ellen M. Conway, Paolo Piaggi, Mary F. Walter, Elizabeth C. Wright, Shanna Bernstein, Amber B. Courville, Michael T. Collins, Kristina I. Rother, Simeon I. Taylor
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Clinical Research and Public Health Bone biology Endocrinology

Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study

Abstract

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. TRIAL REGISTRATION. ClinicalTrial.gov (NCT02404870). FUNDING. Supported by the Intramural Program of NIDDK.

Authors

Jenny E. Blau, Viviana Bauman, Ellen M. Conway, Paolo Piaggi, Mary F. Walter, Elizabeth C. Wright, Shanna Bernstein, Amber B. Courville, Michael T. Collins, Kristina I. Rother, Simeon I. Taylor

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Figure 3

Effect of canagliflozin on serum phosphorus and hormones of mineral metabolism.

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Effect of canagliflozin on serum phosphorus and hormones of mineral meta...
Research subjects (n = 25) were treated with canagliflozin or placebo (Figure 2). Serial blood tests were obtained and analyzed for serum phosphorus (A) and plasma hormones (FGF23, 1,25-dihydroxyvitamin D, and PTH in B–D, respectively). Differences were statistically significant (P < 0.05, paired 2-tailed t tests) for phosphorus (4–76 hours), FGF23 (24–60 hours), 1,25-dihydroxyvitamin D (28–100 hours), and PTH (36 and 52–108 hours). Data are graphed as means ± 95% CIs. Two-tailed P value for PTH refers to the rate of change over time. Data for placebo and canagliflozin are represented in blue and red, respectively.