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 5

Interindividual variation in urinary glucose and sodium excretion and circulating biomarkers of mineral metabolism in response to canagliflozin.

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Interindividual variation in urinary glucose and sodium excretion and ci...
We defined indices of the drug’s effects on serum phosphorus and plasma FGF23 as the mean changes in those parameters on day 2 (24, 26, 28, and 36 hours); plasma 1,25-dihydroxyvitamin D as the mean change on day 3 (48, 52, and 60 hours); and plasma PTH as the mean change on day 5 (96, 98, 100, and 108 hours). (A) Histogram distribution of the ratio of urinary excretions of glucose/creatinine in research subjects treated with canagliflozin (day 1; Figure 2). (B) A similar histogram distribution of the ratio of urinary excretions of sodium/creatinine (day 1; Figure 2). X axes of the histograms (A, B, D–F) depict the ratio of each index during the canagliflozin treatment period divided by the index during the placebo period (i.e., a ratio [canagliflozin/placebo] of ratios [sodium/creatinine or glucose/creatinine]). The x axis for C plots the absolute change in serum phosphorus level (canagliflozin treatment period minus placebo period). The y axes (A–F) depict the number of individuals with the drug responses indicated on the x axes. Bin widths are 6 (A), 0.3 (B), and 0.1 (C, D, F). Data in B include 24 research subjects because of missing data from 1 subject. Data in E include 22 research subjects because of missing data on 3 subjects (see Supplemental Methods). Data in the other 4 panels include all 25 research subjects.