Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study
Jenny E. Blau, … , Kristina I. Rother, Simeon I. Taylor
Jenny E. Blau, … , Kristina I. Rother, Simeon I. Taylor
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e99123. https://doi.org/10.1172/jci.insight.99123.
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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 2

Canaglifozin-induced changes in urinary excretion of glucose, sodium, and phosphate.

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Canaglifozin-induced changes in urinary excretion of glucose, sodium, an...
Research subjects (n = 25) received canaglifozin (Cana) (300 mg/d) for 5 days starting at 0 hours. Urinary excretion of glucose (g/d), sodium (mmol/d), creatinine (g/d), and phosphate (g/d) were collected over 24-hour periods. Ratios of glucose (g)/creatinine (g) excretion (A) and sodium (mmol)/creatinine (g) excretion (B) were plotted as means ± SEM at time points corresponding to the ends of the collection periods. (C) Drug-induced increase in urinary sodium/creatinine ratio as a function of baseline urinary sodium excretion. (D) Percent urinary phosphate excretion on the left axis and % urinary phosphorus absorption on the right axis. Note that the sum of excretion and absorption equals 100% at all time points. Urinary excretion (left axis) is plotted with values increasing, whereas transtubular reabsorption of phosphate (TRP; right axis) is plotted with values decreasing. Daily timed urine specimens were collected at 0, 2, 4, and 12 hours. Aliquots (10 ml) were analyzed to generate data for D, and the remainder of the urine specimen was added to the 24-hour urine collection. (E) Twenty-four–hour urinary calcium excretion (mmol/24 hr)/creatinine (g) excretion as a function of the day on which the urine was collected. In B, D, and E, *P < 0.0001 and ǂP < 0.05 by 2-tailed t test, respectively. Data for placebo and canagliflozin are represented in blue and red, respectively.