Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover
Jenny E Blau1,2, Viviana Bauman1, Ellen M Conway1
1Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and.
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.
Insights
Sodium glucose cotransporter-2 (SGLT2) inhibitors like canagliflozin may increase fracture risk. This study shows canagliflozin alters bone-related minerals and hormones, potentially explaining adverse bone effects in patients.
Area of Science:
- Endocrinology
- Pharmacology
- Metabolic Diseases
Background:
- Sodium glucose cotransporter-2 (SGLT2) inhibitors are a new class of diabetes drugs with proven glycemic and cardiovascular benefits.
- However, safety concerns, including bone fractures, necessitate understanding their effects on bone health.
- This study investigates the mechanisms behind SGLT2 inhibitor-induced adverse effects on bone.
Purpose of the Study:
- To investigate the pathophysiological mechanisms underlying treatment-emergent adverse effects on bone health associated with SGLT2 inhibitors.
- Specifically, to examine the impact of canagliflozin on key bone metabolism markers.
Main Methods:
- A single-blind randomized crossover study was conducted in 25 healthy adults.
- Participants received either canagliflozin (300 mg/d) or placebo for 5 days.
- The primary endpoint measured changes in plasma fibroblast growth factor 23 (FGF23) levels.
Main Results:
- Canagliflozin significantly increased serum phosphorus (+16%), plasma FGF23 (+20%), and parathyroid hormone (PTH) (+25%) compared to placebo.
- A decrease in 1,25-dihydroxyvitamin D (-10%) was observed.
- Increased FGF23 correlated with increased phosphorus, and decreased vitamin D correlated with increased FGF23.
Conclusions:
- Canagliflozin rapidly alters phosphorus, FGF23, vitamin D, and PTH levels.
- These changes suggest a potential mechanism for SGLT2 inhibitor-associated adverse bone effects and fracture risk.
- Further research is needed to develop strategies to mitigate these risks.
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