Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 33 · Cited by 172
Research works printed but not linked: 2
- [27]27. Muskiet MH, van Raalte DH, van Bommel EJ, van Bommel E, Smits MM, Tonneijck L. Understanding EMPA-REG OUT- COME. Lancet Diabetes Endocrinol. 2015;3(12):928-929.
- [29]29. Brenza HL, et al. Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. Proc Natl Acad Sci USA. 1998;95(4):1387-1391.
- Authors
- Blau, J. E., Bauman, V., Conway, E. M., Piaggi, P., Walter, M. F., Wright, E. C., Bernstein, S., Courville, A. B., Collins, M. T., Rother, K. I., & Taylor, S. I.
- Affiliations
- National Institutes of Health (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Nutrition Department, Hatfield Clinical Research Center, and
- University of Maryland, Baltimore (US)
- ORCID
- Venue
- JCI Insight
- Published
- 2018-04-19
- Volume
- 3
- Issue
- 8
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC5931122
- OpenAlex
- W2799518691
- Cited by
- 172
- References
- 33
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 20 · 2023: 26 · 2022: 20 · 2021: 28 · 2020: 20 · 2019: 13 · 2018: 6
- FWCI
- 13.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Disease (N/A)
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- canagliflozin, SGLT2 inhibitors, fibroblast growth factor 23, 1,25-dihydroxyvitamin D, parathyroid hormone, serum phosphorus, bone health, pharmacodynamics, type 2 diabetes, healthy volunteers
- MeSH terms
- Canagliflozin, Sodium-Glucose Transporter 2 Inhibitors, Fibroblast Growth Factor-23, Adult, Diabetes Mellitus, Type 2, Female, Fibroblast Growth Factors, Humans, Male, Middle Aged, Parathyroid Hormone, Phosphorus, Placebos, Vitamin D, Cross-Over Studies, Fractures, Bone, Healthy Volunteers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
