Genetics of Response to Canagliflozin

Summary

Five daily doses of canagliflozin (300 mg) will be administered to healthy volunteers. Pharmacodynamic responses to canagliflozin will be assessed both at 2 days and 6 days after administration of the first dose of canagliflozin. A genome-wide association study (GWAS) will be conducted to search for genetic variants that are associated with each of the pharmacodynamic responses to canagliflozin.

Timeline

Start

2016-09

Primary completion

2023-09-25

Completion

2026-12-25

Outcome

Met primary endpoint

paper VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)2D (from -31.3%±4.7% to -9.3%±8.3%; P = .04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; P = .005). PMID 37738423 ↗

Publications

• Background Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015 Jan;3(1):8-10. doi: 10.1016/S2213-8587(14)70227-X. Epub 2014 Dec 16. No abstract available.
• Background Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015 Aug;100(8):2849-52. doi: 10.1210/jc.2015-1884. Epub 2015 Jun 18.
• Background Blau JE, Bauman V, Conway EM, Piaggi P, Walter MF, Wright EC, Bernstein S, Courville AB, Collins MT, Rother KI, Taylor SI. Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study. JCI Insight. 2018 Apr 19;3(8):e99123. doi: 10.1172/jci.insight.99123. eCollection 2018 Apr 19.
• Background Blau JE, Taylor SI. Adverse effects of SGLT2 inhibitors on bone health. Nat Rev Nephrol. 2018 Aug;14(8):473-474. doi: 10.1038/s41581-018-0028-0.
• Background Beitelshees AL, Leslie BR, Taylor SI. Sodium-Glucose Cotransporter 2 Inhibitors: A Case Study in Translational Research. Diabetes. 2019 Jun;68(6):1109-1120. doi: 10.2337/dbi18-0006.
• Results Shahidzadeh Yazdi Z, Streeten EA, Whitlatch HB, Montasser ME, Beitelshees AL, Taylor SI. Vitamin D Deficiency Increases Vulnerability to Canagliflozin-induced Adverse Effects on 1,25-Dihydroxyvitamin D and PTH. J Clin Endocrinol Metab. 2024 Jan 18;109(2):e646-e656. doi: 10.1210/clinem/dgad554.
• Results Shahidzadeh Yazdi Z, Streeten EA, Whitlatch HB, Montasser ME, Beitelshees AL, Taylor SI. Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism. J Clin Endocrinol Metab. 2025 Jan 21;110(2):e443-e455. doi: 10.1210/clinem/dgae156.
• Results Shahidzadeh Yazdi Z, Streeten EA, Whitlatch HB, Bargal SA, Beitelshees AL, Taylor SI. Value of Vitamin D Metabolite Ratios in 3 Patients as Diagnostic Criteria to Assess Vitamin D Status. JCEM Case Rep. 2024 Jun 28;2(7):luae095. doi: 10.1210/jcemcr/luae095. eCollection 2024 Jul.
• Zhang X, Wang Y, Wang H, Zhang X. Trends in Prevalence of Thyroid Dysfunction and its Associations With Mortality Among US Participants, 1988-2012. J Clin Endocrinol Metab. 2024 Jan 18;109(2):e657-e666. doi: 10.1210/clinem/dgad558.
• Taylor SI, Cherng HR, Shahidzadeh Yazdi Z, Montasser ME, Whitlatch HB, Mitchell BD, Shuldiner AR, Streeten EA, Beitelshees AL. Pharmacogenetics of sodium-glucose co-transporter-2 inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker. Diabetes Obes Metab. 2023 Dec;25(12):3512-3520. doi: 10.1111/dom.15246. Epub 2023 Aug 22.

Drugs

Indications