Clinical trial NCT02891954: Genetics of Response to Canagliflozin
Official title: Pharmacogenomics to Predict Responses to SGLT2 Inhibitors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Keywords: Glucosuria
SGLT2 inhibitors
Canagliflozin
FGF23
Parathyroid hormone
1,25-Dihydroxyvitamin D
Glucagon
Ketone bodies
Uric acid
Pharmacogenomics
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2016-09-08
Enrollment: 700
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed description: After obtaining informed consent, healthy Amish research subjects will be screened for eligibility. Immediately after obtaining blood samples for baseline clinical chemistry tests wills, patients will initiate 5 days of canagliflozin (300 mg) treatment. Fasting blood samples will be obtained to assess pharmacodynamic responses at both 48 hours and 120 hours after initiating canagliflozin. The principal pharmacodynamic responses will include 24 hour urinary excretion of glucose, serum chemistries (phosphorus, FGF23, 1,25-dihydroxyvitamin D, parathyroid hormone (PTH), glucagon, beta-hydroxybutyrate, acetoacetate, procollagen type I N-terminal peptide (P1NP), and beta-CTX). Research subjects will undergo genotyping, and a genome-wide association study will be conducted to search for genetic variants that are associated with pharmacodynamic responses to canagliflozin.

Eligibility criteria: Inclusion Criteria:

* Of Amish descent
* Age 18 or older
* BMI: 18-40 kg/m2

Exclusion Criteria:

* Known allergy to canagliflozin
* History of diabetes, random glucose greater than 200 mg/dL, or HbA1c greater than or equal to 6.5%
* Currently taking diuretics, antihypertensive medication uric acid lowering medications, or other medication that the investigator judges will make interpretation of the results difficult
* Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation
* Seizure disorder
* Unwilling to go off of vitamin supplements and over the counter medication (except for acetaminophen) for at least two weeks prior to the first home visit and agree to avoid these medications for the duration of the study.
* Positive urine human chorionic gonadotropin test or known pregnancy within 3 months of the start of the study
* Estimated glomerular filtration rate less than 60 mL/min
* Currently breast feeding or breast feeding within 3 month of the start of the study
* Liver function tests greater than 2 times the upper limit of normal
* Hematocrit less than 35%
* Abnormal thyroid hormone stimulating hormone

Primary outcomes:
measure: Urinary glucose excretion (during the time interval 24-48 hours after first administration of canagliflozin)
timeFrame: 24-48 hours
Secondary outcomes:
measure: Bone-related biomarkers
timeFrame: 48 hrs
measure: Bone-related biomarkers
timeFrame: 120 hrs
measure: Ketosis-related biomarkers
timeFrame: 48 hrs
measure: Ketosis-related biomarkers
timeFrame: 120 hurs
measure: Serum uric acid
timeFrame: 48 hrs
measure: Serum uric acid
timeFrame: 120 hrs
Other outcomes:
Locations:
Study officials:
affiliation: Unversity of Maryland School of Medicine
name: Simeon I Taylor, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.