Genetics of Response to Canagliflozin

Pharmacogenomics to Predict Responses to SGLT2 Inhibitors

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.

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.

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