Genetics of Response to Canagliflozin ( <scp>GRC</scp> ) Study: Rationale, Design, and Pharmacodynamic Responses

ABSTRACT Sodium glucose cotransporter‐2 (SGLT2) inhibitors are a class of antidiabetics with benefits including HbA1c‐lowering, weight loss, cardiovascular and renal protection in addition to adverse effects including genitourinary tract infections, ketoacidosis, and bone loss. Here, we describe the rationale and design of the Genetics of Response to Canagliflozin (GRC) study and report on the pharmacodynamic findings. This study, for which enrollment has been completed, was conducted in healthy Amish individuals with a goal of identifying genetic predictors of variability in safety and efficacy of the SGLT2 inhibitor canagliflozin. Participants took canagliflozin 300 mg/day for 5 days, completed a 24‐h urine collection, and had blood drawn at baseline, Day 3, and Day 6. The primary endpoint is glucosuria and the secondary endpoints assess additional biomarkers for safety and efficacy related to bone, cardiovascular disease, and ketosis. 402 participants completed the study. We identified significant variability in the degree of canagliflozin‐induced glucosuria with a heritability of 34% ( p = 8.69e−03). Canagliflozin induced significant increases in serum phosphorous (Day 3: +5.0%, p = 5.83e−21) and fibroblast growth factor‐23 (Day 3: +20.2%, p = 1.58e−18), decrease in 1,25‐dihydroxyvitamin D (Day 3: −25.0%, p = 5.71e−54), and increase in parathyroid hormone: (Day 3: +20.8%, p = 1.98e−33). Canagliflozin also significantly decreased serum uric acid (Day 6: −33.2%, p = 1.01e−65) and increased beta‐hydroxybutyrate (Day 3: +71.9%, p = 8.11e−28). The most significant baseline characteristic associated with glucosuria was eGFR ( p = 8.10e−10). This study will provide the opportunity to identify genetic and other 'omic predictors of safety and efficacy biomarkers for SGLT2 inhibitor response that could help guide diabetes treatment in the future.