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Genetics of Response to Canagliflozin (GRC) Study: Rationale, Design, and Pharmacodynamic Responses
May E Montasser1, Salma A Bargal1, Elizabeth A Streeten1
1Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Clinical and Translational Science
|May 17, 2026
Summary
The Genetics of Response to Canagliflozin study found significant genetic influence on how individuals respond to SGLT2 inhibitors, particularly regarding glucosuria. This research aims to identify genetic predictors for canagliflozin
Area of Science:
- Pharmacogenomics
- Metabolic Diseases
- Genetics of Drug Response
Background:
- Sodium glucose cotransporter-2 (SGLT2) inhibitors are antidiabetics with known benefits and adverse effects.
- Variability exists in patient response to SGLT2 inhibitors, necessitating research into predictive factors.
- Understanding genetic influences can optimize SGLT2 inhibitor therapy for diabetes management.
Purpose of the Study:
- To investigate the rationale and design of the Genetics of Response to Canagliflozin (GRC) study.
- To identify genetic predictors of safety and efficacy variability in response to the SGLT2 inhibitor canagliflozin.
- To report on the pharmacodynamic findings related to canagliflozin treatment in healthy individuals.
Main Methods:
- Conducted the GRC study in healthy Amish individuals, enrolling 402 participants.
- Administered canagliflozin 300 mg/day for 5 days, collecting 24-h urine and blood samples at baseline, Day 3, and Day 6.
- Assessed primary endpoint (glucosuria) and secondary endpoints (bone, cardiovascular, ketosis biomarkers).
Main Results:
- Identified significant heritability (34%) for canagliflozin-induced glucosuria.
- Observed significant changes in serum phosphorous, FGF23, 1,25-dihydroxyvitamin D, parathyroid hormone, uric acid, and beta-hydroxybutyrate.
- Estimated Glomerular Filtration Rate (eGFR) was the strongest baseline predictor of glucosuria.
Conclusions:
- Significant genetic variability influences the response to SGLT2 inhibitors like canagliflozin.
- Pharmacodynamic effects on bone metabolism, ketosis, and uric acid levels were observed.
- This study provides a foundation for identifying genetic and 'omic predictors to guide future diabetes treatment.
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