Pharmacogenetics of SGLT2 Inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker

Background SGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes – including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Methods Canagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses – including drug-induced increases in urinary excretion of glucose, sodium, and uric acid. Results This pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (−4.1 mg/dL; p=6×10−5), serum creatinine (+0.05 mg/dL; p=8×10−4), and serum uric acid (−0.90 mg/dL; p=5×10−10). The effects of sex on glucosuria depended upon how data were normalized. Whereas males’ responses were ∼60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m2. Conclusions Normalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study ([NCT02891954][1]) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function. Registration NCT02462421 ([clinicaltrials.gov][2]) Funding Research grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488. ### Competing Interest Statement SIT serves as a consultant for Ionis Pharmaceuticals and, as an inventor on the patent, receives a share of royalties from NIDDK for metreleptin as a treatment for generalized lipodystrophy. ARS is an employee of Regeneron Genetics Center. BDM and MEM receive grant support from Regeneron Genetics Center. BDM, MEM, EAS, and HBW have received partial salary support from funds provided by RGC. ALB, ZSY, and HRC declare no competing interests. ### Clinical Trial NCT02462421 ### Funding Statement Research grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of University of Maryland Baltimore gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data can be shared with qualified academic researcher under the terms of a data transfer agreement to assure protection of privacy of research participants. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02891954&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F13%2F2023.03.07.23286875.atom [2]: https://clinicaltrials.gov