Why the study?
Because responses to SGLT2 inhibitors vary among individuals, investigations were initiated to identify genetic variants associated with the magnitude of drug responses.
Does canagliflozin 300 mg alter urinary excretion of glucose, sodium, and uric acid in healthy volunteers?
Does canagliflozin 300 mg alter urinary excretion of glucose, sodium, and uric acid in healthy volunteers?
p-value: p=6x10-5
Normalizing glucosuria to creatinine excretion provides a sex-agnostic pharmacodynamic biomarker for SGLT2 inhibitor response, facilitating pooled analyses of males and females.
Creatinine-normalized glucosuria may serve as a sex-agnostic SGLT2i biomarker; leaves open validation for pooled analyses in patient cohorts.
Aim 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=6x10), 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/1.73m 2 . 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 ) 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 ) Funding Research grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.
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Taylor et al. (2023) studied Healthy volunteers (n=30). Canagliflozin vs. Baseline was evaluated on Change in fasting plasma glucose (p=6x10-5).
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