Pharmacogenetics of sodium-glucose co-transporter-2 inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker

To validate pharmacodynamic responses to sodium-glucose co-transporter-2 (SGLT2) inhibitors and test for association with genetic variants in SLC5A4, SLC5A9, and SLC2A9. Canagliflozin (300 mg), a SGLT2 inhibitor, was administered to 30 healthy volunteers. Several endpoints were measured to assess cl...

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Veröffentlicht in:Diabetes, obesity & metabolism obesity & metabolism, 2023-12, Vol.25 (12), p.3512-3520
Hauptverfasser: Taylor, Simeon I, Cherng, Hua-Ren, Shahidzadeh Yazdi, Zhinous, Montasser, May E, Whitlatch, Hilary B, Mitchell, Braxton D, Shuldiner, Alan R, Streeten, Elizabeth A, Beitelshees, Amber L
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container_end_page 3520
container_issue 12
container_start_page 3512
container_title Diabetes, obesity & metabolism
container_volume 25
creator Taylor, Simeon I
Cherng, Hua-Ren
Shahidzadeh Yazdi, Zhinous
Montasser, May E
Whitlatch, Hilary B
Mitchell, Braxton D
Shuldiner, Alan R
Streeten, Elizabeth A
Beitelshees, Amber L
description To validate pharmacodynamic responses to sodium-glucose co-transporter-2 (SGLT2) inhibitors and test for association with genetic variants in SLC5A4, SLC5A9, and SLC2A9. Canagliflozin (300 mg), a SGLT2 inhibitor, 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. 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 ), serum creatinine (+0.05 mg/dL; P = 8 × 10 ) and serum uric acid (-0.90 mg/dL; P = 5 × 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 glomerular filtration rate or age in those healthy individuals without diabetes with an estimated glomerular filtration rate of more than 60 mL/min/1.73m . 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 HbA1c and renal function.
doi_str_mv 10.1111/dom.15246
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Canagliflozin (300 mg), a SGLT2 inhibitor, 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. 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 ), serum creatinine (+0.05 mg/dL; P = 8 × 10 ) and serum uric acid (-0.90 mg/dL; P = 5 × 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 glomerular filtration rate or age in those healthy individuals without diabetes with an estimated glomerular filtration rate of more than 60 mL/min/1.73m . 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 HbA1c and renal function.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>37608471</pmid><doi>10.1111/dom.15246</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-7500-7854</orcidid></addata></record>
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subjects Biomarkers
Blood Glucose
Canagliflozin
Creatinine
Diabetes
Diabetes mellitus
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - genetics
Excretion
Fasting
Female
Genetic diversity
Glomerular Filtration Rate
Glucose
Glucose - pharmacology
Glucose transporter
Glucosides - pharmacology
Glycosuria
Humans
Hypoglycemic Agents - pharmacology
Hypoglycemic Agents - therapeutic use
Male
Males
Pharmacodynamics
Pharmacogenetics
Pharmacogenomics
Pilot Projects
Precision medicine
Renal function
Sodium
Sodium-Glucose Transporter 2 Inhibitors - pharmacology
Sodium-Glucose Transporter 2 Inhibitors - therapeutic use
Symporters - pharmacology
Uric Acid
title Pharmacogenetics of sodium-glucose co-transporter-2 inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker
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