title: Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans?
abstract: Sodium glucose cotransporter 2 (SGLT2) inhibition is a novel and promising treatment for diabetes under late-stage clinical development. It generally is accepted that SGLT2 mediates 90% of renal glucose reabsorption. However, SGLT2 inhibitors in clinical development inhibit only 30-50% of the filtered glucose load. Why are they unable to inhibit 90% of glucose reabsorption in humans? We will try to provide an explanation to this puzzle in this perspective analysis of the unique pharmacokinetic and pharmacodynamic profiles of SGLT2 inhibitors in clinical trials and examine possible mechanisms and molecular properties that may be responsible.
authors.affiliation: Medicinal Chemistry, Amgen, Inc, South San Francisco, California, USA. jiwenl@amgen.com
authors.forename: Jiwen Jim
authors.initials: JJ
authors.lastname: Liu
authors.forename: TaeWeon
authors.initials: T
authors.lastname: Lee
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds; D001786:Blood Glucose / Q000378:metabolism; D005947:Glucose / Q000037:antagonists & inhibitors*; D005960:Glucosides / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008954:Models, Biological; D010539:Permeability; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D005947:Glucose