title: Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations.
abstract: BACKGROUND
  Inhibitors of sodium-glucose cotransporters type 2 (SGLT2), which increase urinary glucose excretion independently of insulin, are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  An extensive literature search was performed to analyze the pharmacokinetic characteristics, toxicological issues and safety concerns of SGLT2 inhibitors in humans. This review focuses on three compounds (dapagliflozin, canagliflozin, empagliflozin) with results obtained in healthy volunteers (including drug-drug interactions), patients with T2DM (single dose and multiple doses) and special populations (those with renal or hepatic impairment).
  
  
  CONCLUSIONS
  The three pharmacological agents share an excellent oral bioavailability, long half-life allowing once-daily administration, low accumulation index and renal clearance, the absence of active metabolites and a limited propensity to drug-drug interactions. No clinically relevant changes in pharmacokinetic parameters were observed in T2DM patients or in patients with mild/moderate renal or hepatic impairment. Adverse events are a slightly increased incidence of mycotic genital and rare benign urinary infections. SGLT2 inhibitors have the potential to reduce several cardiovascular risk factors, and cardiovascular outcome trials are currently ongoing. The best positioning of SGLT2 inhibitors in the armamentarium for treating T2DM is still a matter of debate.
authors.affiliation: University of Liège, Center for Interdisciplinary Research on Medicines (CIRM), CHU Sart Tilman, Division of Diabetes, Nutrition and Metabolic Disorders, Division of Clinical Pharmacology, Department of Medicine , B-4000 Liege 1 , Belgium +32 4 3667238 ; +32 4 3667068 ; andre.scheen@chu.ulg.ac.be.
authors.forename: André J
authors.initials: AJ
authors.lastname: Scheen
mesh_terms: D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications; D004347:Drug Interactions; D005960:Glucosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D048550:Hepatic Insufficiency / Q000150:complications; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000150:complications; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D049990:Membrane Transport Modulators; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin; C529054:dapagliflozin; C570240:empagliflozin