title: Safety, pharmacokinetic, and pharmacodynamic profiles of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose co-transporter 2, in patients with type 2 diabetes mellitus.
abstract: BACKGROUND
  The sodium-dependent glucose co-transporter 2 (SGLT2) is a high-capacity, low-affinity transport system primarily expressed in the renal proximal tubules, where it plays an important role in the regulation of glucose levels. Inhibition of SGLT2 represents an innovative approach for plasma glucose control in type 2 diabetes mellitus (T2DM) by blocking glucose reabsorption and enhancing glucose loss in the urine.
  
  
  METHODS
  This Phase 2, randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of the novel oral SGLT2 inhibitor ipragliflozin (ASP1941) in T2DM patients. Sixty-one patients were randomized to placebo or ipragliflozin once daily at doses of 50, 100, 200, or 300 mg for 28 days. Patients were admitted to the clinic during the study and received a weight-maintenance diet.
  
  
  RESULTS
  The incidence of treatment-emergent adverse events was similar for placebo and ipragliflozin groups. There were no deaths, and no patients discontinued ipragliflozin because of adverse events. Ipragliflozin was absorbed rapidly, taking approximately 1 h to reach the maximum concentration. The area under the concentration-time curve and maximum ipragliflozin concentration at steady state displayed dose linearity. All ipragliflozin doses significantly reduced glycosylated hemoglobin, fasting plasma glucose, and mean amplitude of glucose excursions compared with placebo. Significant dose-dependent increases in urinary glucose excretion were observed in all ipragliflozin groups. Mean weight decreased in the placebo and ipragliflozin groups, with greater reductions occurring in ipragliflozin-treated patients.
  
  
  CONCLUSIONS
  Ipragliflozin was generally safe, well tolerated, and effective at blocking renal glucose reabsorption and decreasing plasma glucose levels in T2DM patients.
authors.affiliation: Cetero Research, 5107 Medical Drive, San Antonio, TX 78229, USA. slschwartz@dgdclinic.com
authors.forename: Sherwyn L
authors.initials: SL
authors.lastname: Schwartz
authors.forename: Bola
authors.initials: B
authors.lastname: Akinlade
authors.forename: Sally
authors.initials: S
authors.lastname: Klasen
authors.forename: Donna
authors.initials: D
authors.lastname: Kowalski
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.forename: Wim
authors.initials: W
authors.lastname: Wilpshaar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D019270:Fructosamine / Q000097:blood; D005960:Glucosides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D019270:Fructosamine; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C572941:ipragliflozin