title: Greater dose-ranging effects on A1C levels than on glucosuria with LX4211, a dual inhibitor of SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy.
abstract: OBJECTIVE
  To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor of sodium-glucose cotransporter (SGLT) 1 and SGLT2, in type 2 diabetes.
  
  
  METHODS
  Type 2 diabetic patients inadequately controlled on metformin were randomly assigned to 75 mg once daily, 200 mg once daily, 200 mg twice daily, or 400 mg once daily of LX4211 or placebo. Primary end point was A1C change from baseline to week 12. Secondary end points included changes in blood pressure (BP) and body weight.
  
  
  RESULTS
  Baseline characteristics in 299 patients randomly assigned to LX4211 or placebo in this 12-week dose-ranging study were similar: mean age 55.9 years, A1C 8.1% (65 mmol/mol), BMI 33.1 kg/m(2), and BP 124/79 mmHg. LX4211 significantly reduced A1C to week 12 in a dose-dependent manner by 0.42% (4.6 mmol/mol), 0.52% (5.7 mmol/mol), 0.80% (8.7 mmol/mol), and 0.92% (10.0 mmol/mol), respectively (P < 0.001 each), compared with 0.09% (1.0 mmol/mol) for placebo. Greater A1C reductions were produced by 400 mg once a day than 200 mg once a day LX4211 without higher urinary glucose excretion, suggesting a contribution of SGLT1 inhibition. Significant reductions were seen in body weight (-1.85 kg; P < 0.001) and systolic BP (-5.7 mmHg; P < 0.001), but diastolic BP was unchanged (-1.6; P = 0.164). Adverse events with LX4211 were mild to moderate and similar to placebo, including urinary tract infections and gastrointestinal-related events; genital infections were limited to LX4211 groups (0-5.0%). No hypoglycemia occurred.
  
  
  CONCLUSIONS
  Dual inhibition of SGLT1/SGLT2 with LX4211 produced significant dose-ranging improvements in glucose control without dose-increasing glucosuria and was associated with reductions in weight and systolic BP in metformin-treated patients with type 2 diabetes.
authors.affiliation: Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX juliorosenstock@dallasdiabetes.com.
authors.forename: Julio
authors.initials: J
authors.lastname: Rosenstock
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA.
authors.forename: William T
authors.initials: WT
authors.lastname: Cefalu
authors.affiliation: Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapuerta
authors.affiliation: Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
authors.forename: Ike
authors.initials: I
authors.lastname: Ogbaa
authors.affiliation: Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
authors.forename: Phillip
authors.initials: P
authors.lastname: Banks
authors.affiliation: Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
authors.forename: Arthur
authors.initials: A
authors.lastname: Sands
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006442:Glycated Hemoglobin / Q000187:drug effects; D006027:Glycosides / Q000008:administration & dosage* / Q000009:adverse effects; D006029:Glycosuria / Q000139:chemically induced; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D006027:Glycosides; D007004:Hypoglycemic Agents; D008687:Metformin; D051269:Sodium-Glucose Transporter 1; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol