title: Effects of LX4211, a dual sodium-dependent glucose cotransporters 1 and 2 inhibitor, on postprandial glucose, insulin, glucagon-like peptide 1, and peptide tyrosine tyrosine in a dose-timing study in healthy subjects.
abstract: BACKGROUND
  LX4211 is a first-in-class dual inhibitor of sodium-dependent glucose cotransporters 1 and 2 (SGLT1 and SGLT2). SGLT1 is the primary transporter for glucose absorption from the gastrointestinal tract, and SGLT2 is the primary transporter for glucose reabsorption in the kidney. SGLT1 inhibition reduces postprandial glucose (PPG) levels and increases the release of gastrointestinal peptides such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), whereas SGLT2 inhibition results in increased urinary glucose excretion (UGE).
  
  
  OBJECTIVE
  This study evaluated how timing of dose relative to meals changes the pharmacodynamic (PD) effects of LX4211 treatment, including effects on UGE, fasting plasma glucose, PPG, insulin, total and active GLP-1, and PYY. The safety and tolerability of LX4211 in healthy subjects were also assessed.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled, multiple-dose study to determine the PD effects of LX4211 dose timing relative to meals in 12 healthy subjects. Blood and urine were collected for the analysis of PD variables.
  
  
  RESULTS
  Twelve healthy subjects 30 to 51 years of age were enrolled and treated. Treatment with LX4211 resulted in significant elevation of total and active GLP-1, and PYY while significantly decreasing PPG levels relative to placebo, likely by reducing SGLT1-mediated intestinal glucose absorption. Comparisons performed among the dosing schedules indicated that dosing immediately before breakfast maximized the PD effects of LX4211 on both SGLT1 and SGLT2 inhibition. The comparative results suggested distinct SGLT1 effects on GLP-1, PYY, glucose, and insulin, which were separate from SGLT2-mediated effects, indicating that SGLT1 inhibition with LX4211 may be clinically meaningful. All treatments were well tolerated with no evidence of diarrhea with LX4211 treatment.
  
  
  CONCLUSIONS
  This clinical study indicates that dosing of LX4211 immediately before breakfast maximized the PD effects of both SGLT1 and SGLT 2 inhibition and provided a convenient dosing schedule for future trials. LX4211 was safe and well tolerated and, due to its SGLT1 inhibition, produced strong PPG reductions and low UGE relative to selective SGLT2 inhibitors. LX4211 may provide a promising new therapy for patients with type 2 diabetes mellitus. The potential long-term clinical benefits and safety of LX4211 treatment will need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01334242.
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA. Brian@lexpharma.com
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.forename: Ike
authors.initials: I
authors.lastname: Ogbaa
authors.forename: Kenny
authors.initials: K
authors.lastname: Frazier
authors.forename: Phillip
authors.initials: P
authors.lastname: Banks
authors.forename: Anne
authors.initials: A
authors.lastname: Turnage
authors.forename: Joel
authors.initials: J
authors.lastname: Freiman
authors.forename: Kristi A
authors.initials: KA
authors.lastname: Boehm
authors.forename: Dennis
authors.initials: D
authors.lastname: Ruff
authors.forename: David
authors.initials: D
authors.lastname: Powell
authors.forename: Arthur
authors.initials: A
authors.lastname: Sands
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis*; D004151:Dipeptides / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D006027:Glycosides / Q000008:administration & dosage* / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007328:Insulin / Q000097:blood*; D008297:Male; D062407:Meals; D008875:Middle Aged; D019518:Postprandial Period; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001786:Blood Glucose; D004151:Dipeptides; D006027:Glycosides; D007004:Hypoglycemic Agents; D007328:Insulin; D051269:Sodium-Glucose Transporter 1; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C042696:tyrosyltyrosine; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; D052216:Glucagon-Like Peptide 1
keywords: Diabetes; GLP-1; PYY; SGLT1; SGLT2; urinary glucose excretion