title: LX4211 therapy reduces postprandial glucose levels in patients with type 2 diabetes mellitus and renal impairment despite low urinary glucose excretion.
abstract: OBJECTIVE
  We sought to assess the efficacy and safety profile of LX4211, a dual inhibitor of sodium-glucose cotransporter1 (SGLT1) and SGLT2, in patients with type 2 diabetes and renal impairment.
  
  
  METHODS
  Thirty-one patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) were randomly assigned to receive 400 mg of LX4211 or placebo for 7 days. The primary end point was the change from baseline to day 7 in postprandial glucose (PPG) levels. Other end points included changes in fasting plasma glucose levels, glucagon-like peptide 1 levels, urinary glucose excretion (UGE), and blood pressure.
  
  
  RESULTS
  LX4211 therapy significantly reduced PPG levels relative to placebo in the total population and in patients with an eGFR <45 mL/min/1.73 m(2), with a placebo-adjusted decrease in incremental AUCpredose-4 of 73.5 mg·h/dL (P = 0.009) and 137.2 mg·h/dL (P = 0.001) for the total population and the eGFR <45 mL/min/1.73 m(2) subgroup, respectively. There was a significant reduction in fasting plasma glucose levels relative to baseline of -27.1 mg/dL (P < 0.001). Total and active glucagon-like peptide 1 levels were significantly elevated relative to placebo with LX4211 dosing, and UGE was significantly elevated with placebo-subtracted measures of 38.7, 53.5, and 20.4 g/24 h (P ≤ 0.007 for all 3) in the total population, eGFR 45 to 59 mL/min/1.73 m(2), and eGFR <45 mL/min/1.73 m(2) subgroups, respectively.
  
  
  CONCLUSIONS
  The PPG effects were maintained in patients with an eGFR <45 mL/min/1.73 m(2) despite the expected reduction in UGE, suggesting that dual SGLT1 and SGLT2 inhibition with LX4211 could prove useful for the treatment of patients with type 2 diabetes and renal impairment. ClinicalTrials.gov identifier: NCT01555008.
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas. Electronic address: brian@lexpharma.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapuerta
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas.
authors.forename: Paul
authors.initials: P
authors.lastname: Strumph
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas.
authors.forename: Phillip
authors.initials: P
authors.lastname: Banks
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas.
authors.forename: Alan
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas.
authors.forename: Ike
authors.initials: I
authors.lastname: Ogbaa
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas.
authors.forename: Arthur
authors.initials: A
authors.lastname: Sands
authors.affiliation: Lexicon Pharmaceuticals, Inc, The Woodlands, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Powell
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006027:Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D006029:Glycosuria / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period / Q000187:drug effects; D051437:Renal Insufficiency / Q000097:blood / Q000150:complications / Q000503:physiopathology
chemical_list: D001786:Blood Glucose; D006027:Glycosides; D007004:Hypoglycemic Agents; 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: LX4211; SGLT1; SGLT2; fasting plasma glucose; pharmacokinetics; postprandial glucose; renal impairment; urinary glucose excretion