title: Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects.
abstract: BACKGROUND
  Lixisenatide is a once-daily, prandial, short-acting glucagon-like peptide-1 receptor agonist. Its main antidiabetic effect is to delay gastric emptying to control postprandial plasma glucose excursions. The dose-response relationship of the integrated insulinotropic and gastrostatic response to lixisenatide in healthy volunteers after a standardized liquid meal was investigated.
  
  
  METHODS
  Twenty healthy subjects received acetaminophen 1000 mg with a standardized liquid meal 60 min after a single subcutaneous injection of placebo or lixisenatide 2.5, 5, 10 or 20 µg in randomized order separated by a 2- to 7-day washout. Acetaminophen pharmacokinetics served as a surrogate to assess rate of gastric emptying. Postprandial plasma glucose, insulin, C-peptide and glucagon were assessed for 5 h after the meal test, and lixisenatide pharmacokinetics were determined for 6 h.
  
  
  RESULTS
  After lixisenatide administration and prior to the standardized meal, insulin and C-peptide transiently increased, while fasting plasma glucose decreased in a dose-dependent manner. After the meal, postprandial plasma glucose, insulin and C-peptide were dose proportionally reduced with lixisenatide versus placebo for up to 6 h. Compared with placebo, glucagon levels were transiently lower after any lixisenatide dose, with more sustained reductions after the meal and no apparent dose-related trends. Acetaminophen absorption was significantly reduced and delayed compared with placebo for lixisenatide doses ≥5 µg and demonstrated dose-dependent slowing of gastric emptying. Lixisenatide displayed near dose-proportional exposure, with gastrointestinal events increasing with dose.
  
  
  CONCLUSIONS
  Lixisenatide reduced fasting plasma glucose via stimulation of glucose-dependent insulin release and controlled postprandial plasma glucose by delaying gastric emptying, demonstrating it to be a valuable option for overall glycaemic control.
authors.affiliation: Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
authors.forename: Reinhard H A
authors.initials: RH
authors.lastname: Becker
authors.affiliation: Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Stechl
authors.affiliation: Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Steinstraesser
authors.affiliation: PAREXEL International GmbH, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Golor
authors.affiliation: Sanofi-Aventis R&D, Montpellier, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Pellissier
mesh_terms: D000082:Acetaminophen / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000493:pharmacokinetics; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects*; D005765:Gastrointestinal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000819:agonists* / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019518:Postprandial Period; D055815:Young Adult; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D001786:Blood Glucose; D002096:C-Peptide; D005765:Gastrointestinal Agents; D005934:Glucagon; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor
keywords: gastric emptying; glycaemic control; healthy subjects; lixisenatide; pharmacokinetics; type 2 diabetes mellitus