title: The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus.
abstract: BACKGROUND
  Lixisenatide is a once-daily short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) used in the treatment of type 2 diabetes mellitus (T2DM). It is used in combination with oral antidiabetics and/or basal insulin in patients inadequately controlled on these medications and who are undergoing diet and lifestyle modification. GLP-1RAs glucose-dependently increase insulin secretion, decrease glucagon secretion, and slow gastric emptying, thereby improving glycemic control. GLP-1RAs are associated with body weight benefits and low rates of hypoglycemia which are welcome in patients with T2DM.
  
  
  METHODS
  The authors describe the identification of GLP-1RAs as suitable targets for modification with structure-inducing probe technology to improve stability and resistance to proteolytic degradation. Clinical studies have assessed lixisenatide across > 5000 patients as a monotherapy or add-on to a variety of commonly used antidiabetic medications. These studies highlighted the effects of lixisenatide on gastric emptying, explaining its particular improvements in postprandial plasma glucose (PPG) excursions and underscoring its efficacy in combination with insulin glargine. Lixisenatide was well tolerated, with nausea and vomiting being the most frequently reported adverse events.
  
  
  CONCLUSIONS
  The once-daily administration of lixisenatide as well as its substantial sustained effect on gastric emptying and, hence, PPG excursions are all important features compared with the other GLP-1RAs. The combination of two injectables, such as basal insulin to lower fasting plasma glucose and a GLP-1RA that curtails PPG excursions, is clinically valuable and could differentiate lixisenatide from other GLP-1RAs, especially from those continuously acting GLP-1RAs with little effect on gastric emptying and PPG excursions.
authors.affiliation: University of Copenhagen, Gentofte Hospital, Center for Diabetes Research, Department of Medicine , Niels Andersen Vej 65, DK-2900 Hellerup , Denmark +45 3997 3320 ; +45 3977 7661 ; mch@dadlnet.dk.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Christensen
authors.forename: Patrick
authors.initials: P
authors.lastname: Miossec
authors.forename: Bjarne Due
authors.initials: BD
authors.lastname: Larsen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Werner
authors.forename: Filip K
authors.initials: FK
authors.lastname: Knop
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002986:Clinical Trials as Topic; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D011485:Protein Binding; D018027:Receptors, Glucagon / Q000819:agonists*; D016896:Treatment Outcome; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; C000593833:GLP1R protein, human; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor
keywords: development; diabetes; incretin mimic; lixisenatide