title: The glucagon-like peptide-1-based therapeutics exenatide and saxagliptin did not cause detrimental effects on the pancreas in mice, rats, dogs and monkeys.
abstract: OBJECTIVE
  Recent reports in the literature have suggested that glucagon-like peptide-1 (GLP-1)-based therapies may lead to increased risk of pancreatic pathology leading to chronic pancreatic injury and pancreatic neoplasia. Extensive non-clinical and clinical safety testing was conducted to support the global development of exenatide twice daily, exenatide once weekly and saxagliptin. Our aim was to integrate these non-clinical data obtained with both mechanisms of GLP-1-based drugs to provide complementary data regarding the potential for drug-induced pancreatic safety signals.
  
  
  METHODS
  More than 70 regulated non-clinical toxicology studies in rodents and non-rodents were conducted in accordance with International Conference on Harmonisation and US Food and Drug Administration guidance documents, current industry standards, animal welfare regulations and in compliance with Good Laboratory Practice regulations. Treatment duration was up to 2 years in rodents and up to 12 months in non-rodents using high doses representing large multiples of human exposures (up to 130× for exenatide and 2200× for saxagliptin). Comprehensive pancreas assessments involved more than 2400 pancreata from animals exposed to exenatide and over 1700 pancreata from animals exposed to saxagliptin.
  
  
  RESULTS
  Neither exenatide nor saxagliptin treatment resulted in drug-related microscopic changes indicative of acute or chronic adverse effects (including neoplasia) in the endocrine or exocrine pancreas, at doses far exceeding the maximum human systemic exposures.
  
  
  CONCLUSIONS
  These data substantially add to the weight of evidence supporting the lack of non-clinical drug-induced pancreatic safety signals in animals exposed to GLP-1-based therapies.
authors.affiliation: Nonclinical Drug Safety, Amylin LLC, a Wholly Owned Subsidiary of Bristol-Myers Squibb Company, San Diego, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Roy
authors.forename: K D
authors.initials: KD
authors.lastname: Chadwick
authors.forename: K
authors.initials: K
authors.lastname: Tatarkiewicz
authors.forename: C
authors.initials: C
authors.lastname: LaCerte
authors.forename: A-M
authors.initials: AM
authors.lastname: Bergholm
authors.forename: T
authors.initials: T
authors.lastname: Brodie
authors.forename: R S
authors.initials: RS
authors.lastname: Mangipudy
authors.forename: D
authors.initials: D
authors.lastname: Parkes
authors.forename: M J
authors.initials: MJ
authors.lastname: Graziano
authors.forename: T P
authors.initials: TP
authors.lastname: Reilly
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004151:Dipeptides / Q000494:pharmacology*; D004285:Dogs; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D000882:Haplorhini; D007279:Injections, Subcutaneous; D020714:Maximum Tolerated Dose; D051379:Mice; D009929:Organ Size; D010179:Pancreas / Q000187:drug effects / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D014688:Venoms / Q000494:pharmacology*
chemical_list: D004151:Dipeptides; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; C502994:saxagliptin; D000077270:Exenatide; D000218:Adamantane
keywords: DPP4; GLP-1; exenatide; saxagliptin