title: Effects of the GLP-1 Receptor Agonist Dulaglutide on the Structure of the Exocrine Pancreas of Cynomolgus Monkeys.
abstract: Clinical and nonclinical studies have implicated glucagon-like peptide-1 (GLP-1) receptor agonist therapy as a risk factor for acute pancreatitis in patients with type 2 diabetes. Therefore, it is critical to understand the effect that dulaglutide, an approved GLP-1 receptor agonist, has on the exocrine pancreas. Dulaglutide 8.15 mg/kg (approximately 500 times the maximum recommended human dose based on plasma exposure) was administered twice weekly for 12 months to cynomolgus monkeys. Serum amylase and lipase activities were measured and 6 sections of each pancreas were examined microscopically. Ductal epithelial cell proliferation was estimated using Ki67 labeling. Dulaglutide administration did not alter serum amylase or lipase activities measured at the end of treatment compared to control values. An extensive histologic evaluation of the pancreas revealed no changes in the acinar or endocrine portions and no evidence of pancreatitis, necrosis, or pancreatic intraepithelial neoplasia. An increase in goblet cells noted in 4 of the 19 treated monkeys was considered an effect of dulaglutide but was not associated with dilation, blockage, or accumulation of mucin in the pancreatic duct. There was no difference in cell proliferation in ductal epithelium between control and dulaglutide-treated monkeys. These data reveal that chronic dosing of nondiabetic primates with dulaglutide does not induce inflammatory or preneoplastic changes in exocrine pancreas.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA jvahle@lilly.com.
authors.forename: John L
authors.initials: JL
authors.lastname: Vahle
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Byrd
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Blackbourne
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Martin
authors.affiliation: Covance Laboratories, Madison, Wisconsin, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Sorden
authors.affiliation: Covance Laboratories, Madison, Wisconsin, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryan
authors.affiliation: Covance Laboratories, Madison, Wisconsin, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pienkowski
authors.affiliation: The Ohio State University, Columbus, Ohio, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.affiliation: Purdue University, West Lafayette, Indiana, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Snyder
authors.affiliation: Technical University of Munich, Munich, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
mesh_terms: D000818:Animals; D004763:Glucagon-Like Peptides / Q000031:analogs & derivatives* / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007141:Immunoglobulin Fc Fragments / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000633:toxicity*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; C555680:dulaglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: dulaglutide; monkey; pancreatitis