title: Effects of Dulaglutide on Thyroid C Cells and Serum Calcitonin in Male Monkeys.
abstract: Glucagon-like peptide-1 (GLP-1) receptor agonists, used for the treatment of type 2 diabetes, have caused hyperplasia/neoplasia of thyroid C cells in rodent carcinogenicity studies. Studies in monkeys have not identified an effect of GLP-1 receptor agonists on thyroid C cells; however, group sizes were small. Dulaglutide is a once-weekly, long-acting human GLP-1 receptor agonist recently approved in the United States and the European Union. The objective of this study was to determine whether dulaglutide altered C-cell mass in monkeys. Male cynomolgus monkeys (20 per group) were sc injected with dulaglutide 8.15 mg/kg (∼500-fold maximum human plasma exposure) or a vehicle control twice weekly for 52 weeks. Basal and calcium gluconate-stimulated serum calcitonin concentrations were obtained at 3, 6, 9, and 12 months. Thyroid glands were weighed, fixed, and sectioned at 500-μm intervals. C-cell volumes were measured using an automated image analysis. C-cell proliferation was estimated using Ki67/calcitonin colabeling and cell counting. Administration of dulaglutide 8.15 mg/kg twice weekly for 52 weeks did not increase serum calcitonin in monkeys or affect thyroid weight, histology, C-cell proliferation, or absolute/relative C-cell volume. This study represents a comprehensive evaluation of the monkey thyroid C cells after dosing with a GLP-1 receptor agonist, with a large group size, and measurement of multiple relevant parameters. The lack of effect of dulaglutide on C cells is consistent with other studies in monkeys using GLP-1 receptor agonists and suggests that nonhuman primates are less sensitive than rodents to the induction of proliferative changes in thyroid C cells by GLP-1 receptor agonists.
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: John L
authors: JL
authors: Vahle
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Richard A
authors: RA
authors: Byrd
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Jamie L
authors: JL
authors: Blackbourne
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Jennifer A
authors: JA
authors: Martin
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Steven D
authors: SD
authors: Sorden
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Thomas
authors: T
authors: Ryan
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Thomas
authors: T
authors: Pienkowski
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: John A
authors: JA
authors: Wijsman
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Holly W
authors: HW
authors: Smith
authors: Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210.
authors: Thomas J
authors: TJ
authors: Rosol
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000097:blood / Q000187:drug effects*; D002125:Calcium Gluconate / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides / Q000031:analogs & derivatives* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018027:Receptors, Glucagon / Q000819:agonists; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; D002116:Calcitonin; D002125:Calcium Gluconate; C555680:dulaglutide