title: Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents.
abstract: The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected sc twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma area under the curve. Transgenic mice were dosed sc twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at 0.5 mg/kg or greater (P ≤ .01 at 5 mg/kg), and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared with controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an antidrug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice-weekly sc injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Richard A
authors: RA
authors: Byrd
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Steven D
authors: SD
authors: Sorden
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Thomas
authors: T
authors: Ryan
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Thomas
authors: T
authors: Pienkowski
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Richard
authors: R
authors: LaRock
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Ricardo
authors: R
authors: Quander
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: John A
authors: JA
authors: Wijsman
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Holly W
authors: HW
authors: Smith
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Jamie L
authors: JL
authors: Blackbourne
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Thomas J
authors: TJ
authors: Rosol
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Gerald G
authors: GG
authors: Long
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: Jennifer A
authors: JA
authors: Martin
authors: Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.
authors: John L
authors: JL
authors: Vahle
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000097:blood / Q000187:drug effects; D015197:Carcinogenicity Tests; D018278:Carcinoma, Neuroendocrine; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides / Q000031:analogs & derivatives* / Q000633:toxicity; D006965:Hyperplasia; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007141:Immunoglobulin Fc Fragments / Q000633:toxicity*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists; D011993:Recombinant Fusion Proteins / Q000633:toxicity*; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000139:chemically induced* / Q000473:pathology
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; 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; D016283:Proto-Oncogene Proteins p21(ras); C555680:dulaglutide