The human GLP-1 analogs liraglutide and semaglutide: Absence of histopathological effects on the pancreas in nonhuman primates.

Increased pancreasmass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptinor exenatidetherapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreasweight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1(GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreasweight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks’ duration. No treatment-related histopathologicalabnormalities were observed in any of the studies. Quantitative histology of the pancreasfrom the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutidetreatment. Semaglutideshowed no increase in pancreasweight and no treatment-related histopathologicalfindings in the pancreasafter 13 or 52 weeks’ dosing. Overall, results in 138 nonhuman primates showed no histopathologicalchanges in the pancreasassociated with liraglutideor semaglutide, two structurally different GLP-1 receptor agonists.