The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species

Abstract

Glucagon-like peptide (GLP)-1 analogs have been implicated as a risk factor for pancreatitis in humans. We investigated whether liraglutide, the once-daily human GLP-1 analog, induces pancreatitis in rats, mice, and monkeys. Pancreata from mice, rats, and nonhuman primates were examined macro- and microscopically. Evaluation of preneoplastic proliferative lesions in the pancreata from nonhuman primates was performed. After 2 years of treatment, 3 of 79 male mice in the control group and 2, 1, 1, and 1 mice in the different liraglutide groups (of 67-79 mice per group) had pancreatitis based on microscopic criteria. For females, the numbers were 0 of 79 mice in the control group and 3 mice in all the liraglutide groups (of 66-76 mice per group). Pancreatitis was not the cause of death in any animals. There were no cases of pancreatitis, macroscopically or microscopically, in 400 rats. Neither pancreatitis nor preneoplastic proliferative lesions was found in monkeys dosed for 87 weeks, with plasma liraglutide exposure 60-fold higher than that observed in humans at the maximal clinical dose. In conclusion, liraglutide did not induce pancreatitis in mice, rats, or monkeys when dosed for up to 2 years and at exposure levels up to 60 times higher than in humans.

FIG. 1.

Photomicrographs of exocrine pancreata sections obtained from male control mice (upper panel) and male high-dose liraglutide mice (lower panel; 3 mg/kg/day dose), from the 2-year carcinogenicity study in mice. The left column shows pancreata with no abnormal findings. The middle column shows pancreata with minimal inflammatory cell infiltration. The right column shows pancreata with acute pancreatitis. Magnification is ×10 objective.