The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF rats: a quantitative and qualitative analysis revealing no evidence of drug-induced pancreatitis

Abstract

A possible association between glucagon-like peptide-1 (GLP-1) analogs and incidences of pancreatitis has been suggested based on clinical studies. In male and female diabetic Zucker diabetic fatty (ZDF) rats, we investigated the effects of continuous administration of liraglutide and exenatide on biochemical [lipase, pancreatic amylase (P-amylase)] and histopathological markers of pancreatitis. Male and female ZDF rats were dosed for 13 wk with liraglutide (0.4 or 1.0 mg·kg(-1)·day(-1) sc once daily) or exenatide (0.25 mg·kg(-1)·day(-1) sc, Alzet osmotic minipumps). P-amylase and lipase plasma activity were measured, and an extended histopathological and stereological (specific cell mass and proliferation rate) evaluation of the exocrine and the endocrine pancreas was performed. Expectedly, liraglutide and exenatide lowered blood glucose and Hb A(1c) in male and female ZDF rats, whereas β-cell mass and proliferation rate were increased with greatly improved blood glucose control. Whereas neither analog affected lipase activity, small increases in P-amylase activity were observed in animals treated with liraglutide and exenatide. However, concurrent or permanent increases in lipase and P-amylase activity were never observed. Triglycerides were lowered by both GLP-1 analogs. The qualitative histopathological findings did not reveal adverse effects of liraglutide. The findings were mainly minimal in severity and focal in distribution. Similarly, the quantitative stereological analyses revealed no effects of liraglutide or exenatide on overall pancreas weight or exocrine and duct cell mass or proliferation. The present study demonstrates that, in overtly diabetic male and female ZDF rats, prolonged exposure to GLP-1 receptor agonists does not affect biochemical or histopathological markers of pancreatitis, and whereas both exenatide and liraglutide increase β-cell mass, they have no effect on the exocrine pancreas. However, clinical outcome studies and studies using primate tissues and/or studies in nonhuman primates are needed to further assess human risk.

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

“…In contrast, hundreds of other studies have investigated effects of these drugs on the pancreas but have not reported adverse effects; a few are referenced here for liraglutide (37)(38)(39). A study, Animals examined 3 3 3 3 3 3 3 3 Endocrine pancreas No abnormality detected 3 3 3 3 3 3 3 3 Exocrine pancreas No abnormality detected 3 3 3 3 3 3 3 3 13-week liraglutide dose levels (mg/kg/day) 0 0.05 0. performed after others had reported potential adverse findings, confirmed the absence of pathology in diabetic rats and also did not show any regional differences in the pancreas induced by liraglutide when the pancreas was divided into four regions and examined by stereology (40). A recent publication used a human islet amyloid polypeptide transgenic model similar to one of the earlier studies, just in mice instead of in rats, treats the animals for 1 year instead of 12 weeks, used 20-25 animals in each group instead of 8, and found no pancreas pathology associated with sitagliptin (25,41).…”

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

“…We did not observe increases in pancreatic amylase gene expression, and lipase mRNA transcripts were significantly lower after Ex-4 administration. Furthermore, studies of pancreatic enzyme levels in rodents have been inconsistent, demonstrating either no change or small increases in amylase following administration of GLP-1R agonists (17,(33)(34)(35). Our current studies demonstrate that serum lipase levels were lower, whereas amylase levels and pancreatic content of amylase and lipase proteins (Supplementary Table 2) remained similar after treatment with Ex-4.…”

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

“…There was a nonsignificant difference in duct cell proliferation after 6 weeks of treatment. These observations and the findings of other studies [27][28][29][30][31][32] raise the issue of whether GLP-1-based therapies are a potential risk for pancreatitis; some studies did not observe this effect [33,34], however, which may reflect the animal model used, the age of the animals and/or the labelling and counting methods used for proliferating cells. In our study, there was no indication of a systemic inflammatory state.…”