GLP-1 Receptor Agonist Effects on Normal and Neoplastic Pancreata
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Corresponding author: Michael Goggins, .
In this issue of Diabetes, two articles describe preclinical studies evaluating the effects of chronic glucagon-like peptide 1 (GLP-1)–based therapy on development of pancreatitis and pancreatic neoplasia (1,2). These studies were performed in light of recent case reports and a case-control study suggesting that diabetic individuals using sitagliptin or exenatide have a several-fold increased likelihood of developing pancreatitis and pancreatic cancer (3). Related to the latter association are recent case-control studies reporting that metformin therapy, which can counteract proliferative effects of GLP-1 receptor (GLP-1R) agonists, is associated with a reduced risk of pancreatic cancer (4). Some preclinical studies have found that GLP-1R agonists can cause pancreatitis in some mice, but others have found no such effect, and recent clinical trials found evidence for only a small increased risk of pancreatitis with liraglutide use (5).
In this issue, Nyborg et al. (2) find no evidence for an increased risk of pancreatitis in liraglutide-treated compared with control-treated animals. In contrast, Gier et al. (1) find exendin-4 had multiple effects, including increasing the extent of chronic pancreatitis-like changes in a genetically engineered mouse model (KrasG12D) of pancreatic neoplasia. How do we reconcile the different animal responses to GLP-1R agonists? It does not seem likely that these differences reflect variability in the properties of the different GLP-1R agonists in the two studies. The lack of effect of liraglutide in healthy mice, rats, and monkeys (2) probably reflects what generally occurs in individuals with normal pancreata. Any increase in cell proliferation by GLP-1R agonists may not have pathological effects if …