The scientists explained that patients on incretin therapy were more likely to have rapid multiplication of pancreatic cells that may be associated with a higher risk of neuroendocrine tumors.
While analyzing the organs of deceased donors who had type 2 diabetes, the researchers found that those who had been treated with incretin therapy had about 40% more cell mass in their pancreases.
Incretin therapy takes advantage of the action of the intestinal hormone GLP-1 (glucagon-like peptide 1) to reduce blood-sugar levels.
There have been several reports on what the effects of incretin therapies are on the pancreas in animal studies, and with conflicting results. The authors in this study say that theirs is the first to identify alterations in the human pancreas.
Co-team leader, Dr. Mark Atkinson, a professor of pathology and pediatrics at the University of Florida, also leads the Network for Pancreatic Organ Donors with Diabetes (nPOD), a research consortium sponsored by the Juvenile Diabetes Research Foundation which receives pancreases from deceased organ donors (with permission of their next-of-kin). The aim is to gain a better understanding of diabetes by investigating tissues of those with diabetes.
Co-team leader, Dr. Peter Butler, director of UCLA's Hillblom Islet Research Center and chief of the endocrinology, diabetes and hypertension unit, said:
"There is an increasing appreciation that animal studies do not always predict findings in humans. The nPOD program is therefore a very precious resource."
The team looked at the pancreases of 20 deceased organ donors; they had all suffered from type 2 diabetes:
- 8 of the deceased had received incretin therapy for at least a year
- 12 had been treated for type 2 diabetes, but never with incretin-based drugs
- 14 pancreases from donors who were not diabetic were also examined (the control group)
Incretin therapy increases pancreas sizeThose who had been on incretin therapy had larger pancreases than the diabetes patients who had never been on incretin therapy. The larger pancreas size was associated with a greater number of pancreatic cells. The individuals who had been on incretin-based drugs showed an increase in pancreas dysplasia, an unusual form of cell proliferation that is a risk factor for pancreatic cancer.
The scientists also observed a considerably greater number of alpha cells (cells that make glucagon) in the pancreases of donors who had been on incretin therapies. Most likely, this is because GLP-1-based therapies suppress the release of glucagon by alpha cells. Previous studies have shown that reducing the availability or actions of glucagon induces a proliferation of pancreatic alpha cells. This increase in alpha-cell numbers has been linked to the development of pancreatic neuroendocrine tumors. Three of the patients on incretin therapy had microadenomas and one had a neuroendocrine tumor consisting of alpha cells.
Seven of the eight patients receiving incretin therapy had been on sitagliptin, taken in pill form under the brand name Januvia (Merck product), and one had been taking exenatide, sold as Byetta (Bristol-Myers Squibb product).
These medications, and others like them are currently being investigated by the FDA for their possible associations with pancreatic cancer and pancreatitis. The European Medicines Agency is also investigating a possible increased risk of pancreatitis and pancreatic duct metaplasia in patients treated with GLP-1-based therapies and and dipeptidylpeptidase-4 (DPP-4) inhibitors).
The authors wrote:
"These findings lend additional weight to concerns regarding the effects of long term GLP-1-related therapy, with respect to both unintended proliferative actions on the exocrine pancreas and now also a possible increased risk of neuroendocrine tumors. In addition to the surveillance previously recommended for the potential association of GLP-1- based therapy and pancreatic cancer risk, the current data imply that surveillance for a possible increased risk of pancreatic neuroendocrine tumors is warranted."
Butler suggests that the surveillance approaches should include MRI scans of the pancreas and screening for neuroendocrine tumors.
Butler said "The present studies are only from a small number of individuals, and while the findings do raise concerns, it will be important that other approaches are now used in a larger group of living individuals to further investigate these findings."
The authors cite a recent study carried out by Dr. Sonal Singh and team at Johns Hopkins University School of Medicine and Public Health which indicated that GLP-1 based therapies double the risk of being hospitalized with acute pancreatitis. The study was published in JAMA Internal Medicine
Singh said "Since most risk factors for acute pancreatitis are also linked to an increased risk of pancreatic cancer, these findings of changes in the human pancreas are very concerning. Now that GLP-1-based therapies have been shown to increase the risk of pancreatic inflammation and abnormal cell proliferation, further studies are needed to urgently clarify whether these linkages lead to pancreatic cancer with long-term use."