GLP-1 based therapies and cancer
An innovative approach to the therapy of diabetes has been based upon the properties of the gut hormone Glucagon-Like Peptide-1 (GLP-1). GLP-1 has a range of actions that are potentially useful in type 2 diabetes, including potentiation of insulin release in response to food, inhibition of glucagon secretion, delayed gastric emptying and central effects upon appetite. GLP-1 itself has a very short half-life, and is thus of limited therapeutic value. This limitation has been overcome by inhibition of the dipeptidyl peptidase-4 (DPP-4) enyzmes that normally inactivate GLP-1. An alternative approach has been the development of GLP-1 analogues resistant to enzymatic degradation. GLP-1 receptors are widely distributed in the body, establishing the potential for off-target effects impacting upon the exocrine pancreas, thyroid, cardiovascular system, kidneys and other tissues. DPP-4 inhibition might also have unpredictable consequences for other regulatory pathways. Animal studies have identified an increased risk of C-cell thyroid tumours in rats, and a signal for human pancreatic adenocarcinoma has been detected in two regulatory databases. This article discusses possible implications of these observations.
GLP-1 based therapies include the dipeptidyl peptidase-4 (DPP-4) inhibitors, which enhance levels of endogenous GLP1, and the GLP-1 agonists, analogue agents which act directly upon GLP-1 receptors. This approach to therapy has proved popular because there is less risk of hypoglycemia and the GLP-1 agonists promote weight loss.
The useful actions of GLP-1 include stimulation of glucose-dependent insulin secretion, inhibition of glucagon release, delayed gastric emptying, and central effects affecting appetite. GLP-1 receptors are also present in other tissues including the exocrine pancreas and thyroid, raising the possibility of off-target effects, especially at the supraphysiological or pharmacological levels achieved by DPP4 inhibitors and GLP-1 agonists respectively. Furthermore, DPP-4 inhibition also impacts upon a number of other regulatory systems, and the long term consequences of this are still uncertain.
GLP-1 based therapies and the thyroid
Medullary thyroid cancer arises from the parafollicular or C-cells of the thyroid, which produce calcitonin. These are relatively rare tumours in humans, accounting for about 3% of all thyroid cancers. About 25% are familial, sometimes seen in association with type 2 multiple endocrine neoplasia (MEN2).
C-cell tumours were observed in rats during the development phase of liraglutide, but these tumours are more common in rodents than humans, and initial concerns were allayed to some extent by studies sponsored by the manufacturers which indicated that human C-cells in humans do not express the GLP-1 receptor, that calcitonin levels did not rise in response to therapy, and that thyroid tumours were not seen in non-human primates treated with liraglutide.
In contrast, an independent study found that a subpopulation of human C-cells do in fact express the GLP-1 receptor, and also found that GLP-1 receptor expression was more abundant in C-cell hyperplasia, a potential precursor of medullary thyroid cancer. The GLP-1 receptor is also expressed in 20% of papillary thyroid cancers. Medullary thyroid cancer is rare, but a relatively high proportion of the population has apparently quiescent micro foci of papillary thyroid cancer.
There are no formal case reports of thyroid tumours in people taking this class of agent, but adverse event reporting to the FDA showed (as of December 2012) an excess of reported thyroid cancer on both exenatide (74 thyroid cancer events) and liraglutide (57 events). There is currently no such signal for the DPP4 inhibitors.
GLP-1 based therapies and Carcinoma of the Pancreas
GLP-1 receptors are present in exocrine cells in the pancreatic ducts, and stimulation results in proliferation of these cells, which explains why an increase in pancreatic weight is frequently observed in animals treated with this class of agents.
Exposure to GLP-1 promotes proliferative signals in human pancreatic duct cells, and the pancreatic duct gland (PDG) compartment, which regulates new cell formation, is particularly responsive. The GLP-1 receptor is also abundantly expressed in pre-malignant pancreatic intraepithelial (PanIN) lesions (see Pancreatic cancer) and on pancreatic cancer cells.
The proposed model for exocrine pancreatic damage proposes that proliferation of duct cells results in metaplasia, partial or complete ductal obstruction, increased back-pressure upon the acini, activation of pancreatic digestive enzymes normally packaged in an inert form as zymogen granules within the acinar cells and (most typically) subsequent low grade localized pancreatic inflammation, only rarely expressed as typical acute pancreatitis.
Healthy pancreatic duct cells, as present in experimental animals, will, on this scenario, be relatively unaffected by exposure to increased levels of GLP-1, but the situation may not be representative of middle-aged and elderly humans, in whom PanIN lesions and quiescent foci of pancreatic cancer are frequently present. If this model is correct, the combination of low-grade inflammation and pro-proliferative signalling would be expected to promote malignant change in the pancreas.
Two short term studies carried out at the request of the FDA in the ZDF rat model of diabetes provided some reassurance as to the effect of exposure to the GLP-1 agonists upon the exocrine pancreas, but pancreatic enzymes were increased in both studies, and one of 1 of 12 animals treated with exenatide died of massive pancreatic necrosis. Furthermore, pathological findings in treated animals included acinar to ductal metaplasia and foci of ductal hyperplasia.
To date, only one observational study of GLP-1 therapies and cancer in humans has been reported, based on data from the US FDA’s voluntary system of reported adverse events; this study observed an increased risk of pancreatitis, pancreatic cancer, and thyroid cancer associated with GLP-1 therapies. In contrast, a recent meta-analysis of RCTs using DPP-4 inhibitors found no short-term effect of DPP4 on the incidence of cancer.
In conclusion, there are grounds for concern that the GLP-1 based therapies have the potential to promote low-grade pancreatic inflammation, proliferation of pancreatic duct cells, and acceleration of premalignant changes in the exocrine pancreas. This appears to be a class effect. Examination of post-mortem pancreas in people exposed to these therapies will offer a key step forward in understanding of these issues [^8].
There are parallel concerns relating to the thyroid, in particular the possibility that exposure to pharmacological levels of GLP-1 might activated pre-existing foci of thyroid papillary cancer. Such an effect might (on current evidence) be limited to the GLP-1 agonists.
In sum, there is currently no conclusive evidence to suggest that the GLP-1 based therapies accelerate concer development, but this possibility has certainly not been excluded and will remain a concern until this issue has been put to rest by more definitive studies.
^ Bjerre Knudsen L et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010;151:1473-1486
^ Gier B et al. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab 2012;97:121-131
^ Bondeson L, Ljungberg O. Occult papillary thyroid carcinoma in the young and the aged.
^ Butler PC et al. Are the GLP-1 based therapies safe? Diabetes Care (in review)
^ Nachnani JS et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia 2010;53:153-159
^ Tatarkiewicz K et al. Exenatide does not evoke pancreatitis and attenuates chemically-induced pancreatitis in normal and diabetic rodents. Am J Physiol Endocrinol Metab 2010;
^ Elashoff M et al. Pancreatitis, pancreatic, and