Glucagon-like peptide-1 (GLP-1) analogs, also known as incretin mimetics, represent a class of medications developed over the past few years for the treatment of diabetes mellitus (DM). These medications include the GLP-1 agents exenatide and liraglutide, as well as the dipeptidyl peptidase 4 (DPP-4) inhibitors sitagliptin, saxagliptin, alogliptin, vildagliptin, and linagliptin.
Although the exact side effect profile is still being determined through post-marketing surveillance and adverse event reporting to the United States Food and Drug Administration (FDA), there has been some concern regarding the potential risk for pancreatic cancer in patients using these agents.
On March 14, 2013, the FDA issued a report stating that they were actively investigating a collection of unpublished data that indicated an increased risk of pancreatitis and precancerous changes in the pancreatic ducts of patients who had been taking GLP-1 analogs.1 The FDA noted that these are just preliminary reports and the research group has been asked to further clarify their methods and findings.
A recent study published by Singh and colleagues also showed that patients receiving GLP-1 analogs had almost double the risk for being hospitalized for acute pancreatitis compared with patients who did not use these agents.2 In another recent study by Elashkoff et al, there was between a 2.7- and 2.9-times increased risk of pancreatic cancer in patients receiving exenatide and sitagliptin, respectively, during a 5-year span of adverse event reporting to the FDA.3 GLP-1 agonists also have been shown in rat models to induce exocrine pancreas ductal metaplasia, which is thought to predispose the pancreas to future cancer.4,5
Based on this data, if GLP-1 analogs do, in fact, increase the risk of pancreatitis, this could lead to an increased risk of cancer after years of chronic use. It has also been hypothesized that DPP-4 inhibitors could also have detrimental immunomodulatory effects that might predispose a patient to pancreatic cancer with long-term use. However, since many of these agents are still relatively new to the market—available for less than 10 years— data supporting these concepts would not be available yet.
Although the much of the preliminary data does suggest some link between the use of GLP-1 analogs and pancreatic cancer, the exact correlation has yet to be determined as more adverse event data remains to be collected. In addition to more clinical data, preclinical studies to further elucidate the numerous biochemical pathways involved in the signaling of these medications would also be critical to understanding the link between GLP-1 analogs and pancreatic cancer.
1. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm. Last accessed June 6, 2013.
2. Singh S, Chang HY, Richards TM, et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013 Apr 8;173(7):534-9.
3. Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011 Jul;141(1):150-6.
4. Gier B, Matveyenko AV, Kirakossian D, et al. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes. 2012 May;61(5):1250-62.
5. Matveyenko AV, Dry S, Cox HI, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes. 2009 Jul;58(7):1604-15. doi: 10.2337/db09-0058. Epub 2009 Apr 29.