Diabetes Agencies Comment on Incretin Agents and Pancreatic Disease Risk

Diabetes Agencies Comment on Incretin Agents and Pancreatic Disease Risk

In April 2005, the U.S. Food and Drug Administration (FDA) approved the first incretin mimetic, exenatide (Byetta), a glucagon-like peptide 1 (GLP-1) receptor agonist, and in October 2006, the FDA approved the first oral incretin agent, the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin (Januvia). To date, another 5 incretin mimetics have come to market, and even more are in the pipeline and will likely be available in the future.

Post-marketing reports suggest that incretin mimetic medications may be associated with an increased risk of pancreatitis, and although no causal link has been established, the FDA has added warnings about the risk of acute pancreatitis to the drug labels and medication guides for the entire class of incretin-based therapies.

The risk of pancreatitis with incretin mimetics is a subject of heated debate. A study by Singh et al., published online in JAMA Internal Medicine in February 2013, suggested that treatment of type 2 diabetes with sitagliptin or exenatide may be associated with an increased risk of developing acute pancreatitis severe enough to require hospitalization.1 In response, the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) issued a joint statement noting that the Singh study was a retrospective analysis and as such does not provide a strong enough evidence base for changing treatment in people with diabetes.2 The Endocrine Society issued another statement with a similar conclusion.3

Fueling the controversy, an autopsy study published online in Diabetes in March 2013 highlighted abnormal pancreatic findings from patients who had been treated with GLP-1 receptor agonists or DPP-4 inhibitors. In their study conclusions, the investigators raised the possibility that incretin mimetic therapy may be associated with a potential risk of pancreatic cancer.4

In mid-June, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a 2-day meeting to review available data on pancreatic disease and incretin mimetics. During this workshop, physicians and scientists from academia and the pharmaceutical industry reviewed findings from epidemiologic studies that demonstrated that diabetes itself is associated with an 82% increased risk of pancreatic malignancy, independent of therapy. In addition, preclinical pathology reports assembled by the FDA from submissions of all marketed incretin products and those still under development did not support changes to current package insert information on pancreatic disease. Finally, a discussion of the human autopsy study highlighted significant study limitations, and meeting attendees called for additional studies to test alternative explanations for the autopsy findings.

Based on the NIDDK workshop discussions, the ADA, the European Association for the Study of Diabetes (EASD), and the International Diabetes Federation (IDF) issued a joint statement affirming no change to current treatment recommendations, based on a lack of evidence of harm.5 These agencies noted that over 80,000 patients have been enrolled in studies using incretin therapies, all of which have been closely monitored by the Data and Safety Monitoring Boards. To date, no signal of adverse pancreatic outcomes has appeared, and no incretin study has been terminated for safety reasons.

All of the statements issued by the various endocrine and diabetes associations have reiterated that treatment decisions should be made by healthcare providers in consultation with patients after a thorough discussion of the risks and benefits of the therapy in question, as well as consideration of the individual patient’s needs and characteristics. Currently, the labeling for GLP-1 receptor agonists and DPP-4 inhibitors includes warnings about use in patients with a history of pancreatic disease and recommendations to discontinue treatment in patients who develop pancreatitis.

Most recently, after a thorough review of the same evidence, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a statement in July that currently available data do not confirm an increased risk of pancreatic adverse events with either GLP-1 receptor agonists or DPP-4 inhibitors.6

The bottom line:

The safety of a drug is assessed by determining whether its benefits outweigh its risks.

Therefore, treatment decisions should be made by healthcare providers in consultation with patients after a thorough discussion of the risks and benefits of the therapy in question.

Furthermore, patients should be aware of the potential risk of pancreatitis and contact their healthcare professionals immediately if they develop abdominal pain or vomiting. If the diagnosis of pancreatitis is established, the medication should be discontinued and not resumed.

1. Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. 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;173:534-539.

2. American Association of Clinical Endocrinologists, American Diabetes Association issue joint response to published JAMA article [news release]. Jacksonville, FL: American Association of Clinical Endocrinologists, American Diabetes Association; February 27, 2013. http://aace.newshq.businesswire.com/press-release/correcting-and-replacing-american-association-clinical-endocrinologists-american-diabe. Accessed August 14, 2013.

3. Experts raise concerns about JAMA study and pancreatitis risk of diabetes medications [news release]. Chevy Chase, MD: The Endocrine Society; March 1, 2013.  https://www.endocrine.org/news-room/current-press-releases/experts-raise-concerns-about-jama-study-and-pancreatitis-risk-of-diabetes-medications. Accessed August 14, 2013.

4. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62:2595-2604.

5. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013.  http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html. Accessed August 14, 2013.

6. Investigation into GLP-1 based diabetes therapies concluded [news release]. London, UK: European Medicines Agency; July 26, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146619.pdf. Accessed August 14, 2013.