FDA to Examine Pancreatic-Duct Metaplasia With Incretins

Lisa Nainggolan

March 14, 2013

The US Food and Drug Administration (FDA) is evaluating an increased risk for pancreatitis and precancerous cellular changes called pancreatic-duct metaplasia associated with incretin mimetic drugs used to treat patients with type 2 diabetes. This covers the glucagonlike peptide-1 (GLP-1) agonists and the DPP-4 inhibitors, or "gliptins," both relatively new classes of agent used to treat adults with type 2 diabetes.

In the drug-safety communication, issued today, the agency says this is in response to "unpublished new findings by a group of academic researchers," based on examination of a small number of pancreatic-tissue specimens taken from patients after they died from unspecified causes.

This is the first time the FDA has issued a communication with regard to the potential risk for precancerous findings of the pancreas with incretin mimetics. It emphasizes, however, that it "has not concluded these drugs may cause or contribute to the development of pancreatic cancer."

The FDA has asked the academic researchers to provide the tissue samples so it can further investigate this potential toxicity. Incretin mimetic agents on the market in the US include exenatide (Byetta/Bydureon, Lilly/Amylin Pharmaceuticals), liraglutide (Victoza, Novo Nordisk), sitagliptin (Januvia/Janumet/Janumet XR/Juvisync, Merck), saxagliptin (Onglyza/Kombiglyze XR, Bristol-Myers Squibb/AstraZeneca), alogliptin (Nesina/Kazano/Oseni, Takeda Pharmaceuticals/Furiex), and linagliptin (Tradjenta/Jentadueto, Boehringer Ingelheim).

The FDA notes, however, that it "has not reached any new conclusions about safety risks with incretin mimetic drugs. This early communication is intended only to inform the public and healthcare professionals that the agency intends to obtain and evaluate this new information."

And it stresses: "At this time, patients should continue to take their medicine as directed until they talk to their healthcare professional, and healthcare professionals should continue to follow the prescribing recommendations in the drug labels."

Not the First Warning About Pancreatitis

The FDA has previously alerted the public to postmarketing reports of acute pancreatitis, including fatal and serious nonfatal cases, associated with the use of exenatide and sitagliptin. The "Warnings and Precautions" section of the drug labels and the patient medication guides for incretin mimetics contain warnings about the risk for acute pancreatitis, it notes.

Most recently, a study published last month that examined insurance records found the use of exenatide or sitagliptin could double the risk of developing acute pancreatitis, but the authors of that paper also urged patients not to stop taking their medication.

In addition, in a joint statement, the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association called into question the strength of the study's findings, noting that the analysis linked the drug class with a relatively small excess risk for hospitalization for acute pancreatitis — only 2 additional cases per 100 patients over a 3-year period. Both the AACE and ADA reiterated that patients should not change their treatment on the basis of this research.

The FDA says it is continuing to evaluate all available data to further understand this potential safety issue and will participate in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Cancer Institute (NCI) Workshop on Pancreatitis-Diabetes-Pancreatic Cancer in June 2013 to gather and share additional information.

FDA will communicate its final conclusions and recommendations when its review is complete or when the agency has additional information to report.

More information about today's drug safety communication is available on the FDA website.

To report adverse events involving incretin mimetics, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online ; with postage-paid FDA form 3500; or by mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787.