Incretins and Pancreatic Damage   (June 20, 2013)

The American Diabetes Association (ADA) has recently voiced concerns about pancreatic side effects of several diabetes drugs, all of which are related in one way or another to two gut hormones called incretins. The incretins, GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) lower blood glucose levels by increasing insulin secretion from the beta cells of the pancreas.

Drugs that mimic the blood-glucose lowering effects of GLP-1 have been developed, and are called incretin mimetics or GLP-1 receptor agonists. The three that are presently approved by the FDA are Byetta (exenatide), Victoza (liraglutide), and Bydureon (long-acting exenatide).

Both incretin hormones are rapidly inactivated by an enzyme called DPP-4 (dipeptidyl peptidase-4). Drugs have been developed that inhibit DPP-4, and thereby enhance the effect of the incretins to reduce BG levels. At least five DPP-4 inhibitors have been developed, and four are currently available in the US: Januvia (sitagliptin), Onglyza (saxagliptin), Trajenta (linagliptin), and Nesina (alogliptin). Another gliptin, Galvus (vildagliptin) is approved in other countries but not in the US.

It is well-known that these drugs may contribute to the development of pancreatitis. I have written about this previously: Incretin Mimetics and Pancreatitis and Pancreatitis: a class effect for the GLP-1 mimetics? And pancreatitis is mentioned as a possible side effect in the label for both the insulin mimetics and the DPP-4 inhibitors.

The possibility that the incretins might be a risk factor for pancreatic cancer has been less clear. That hasn’t stopped the watchdog organization, Public Citizen, from suggesting banning the incretins. Public Citizen obtained reports of pancreatic cancer reported to the FDA, and found “a total of 292 reports of pancreatic tumors between January 1, 2010, and June 30, 2012, for these three incretin drugs [Byetta, Victoza and Januvia], but only one report for glipizide, an older diabetes drug not in this family.”

The ADA has suggested that the manufacturers of the incretins release their safety data for an independent analysis by an academic and research organization to be selected by the ADA. Sounds like a noble and grandiloquent idea, but it’s obviously going to be a bureaucratic nightmare to set up and to fund such a program, and is not necessary if the FDA is doing its job.

The FDA has plenty of authority to force the manufacturers to submit data, report a meta-analysis of prior clinical trials, start new safety trials, respond to safety requests at Advisory Committee meetings, revise labels, limit distribution, and/or pull drugs off the market. It’s already likely that the FDA has requested, and reviewed, safety documents from the companies that are not usually submitted to the FDA including Periodic Safety Update Reports  (PSURs) and Development Update Safety Reports (DSURs) (which are aggregated safety documents submitted to Health Authorities in other countries).

Unfortunately, the ADA’s suggested solution to find the answers doesn’t even mention the FDA. It should have. The FDA, working together with the drug manufacturers, could get to the bottom of the question of the risk of the incretins and has the regulatory authority to force the companies to cooperate if they are reluctant.

One way or the other, it will be important to answer the questions being posed: how do the incretins change the risk of pancreatitis and pancreatic cancer, and is it enough of a risk to restrict the use of these drugs?