EU Will Study Risks of Incretin Mimetics for Diabetes

Disclosures

March 27, 2013

Taking a cue from their US counterparts, European drug regulators announced Wednesday that they will investigate the findings of a recent study in the journal Diabetes suggesting that incretin mimetic drugs for type 2 diabetes increase the risk for pancreatitis and precancerous cellular changes called pancreatic duct metaplasia.

On March 14, the US Food and Drug Administration (FDA) announced that it will review the same research results on incretin mimetics. At that time, the study was unpublished, according to the FDA.

Incretin mimetics mimic intestinal hormones such as glucagonlike peptide-1 (GLP-1) that stimulate the release of insulin after a meal.

The study in Diabetes is the latest in a series that raises safety concerns about incretin mimetics — specifically, GLP-1–based therapies that include GLP-1 agonists and dipeptidylpeptidase-4 (DDP-4) inhibitors. An article published online in JAMA Internal Medicine last month reported that people with type 2 diabetes who use the GLP-1 agonist called exenatide (Byetta, Amylin Pharmaceuticals) and the DDP-4 inhibitor called sitagliptin (Januvia, Merck) double their risk of being hospitalized for acute pancreatitis.

The European Medicines Agency (EMA), the European Union equivalent of the FDA, said in a press release that there is no need for patients to stop taking the incretin mimetics in question because it has not reached any conclusions in its review. Nor are there any changes to EMA recommendations on using the drugs. The agency noted that its initial evaluation of these drugs identified adverse effects involving the pancreas as a possible risk.

"Marked" Alpha Cell Hyperplasia

The study published in Diabetes analyzed transplant-grade pancreases obtained from 34 brain-dead organ donors, 20 with type 2 diabetes and 14 without. Of those with type 2 diabetes, 7 had received sitagliptin and 1 had received exenatide for a year or longer.

Lead author and pathologist Alexandra Butler, MD, and her colleagues write that pancreatic mass in patients with diabetes treated with an incretin mimetic grew 40% compared with that in patients with diabetes who did not receive such drugs. That change was accompanied by increased exocrine cell proliferation and dysplasia. Furthermore, researchers observed "marked" alpha cell hyperplasia and glucagon expression of microadenomas and a neuroendocrine tumor, writes Dr. Butler, an assistant professor at the David Geffen School of Medicine at the University of California-Los Angeles.

The study represents an "I told you so" for the consumer watchdog group Public Citizen, which has asked the FDA to ban the GLP-1 agonist liraglutide (Victoza, Novo Nordisk). Sidney Wolfe, MD, director of Public Citizen's Health Research Group, said in a press release last week that the study's findings "are in accord" with a rapidly growing number of reports of pancreatic cancer in patients taking incretin mimetics.

"It is likely that they will all have to be removed from the market," said Dr. Wolfe.

More information the EMA announcement is available on the agency's Web site.

To report problems with 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 at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

The authors have disclosed no relevant financial relationships.

Diabetes. Published online March 22, 2013. Abstract

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