Earlier this year the FDA started evaluating unpublished reports from a group of academic researchers suggesting an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with Type 2 Diabetes (T2DM) treated with a class of drugs called incretin mimetics.

In recent years a class of drugs has been introduced for treatment of T2DM that takes advantage of the properties of the gut hormone glucagon-like peptide-1 (GLP-1). GLP-1, secreted by L-type endocrine cells in the distal ileum in response to food ingestion, amplifies glucose-mediated insulin secretion. GLP-1 has a short half-life, degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) in the circulation. To therapeutically accomplish sustained GLP-1 receptor activation researcher have developed 2 treatment options.

Pancreatic Cancer was more Commonly Reported Among Patients who took Sitagliptin or Exenatide as Compared with other Therapies

The first treatment strategy includes GLP-1 agonists exenatide and liraglutide that are resistant to DPP-4 degradation. The second strategy uses the inhibitors of DPP-4, such as sitagliptin, which, when administered orally, enhance levels of endogenously secreted GLP-1.

Incretin Mimetics
Incretin mimetics, include a variety of drugs such as exenatide (Byetta/Bydureon; Amylin Pharmaceuticals), liraglutide (Victoza; Novo Nordisk), sitagliptin (Januvia/ Janumet/Janumet XR/Juvisync; Merck & Co), saxagliptin (Onglyza/Kombiglyze XR; Bristol-Myers Squibb), alogliptin (Nesina, Kazano, Oseni; Takeda Pharmaceuticals), and linagliptin (Tradjenta, Jentadueto; Boehringer Ingelheim Pharma). These drugs work by mimicking the incretin hormones that the body usually produces naturally to stimulate the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar in adults with T2DM.

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With more than 20 million known patients with T2DM in the United States alone and many more around the world, the potential of impact of adverse events with GLP-1?based drugs currently on the market or in the final stages of development can beenormous. Togain insight into the potential of adverse events, researchers at the Larry L. Hillblom Islet Research Center at David Geffen School of Medicine and Department of Biomathematics, University of California, Los Angeles, Californiaexamined the adverse events included in the FDA AERS (Adverse Event Reporting System) database. [1]

The researchers confirmed that the treatment of T2DM withsitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P< 2 ? 10?16). They also noted that pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P< .008,P< 9 ? 10?5). All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20). [1]

Adverse Events
These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. Based on these reports, the FDA asked these researchers to provide the methodology used. The regulatory agency also asked the researchers to collect and study these specimens and to share tissue samples for further investigations designed to review the potential of pancreatic toxicity associated with the incretin mimetics.

After reviewing the UCLA study and other available data, the FDA has not yet reached new conclusions about safety risks with incretin mimetic drugs. However, the Agency did participate in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Cancer Institute?s (NCI) Workshop on Pancreatitis-Diabetes-Pancreatic Cancer being held on June 12 and 13, 2013 in Bethesda, MD, to gather and share additional information. They are expected to release their finding, conclusions and recommendations later this year or early next year.

First lawsuit
The law firm of Rheingold, Valet, Rheingold, McCartney & Giuffra LLP earlier today commenced what is believed to be the first suit in New York for the development of pancreatic cancer in the user of of the common anti-diabetic drugs. The suit, by Staten Island resident Robert Cataletto, was filed on June 14, 2013, and it is captioned Cataletto v. Amylin Pharmaceuticals, LLC, et al., E.D.N.Y. 13-cv-3411.

Broader Group
Cataletto received prescriptions from the doctor attending to his adult diabetes condition in the period from 2009 to 2012 for exenatide, which has been on the market since 2005 and is known as a glucagen-like peptide treats diabetes by preventing a build- up of sugar in the body. He also received a prescription for sitagliptin, which was first marketed in 2007 and belongs to the category of a dipeptidyl-peptidase-4 drug designed to reduces blood glucose levels. When combined with an older drug, metformin, the drug is known as Janumet. The broader category for the drugs involved in this law suit is known as “incretins.”

Legal case
The complaint alleges that the manufacturers of both of these products were alerted starting in 2010 that there was an increased incidence of pancreatic cancer in users of these drugs as compared to diabetics treated with the older, more proven forms of treatment. The notice also came from the German Medical Association and a petition by Public Citizen, a non-profit health group in Washington.

Disregardfor human life
There have been similar reports of a sharp increase in pancreatitis?inflammation of the pancreas gland?in users of these same drugs. The complaint alleges that pancreatitis may be a forerunner of pancreatic cancer. Pancreatic cancer is among the deadliest of all cancers, for which there are no satisfactory treatments.

The complaint charges that the defendants were aware of the serious health risks associated with the use of these drugs, and concealed them from the public, prescribing doctors and governmental regulatory bodies. It not only seeks damages for the pain and suffering and economic loss sustained by the Cataletto family but also punitive or punishment damages based on “disregard for human life.”

“From our examination of the data, it appears to us that there has been over promotion and under warning by the sellers of these and other drugs in the incretin category,” says Paul D. Rheingold, senior partner in the law firm. The firm specializes in representing persons injured by drugs and medical devices. The firm is also involved with litigation involving metal-on-metal hips made by Biomet, DePuy, Stryker and Wright Medical, all of which have genotoxic galvanic reactions known to be carcinogenic.

[1] Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011 Jul;141(1):150-6. doi: 10.1053/j.gastro.2011.02.018. Epub 2011 Feb 18. [Abstract][Full Article]

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