Kathleen Louden

September 23, 2011

September 23, 2011 — Patients who are using the type 2 diabetes medications sitagliptin and exenatide appear more likely to report pancreatitis and pancreatic cancer, a new study has found. The retrospective study, which analyzed a US Food and Drug Administration (FDA) reporting system, also found a possible association of thyroid cancer with the use of exenatide.

These results were presented September 14 at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting. The study, by Michael Elashoff, from the Larry L. Hillblom Islet Research Center, University of California, Los Angeles, and colleagues, was published in the July issue of Gastroenterology.

"[Our analysis] suggests that the [glucagon-like peptide 1 (GLP-1)] class of drugs being widely promoted for treatment of type 2 diabetes could have serious unintended and unpredicted side effects," the authors write.

Need for Caution

However, Peter Butler, MD, a study coauthor and director of the Larry L. Hillblom Islet Research Center, recently injected a cautionary note after reportedly receiving questions from concerned patients using these drugs.

"Our study does not prove an association between GLP-1-based therapy and pancreatitis and pancreatic and thyroid cancer," Dr. Butler told Medscape Medical News. "It shows that there is a concern of a possible association, and that appropriate prospective studies are required to rule out an association."

In their study, the researchers examined the FDA adverse events reporting system (AERS) between 2004 and 2009 for events of pancreatitis, pancreatic cancer, thyroid cancer, and other cancers reported in association with prescription of sitagliptin (Januvia, Merck) or exenatide (Byetta, Amylin Pharmaceuticals). They compared these incretin-based drugs with 4 other diabetes medications used as controls: rosiglitazone, nateglinide, repaglinide, and glipizide.

As a second control, the investigators compared the study adverse events with the following control events, which have no known association with the test drugs: back pain, urinary tract infection, chest pain, cough, and syncope.

They found a more than 6-fold increase in the odds ratio for reported cases of pancreatitis in patients receiving sitagliptin (odds ratio [OR], 6.74; 95% confidence interval [CI], 4.61 - 10.0) or exenatide (OR, 10.68; 95% confidence interval, 7.75 - 15.1) compared with the control diabetes therapies (P < 2 × 10−16). Compared with these other medications, the reported event rate of pancreatic cancer was 2.9-fold higher in patients receiving exenatide (P = 9 × 10−5) and 2.7-fold higher in those receiving sitagliptin (P = .008), according to the article.

For thyroid cancer, the event rate was significantly higher only for the exenatide group (OR, 4.73; P = 4 × 10−3) compared with rosiglitazone, the authors report. No difference existed between the study and control drugs in the event rates reported for other cancers.

Study Rationale

The authors state that they undertook the study because animal studies and case reports indicated an increased risk for pancreatitis with GLP-1-based therapy.

The FDA revised the prescribing information for sitagliptin and sitagliptin-metformin (Janumet, Merck) in September 2009, and for exenatide in October 2007, to include information on reported postmarketing cases of acute pancreatitis in patients using these medications. Several cases of hemorrhagic or necrotizing pancreatitis also were reported with use of exenatide, the FDA reported in August 2008.

Because chronic pancreatitis is a risk factor for pancreatic cancer, the authors write that they analyzed the FDA data for cases of cancer, as well as pancreatitis. They did not differentiate between cases of chronic and acute pancreatitis in their article.

Dr. Butler said the AERS has limitations, including not reporting the duration of drug use, but it also has the advantage of being independent from drug manufacturers. He cited limited safety data available for this class of drugs that do not come from pharmaceutical industry–sponsored studies as a reason for performing the study.

"We hope there will be prospective studies by independent bodies looking at this issue," Dr. Butler told Medscape Medical News.

He added: "There is no need to change practice. Physicians prescribing one of these drugs should keep a close watch on the patient. And if the patient is not also on metformin, the physician should add metformin [to the treatment regimen]."

Some studies show that metformin decreases the risk for pancreatic cancer, he said.

Furthermore, both the American Diabetes Association and the EASD recommend metformin as first-line medical therapy for type 2 diabetes. Despite this, some clinicians are prescribing the new GLP-1 drugs as early monotherapy, Dr. Butler said.

Conclusions Disputed

Others questioned the authors' conclusions and methods of analysis, particularly the use of the AERS, which they said can include incomplete data and can allow for a reporting bias.

In an editorial accompanying the July Gastroenterology article, Joachim Spranger, MD, from the Department of Endocrinology Diabetes and Nutrition Charité-Universitätsmedizin, Berlin, and Drug Commission of the German Medical Association, Berlin, Germany, and colleagues called the use of the FDA database a major drawback of the study.

"Analysis of spontaneous reports does not allow for adjustment of known risk factors for pancreatic cancer such as obesity, smoking, family history, or chronic pancreatitis, even if this information is available," the editorialists write.

The FDA Web site states: "AERS cannot be used to calculate the incidence of an adverse event in the U.S. population."

There also was disagreement among diabetes researchers about the possibility that GLP-1 therapies, which have been on the market 6 years or less, could cause cancer.

"Although there are important questions which currently need to be answered with respect to the safety of incretin-based medications, there is no definitive evidence pointing to an increase in cancer risk," states a commentary by the EASD.

Published after a draft of the Gastroenterology article appeared online in February, the commentary concludes: "There is no immediate need for action, and patients should under no circumstances stop taking any medication and should consult their physicians to be advised on their diabetes therapy."

This study was supported by the Larry L. Hillblom Foundation. The article authors have disclosed no relevant financial relationships. Dr. Spranger has disclosed that he has lectured for or received consultant honoraria from Eli Lilly, which developed exenatide with Amylin Pharmaceuticals, and from Merck, maker of sitagliptin. The other editorialists have disclosed no relevant financial relationships.

Gastroenterology. 2011;141:20-23, 150-156. Article full text, Editorial full text

European Association for the Study of Diabetes (EASD) 47th Annual Meeting: Press briefing. Presented September 14, 2011.

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