Diabetes therapy, cancer connection scrutinized

The relationship between glucagon-like peptide 1-derived diabetes medications and risk for cancer has become a topic of recent controversy in the cancer and diabetes communities. This year, at the European Association for the Study of Diabetes Annual Meeting, Peter C. Butler, MD, argued the reality of the risk for cancer these agents pose to patients, and Michael A. Nauck, MD, made a case against the connection.

“In science, nothing is ‘yes’ or ‘no’. Truthfully, I think the answer we may both come to is maybe,” Butler, who is chief of the division of endocrinology, metabolism, diabetes and hypertension at University of California, Los Angeles, said during a press conference.

Connection assessed

In July, research conducted by Butler and colleagues on the risk for pancreatitis and pancreatic and thyroid cancers associated with GLP-1-derived agonists was published in Gastroenterology. The researchers analyzed data from the FDA Adverse Events Reporting System database to locate adverse events associated with sitagliptin (Januvia, Merck) or exenatide (Byetta, Amylin) treatment between 2004 and 2009. Their analysis revealed a sixfold increase in the odds ratio for reported cases of pancreatitis associated with GLP-1-based antidiabetic medications, when compared with four other diabetes therapies used as controls. In addition, for patients receiving these two drugs, a higher number of cancer cases had been reported to this database compared with those treated with the other therapies.

Michael A. Nauck

“[GLP-1] is a hormone that drives cellular replication,” Butler, who is also director of the Larry Hillblom Islet Research Center at UCLA, said here. “To my knowledge, we do not have any other therapy that does this. The issue I am most concerned with is whether it has an unintended effect to drive new cell formation in pancreatic duct cells.”

Butler noted both the advantages and limitations to the FDA database used. Advantages included: a large sample size, independence from marketing companies, a real-world use of the drugs, open access and a history of success in detecting adverse side effects. Among the limitations were the limited data entry and the fact that the data are subject to confounding variables.

Based on a report submitted to the FDA noting an increase in thyroid tumors among rats treated with liraglutide (Victoza, Novo Nordisk), Butler and colleagues compared the frequency of reports of thyroid cancer by physicians in patients treated with GLP-1-derived agonists with reports of thyroid cancer in those treated with meglitinides, glipizide or rosiglitazone. According to the study, the event rate was increased and reached statistical significance in the exenatide group (OR=4.73; P=4x10^-3), but not in the sitagliptin group (OR=1.48; P=.65).

“We wrote in the report: ‘For now, this analysis of the FDA database does not establish that pancreatitis, pancreatic and thyroid cancer are caused by GLP-1-based therapy. It simply raises the level of concern that they may be, and that the appropriate prospective studies are required to rule them out,’” Butler said.

Careful surveillance needed

Both Butler and Nauck agreed that additional studies are needed in broader research communities to rule out this connection.

“[This is] a real controversy; there is no easy way to agree other than to say that I would support the idea that we need more studies in this area to finally decide who is right,” Nauck, from the Diabetes Center in Bad Lauterberg, Germany, said during the press conference.

Nauck questioned whether the results of animal studies published by Butler et al in Gastroenterology are readily reproducible in other animal models of type 2 diabetes. Butler countered that, as he presented in the debate, most of the reports of proliferation of pancreatic cells in animals by GLP-1 are from labs other than his own. Nauck also argued that the FDA database used is questionable due to its susceptibility to bias. However, excluding cancer as a risk would require a large clinical trial including 80,000 or more patients, and the data needed would not be available for years, he said. Therefore, in the meantime, it is important to carefully and critically analyze the data presented in favor of an increased risk for cancer.

“In the end, it is a balance of risk and benefit that is often very difficult to divide. The evidence in favor of incretin-based drugs causing cancer is not at all convincing, but these issues need to be resolved by careful surveillance of large populations of patients treated with these drugs in order to finally prove their long-term safety. I hope that these [future] findings will then, more or less, exclude this kind of risk,” Nauck said. –by Stacey L. Fisher

For more information:

• Butler PC. Yes. Do GLP-1 based therapies increase cancer risk?
• Nauck MA. No. Do GLP-1 based therapies increase cancer risk? Both presented at: The European Association for the Study of Diabetes 47th Annual Meeting; Sept. 12-16, 2011; Lisbon.
• Elashoff M. Gastroenterology. 2011;141:150-156.

Disclosures: Dr. Butler reports no relevant financial disclosures. Dr. Nauck reports relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi Aventis and Takeda.

Ulf Smith

At this stage, speaking as a physician and not on behalf of the EASD, I do not think [this] leads to any real consequences [of treatment] except raised awareness. In terms of patients, for instance those with thyroid nodules or specific individuals, I would be aware. If something signals [the risk for cancer] is there, I would certainly analyze it. But, it doesn’t lead to a change in my view of how to treat my patients at present.

– Ulf Smith, MD, PhD

EASD President

Disclosures: Dr. Smith reports no relevant financial disclosures.

Derek LeRoith

The controversy regarding the potential link between GLP-1 agonists and cancer reminds one of the questionable connection between insulin analogues and cancer risk; both have limited data from scientifically sound studies in humans and at the basic level. Having said that, the academic and practicing endocrinologist should weigh the data carefully and needs to be aware of the issues to make an educated decision for the care of his or her patient with diabetes. Although the data by Butler and colleagues published in Gastroenterology in July seemed statistically flawed, they should raise one’s awareness of the issues involved. On the other hand, there are some developing studies that potentially point in the opposite direction, such as the effect of GLP-1 agonists inhibiting cancer cell growth (Wolf I. Breast Cancer Res Treat. 2011;doi:10.1007/s10549-011-1585-0).

– Derek LeRoith, MD, PhD

Chief, Division of Endocrinology, Diabetes & Bone Diseases Mount Sinai School of Medicine New York, New York

Disclosure: Dr. LeRoith is a consultant for Bristol-Myers Squibb and AstraZeneca.