Safety of Incretin-Based Therapies Hotly Debated

Marlene Busko

May 08, 2013

Should clinicians be concerned about early signals of potential thyroid or pancreatic cancer with incretin mimetic drugs for type 2 diabetes? Yes, say some experts. No, says another expert, who maintains that proven benefits from these therapeutic agents far outweigh any uncertainty about their safety.

In a critical analysis of the clinical use of incretin-based therapies published online May 3 in Diabetes Care, Peter C. Butler, MD, from the University of California, Los Angeles, and colleagues express alarm regarding the potential long-term cancer risk associated with use of incretin-based glucose-lowering agents — glucagonlike peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.

But Michael A, Nauck, MD, from the Bad Lauterberg Diabetes Center, in Germany, presents the opposing view. Concerns about pancreatic or thyroid cancer with these agents are not well substantiated, and "such considerations should not currently influence our treatment decisions regarding the potential prescription of GLP-1 receptor agonists or DPP-4 inhibitors within a treatment regimen for type 2 diabetes," he writes.

Point: Incretin-Based Therapies Have Questionable Safety

According to Dr. Butler and colleagues, "The story is familiar. A new class of antidiabetic agents is rushed to market and widely promoted in the absence of any evidence of long-term beneficial outcomes. Evidence of harm accumulates but is vigorously discounted. The regulators allow years to pass before they act. The manufacturers are expected — quite unrealistically — to monitor the safety of their own product."

For example, the first GLP-1-based therapy, exenatide (Bydureon, Lilly/Amylin Pharmaceuticals), was launched in the United States in 2005, and a single case of acute pancreatitis was reported in 2006. However, by the second quarter of 2012, US Food and Drug Administration (FDA) adverse-event reports listed 2327 cases of acute pancreatitis with exenatide, as well as 718 with sitagliptin (Januvia, Merck), 888 with liraglutide (Victoza, Novo Nordisk), 125 with saxagliptin (Onglyza, AstraZeneca), and 43 with linagliptin (Tradjenta, Boehringer Ingelheim). The existing evidence therefore suggests that these widely used GLP-1–based therapies are associated with acute pancreatitis, they say.

And more important, pancreatitis is a risk factor for pancreatic cancer. "There is a signal for cancer of the pancreas for exenatide in both the FDA and German regulatory databases and for sitagliptin in the FDA database," they observe. "The signal has grown stronger," with 258 pancreatic cancers reported to the FDA for exenatide, 63 for liraglutide, 81 for sitagliptin, 18 for saxagliptin, and 1 for linagliptin.

Similarly, 74 cases of thyroid cancer have been reported with use of exenatide and 57 cases with liraglutide, although no comparable safety signal has been seen with DPP-4 inhibitors.

They predict, however, that "rapid developments" will soon clarify the true safety of these drugs. In the meantime, "the case presented here does not prove that these agents are unsafe, but it does suggest that the burden of proof now rests with those who wish to convince us of their safety," they conclude.

Counterpoint: Risks Are Rare and Unsubstantiated

Dr. Nauck begs to differ. The benefits of incretin-based antidiabetic agents greatly outweigh any potential risks, since they effectively lower blood glucose levels without promoting weight gain or exposing a patient to risk for hypoglycemia, he writes.

It is "reassuring" that no case of clinically evident chronic pancreatitis has been described after initiating treatment with incretin-based medications, according to Dr. Nauck. "There is also no case report of pancreatic cancer diagnosed after exposing a patient to GLP-1 receptor agonists or DPP-4 inhibitors in a patient in whom there had previously been a morphologically tumor-free pancreas," he points out, noting also that pancreatic carcinomas develop slowly, so it is unlikely such cases would occur after the relatively recent introduction of incretin-based therapies.

The bottom line is that there is no convincing evidence that incretin-based therapies increase the risk for acute pancreatitis, chronic pancreatitis, and eventual pancreatic cancer, he states.

With regard to thyroid cancer, he says the evidence linking GLP-1 receptor agonists to thyroid cancer is weak and mainly relates to work done in rodents. However, he advises that these therapies should not be used to treat patients who are genetically predisposed to this cancer. The DPP-4 inhibitors are not associated with thyroid cancer, however, he stresses.

"Thus, while the benefits — expected or proven — from using incretin-based medications seem to be substantial and address risks central to patients with type 2 diabetes, the potential…risks typically refer to rare events and are discussed in a controversial manner, eg, without certainty regarding a potential role of incretin-based medications to cause substantial harm," he writes.

"Based on today's available knowledge, incretin-based medications can be considered effective and safe," he concludes.

Dr. Butler is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Larry L. Hillblom Foundation, and the Peter and Valerie Kompaniez Foundation. Disclosures for the coauthors are listed in the article. Dr. Nauck has received research grants to his institution from Berlin-Chemie/Menarini, Eli Lilly, Merck Sharp & Dohme, Novartis, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Lilly Deutschland, MetaCure, Roche Pharma, Novo Nordisk, and Tolerx for participation in multicenter clinical trials. He has received consulting fees and/or honoraria for membership in advisory boards and/or honoraria for speaking from Amylin, AstraZeneca, Berlin-Chemie/Menarini, Boehringer Ingelheim, Bristol-Myers Squibb, Diartis Pharmaceuticals, Eli Lilly, Hoffmann-LaRoche, GlaxoSmithKline, Intarcia Therapeutics, MannKind, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda, Versartis, and Wyeth Research, including reimbursement for travel expenses.

Diabetes Care. Published online May 3, 2013. Butler article Nauck article