The development of new incretin mimetic drugs has added to the repertoire of anti-diabetic therapy options in the management of type 2 diabetes. However the adverse effects associated with these medications have made some physicians reluctant to use them, whereas others have had great success in achieving glucose control in their patients. A recent point-counterpoint narrative, published in Diabetes Care on the critical analysis of the clinical use of incretin-based therapies, expresses expert opinions on the benefit and risks with using these medications.
Michael A, Nauck, MD, from the Bad Lauterberg Diabetes Center, in Germany is a strong supporter in the use of incretin-based therapy. He reports that some of the great benefits from using these medications include: effective lowering of fasting and postprandial glucose, avoidance of hypoglycemic events, no weight gain but possible weight loss, improved durability compared to sulfonylureas, reduction in systolic blood pressure, and the prevention of microvascular complications.
Peter C. Butler, MD, from the University of California, Los Angeles, disagrees with Dr. Nauck and expresses concern that the potential long-term cancer risk associated with use of incretin mimetic outweighs the benefits. Dr. Butler exclaimed, "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."
Adverse drug reporting through the FDA’s Medwatch provides evidence to support Dr. Butler’s stance, "Exenatide, the ﬁrst GLP-1–based therapy, was launched in the U.S. on April 29, 2005. A single case report of acute pancreatitis appeared in 2006. Fast-forward to 2012, a total of 2,327 cases of acute pancreatitis was associated with exenatide as well as increasing reports with the other incretin mimetic drugs. The other GLP-1 agonist, liraglutide, had 888 case reported with its use. DPP-4 inhibitors are not without increased scrutiny either, the number of acute pancreatitis cases reported with sitagliptin, saxagliptin, and linagliptin were 718,125 and 43 respectively."
The concern here is that episodes of pancreatitis are a risk factor for pancreatic cancer. Dr. Butler reported, "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." By 2012, a total of 258 cases of pancreatic cancers were reported for exenatide, 63 for liraglutide, 81 for sitagliptin, 18 for saxagliptin, and 1 for linagliptin.
During drug development, preclinical studies of liraglutide found an increased number of C-cell tumors of the thyroid in rodents. The exact mechanism of malignancy growth has not been confirmed in people, but Dr. Butler points out that cases of thyroid cancer have been reported with the use of both GLP-1 agonists. A total of 74 cases have been reported with the use of exenatide and 57 cases with liraglutide but no cases of thyroid cancer have been reported with the use of DPP-4 inhibitors.
Dr. Butler and colleagues concluded, "The safety of the GLP-1 therapies can no longer be assumed. 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."
Dr. Nauck disagrees with the arguments that Butler and colleagues presented. Dr. Nauck explains, "It is reassuring that no case of clinically evident chronic pancreatitis has been described after initiating treatment with incretin-based medications. Certainly, 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."
As for the increased incidence of thyroid cancers with the use of GLP-1 agonists, Dr. Nauck claims the evidence is weak, "Whereas rodent C-cell lines are equipped with GLP-1 receptors at a high level of expression, this is not the case in their human counterparts… the ability of GLP-1 receptor stimulation to induce proliferative responses in human C cells has been judged as probably absent." Dr. Nauck later explains that no case reports have been published describing medullary thyroid cancer in patients receiving a treatment with a GLP-1 receptor agonist with normal thyroid gland.
With his expert opinion on incretin mimetic therapy, Dr. Nauck concluded, "Safety concerns related to the exocrine pancreas and the thyroid are not substantiated enough. 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."
Nauck, M. "A Critical Analysis of the Clinical Use of Incretin-Based Therapies: The benefits by far outweigh the potential risks". Diabetes Care May 3, 2013. doi: 10.2337/dc12-2504
Butler, P., Elashoff, M. Elashoff, R. et al. "A Critical Analysis of the Clinical Use of Incretin-Based Therapies: Are the GLP-1 therapies safe?" Diabetes Care May 3, 2013. doi: 10.2337/dc12-2713