Abstract and Introduction
Background & Aims: Glucagon-like peptide-1–based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.
Methods: We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase–4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004–2009; data on adverse events associated with 4 other medications were compared as controls. The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.
Results: Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies P < 2 × 10 ). Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies P < .008, P < 9 × 10 ). All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P = 20).
Conclusions: These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1–based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.
Hyperglycemia in type 2 diabetes is due to inadequate insulin secretion in the setting of insulin resistance. A new class of drugs has been introduced for treatment of type 2 diabetes that takes advantage of the properties of the gut hormone glucagon-like peptide-1 (GLP-1). GLP-1 is secreted by L-type endocrine cells in the distal ileum in response to food ingestion and 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 accomplish sustained GLP-1 receptor activation therapeutically, 2 strategies have been developed. In one, GLP-1 agonists that are resistant to DPP-4 degradation are administered by injection, including exenatide (Byetta; Amylin Pharmaceuticals, San Diego, CA) and liraglutide (Victoza; Novo Nordisk, Bagsværd, Denmark). The alternative strategy is use of inhibitors of DPP-4, such as sitagliptin (Januvia; Merck & Co, Inc, Whitehouse Station, NJ), when administered orally enhance levels of endogenously secreted GLP-1.
The attributes of GLP-1–based therapy for type 2 diabetes have been extensively reviewed. Interest has recently been focused on the potential adverse effects of these new therapies. Nausea is relatively common with the injected GLP-1 receptor agonists. Acute pancreatitis after administration of exenatide was originally reported in the form of case reports, but then followed by a cautionary letter from the US Food and Drug Administration (FDA). Recently, a similar caution was made by the FDA with regard to pancreatitis associated with sitagliptin treatment.
The manufacturers of exenatide and sitagliptin have suggested that the most likely reason for the apparent association between the use of these drugs and acute pancreatitis is the increased risk of pancreatitis in patients with type 2 diabetes. Recent animal studies showing pancreatitis as a consequence of GLP-1 mimetic therapy challenge that assumption and raise concerns about whether the asymptomatic chronic pancreatitis might be an as yet undetected adverse effect of GLP-1–based treatment. Moreover, because pancreatitis is a risk factor for pancreatic cancer, long-term GLP-1 receptor activation might lead to increased risk for pancreatic cancer. It has also been suggested that immunomodulatory effects of DPP-4 inhibition might increase risk for all cancers. Also, thyroid tumors were reported to be more common in rodent toxicology studies with the GLP-1 agonist liraglutide, although the relevance of this in humans has been questioned.
Given the >20 million known patients with type 2 diabetes in the United States alone and the numerous GLP-1–based drugs either available now or in the final stages of development, the potential impact of adverse effects of this class of drugs is considerable. However, because this class of drugs is relatively newly available, there are limited data on adverse effects. In addition, available reports were sponsored by pharmaceutical companies and arguably have a limited capacity to detect adverse outcomes. The purpose of the present study was to gain the best possible insight into these potential adverse effects by examining the FDA adverse event reporting system (AERS) database.