The drugs sitagliptin and exenatide, used to treat patients with type 2 diabetes, increase risk for pancreatitis and cancer, according to a study from Michael Elashoff and colleagues published in the July issue of Gastroenterology.
The authors examined the United States (US) Food and Drug Administration’s database of reported adverse events for those associated with the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin and the glucagon-like peptide (GLP)-1 mimetic exenatide, from 2004 to 2009. They compared the numbers of adverse events reported for these drugs with those for 4 other medications for diabetes.
Elashoff et al. found that sitagliptin and exenatide increased the risk for pancreatitis 6-fold, compared with other drugs used to treat type 2 diabetes. The incidence of pancreatic cancer (but not other types of cancer) also increased among patients who took sitagliptin or exenatide, compared with other therapies. The reported rate of thyroid cancer in patients treated with GLP-1 mimetic therapy increased in the exenatide group, but not in the sitagliptin group.
GLP-1 amplifies glucose-mediated insulin secretion; it is secreted by L-type endocrine cells in the distal ileum in response to food ingestion. The peptide has a short half-life, and is degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) in the circulation. GLP-1 receptor activation can be sustained using agonists that are resistant to DPP-4 degradation (such as exenatide or liraglutide). As an alternate strategy, inhibitors of DPP-4, such as sitagliptin, increase levels of secreted GLP-1.
There have been case reports that exenatide or sitagliptin produced some side effects, including nausea and pancreatitis; the FDA has issued cautionary letters about these therapeutics. Animal studies have shown that that GLP-1 mimetics cause pancreatitis, and thyroid tumors were reported to be more common in rodent toxicology studies with the GLP-1 agonist liraglutide. However, data on the side effects of these drugs in patients are conflicting.
How might the GLP-1 pathway lead to inflammation and cancer? Activation has been proposed to increase proliferation and reduce apoptosis of β-cells, signaling via phosphatidylinositol-3 kinase, Akt, mitogen-activated protein kinase, protein kinase Cζ, Src, and the epidermal growth factor receptor (EGFR; see below figure). These events could cause hyperplasia and inflammation in the pancreatic ductal epithelium.
There are approximately 20 million known patients with type 2 diabetes in the US alone, and the numerous GLP-1–based drugs are either available now or in the final stages of development. Elashoff et al. state that the potential impact of adverse effects from this class of drugs is considerable, and that careful, long-term monitoring of patients treated with GLP-1 mimetics or DPP-4 inhibitors is required.
Almost all clinical trials of these drugs include metformin, the unchallenged first-line therapy of choice for type 2 diabetes. In contrast, in clinical practice, the new drugs are being used as early monotherapies. Elashoff et al. state that because metformin likely suppresses the putative abilities of GLP-1–based drugs to promote pancreatitis and pancreatic cancer, it will be important to establish the impact of GLP-1 mimetic therapy in the absence of metformin in prospective clinical trials.
Elashoff et al. admit that analysis of the FDA adverse event reporting database is not the ideal mechanism for determining adverse event rates of drugs. Limitations include incomplete data and reporting biases. However, the database has proven effective in similar earlier evaluations at detecting unintended drug side effects.
In an accompanying editorial, Joachim Spranger et al. warn “drug regulatory agencies are unlikely to receive data on drug safety that are independent of industry ties. Moreover, university-based medicine institutions have not viewed the problem of drug surveillance as a worthy academic pursuit. Until surveillance tools devoid of industry influence have been established to provide more robust data, such dilemmas of uncertainty regarding adverse effects will remain unsolved.”
Read the article online:
Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1–based therapies. Gastroenterology 2011;141:150–156.
Read the accompanying editorial:
Spranger J, Gundert-Remy U, Stammschulte T. GLP-1-based therapies: the dilemma of uncertainty. Gastroenterology 2011;141:20–23.