The Safety of Incretin-Based Therapies—Review of the Scientific Evidence

CONTEXT: Antidiabetic therapies based on potentiation of incretin action are now widely used; however, understanding of their long-term safety remains incomplete. EVIDENCE ACQUISITION: We searched articles in PubMed for data assessing the safety of incretin-based therapies. EVIDENCE SYNTHESIS: Three major areas of interest are reviewed: incretin action in the cardiovascular system, pancreatitis, and cancer. Incretin therapies reduce weight gain, minimize hypoglycemia, decrease inflammation, and are cardioprotective in preclinical studies. However, data permitting conclusions about whether incretin therapies modify the development of cardiovascular events in humans are not available. Case reports link incretin therapies to pancreatitis, but retrospective case control studies do not associate pancreatitis with glucagon-like peptide-1 receptor (GLP-1R) agonists or dipeptidyl peptidase-4 inhibitors. Preclinical studies of pancreatitis have yielded conflicting results, and mechanisms linking incretin receptor activation to pancreatic inflammation have not yet been forthcoming. GLP-1R activation promotes C-cell hyperplasia and medullary thyroid cancer in rodents; however, long-term clinical studies of sufficient size and duration to permit conclusions regarding cancer and incretin therapeutics have not yet been completed. CONCLUSIONS: The available data on incretin action and incidence of cardiovascular events, pancreatitis, or cancer are not yet sufficient or robust enough to permit firm conclusions regarding associations with incretin-based therapies in humans with diabetes. The forthcoming results of long-term cardiovascular safety studies should provide more conclusive information about the safety of GLP-1R agonists and dipeptidyl peptidase-4 inhibitors in diabetic patients.