A systematic review of acute pancreatitis as an adverse event of type 2 diabetes drugs: from hard facts to a balanced position.

The question whether antidiabetes drugs can cause acute pancreatitis dates back to the 1970s. Recently, old concerns have re-emerged following claims that use of incretins, a new class of drugs for type 2 diabetes, might increase the relative risk of acute pancreatitis up to 30-fold. Given that diabetes is per se a potent risk factor for acute pancreatitis and that drug-related acute pancreatitis is rare and difficult to diagnose, we searched the medical databases for information linking acute pancreatitis and type 2 diabetes drugs. Among the biguanides, both phenformin and metformin (the latter in patients with renal insufficiency) have been cited in case reports as a potential cause of acute pancreatitis. Sulphonylureas, as both entire class and single compound (glibenclamide), have also been found in cohort studies to increase its risk. No direct link was found between pancreatic damage and therapy with metaglinide, acarbose, pramlintide or SGLT-2 inhibitors. In animal models, thiazolinediones have demonstrated proprieties to attenuate pancreatic damage, opening perspectives for their use in treating acute pancreatitis in humans. Several case reports and the US Food and Drug Administration pharmacovigilance database indicate an association between acute pancreatitis and incretins, dipeptidyl peptidase-4 (DPP-4) inhibitors, and GLP-1 receptor agonists. To date, however, a clear-cut odds ratio for this association has been reported in only one of eight pharmacoepidemiological studies. Finally, none of the intervention trials investigating these compounds, including two large randomized controlled trials with cardiovascular endpoints, confirmed the purportedly increased risk of acute pancreatitis with incretin use.