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Incretin‐based glucose‐lowering medications and the risk of acute pancreatitis and malignancies: a meta‐analysis based on cardiovascular outcomes trials

Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon‐like peptide (GLP)‐1 receptor agonists and dipeptidyl peptidase (DPP)‐4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta‐analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP‐1 receptor agonists and DPP‐4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient‐years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP‐1 receptor agonists and DPP‐4 inhibitors. Neither data on individual CVOTs of GLP‐1 receptor agonists nor their meta‐analysis [rate ratio: 1.05 (0.78–1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP‐4 inhibitors displayed a non‐significant trend towards an increased risk of acute pancreatitis, which was significant in the meta‐analysis [1.75 (1.14–2.70); P = 0.01]. Neither GLP‐1 receptor agonists nor DPP‐4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo‐controlled, prospective cardiovascular outcomes studies with GLP‐1 receptor agonists and DPP‐4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta‐analysis of DPP‐4 inhibitor CVOTs.