Risk of Pancreatitis with Incretin-based Therapies

What are the true risks of pancreatitis when using glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl-peptidase 4 (DPP-4) inhibitors, also known as incretin-based therapies? Isolated reports have suggested these therapies increase a patient’s risk of pancreatitis, but the relatively small number of cases in phase 2 and 3 clinical trials has made a true determination difficult.

Retrospective reviews of health insurance claims or adverse event reports have yielded controversial results due to methodological uncertainties. Additionally, the very low incidence of pancreatitis makes it difficult to determine the effects of incretin-based therapies via individual prospective trials.

In an April 2014 study published in Diabetologia, researchers in Germany reviewed phase 3 clinical trial data from all pharmaceutical companies that produced GLP-1 receptor agonists and DPP-4 inhibitors. The investigators used pooled data to increase the statistical power, which created a more accurate analysis, and they analyzed the incretin-based therapy data against comparator therapies, as well as GLP-1 therapies against DPP-4 therapies. The data was further analyzed against 2 saxagliptin endpoint trials, EXAMINE and SAVOR-TIMI.

The analysis revealed 38 cases of pancreatitis associated with 17,775 patient-years exposure (PYO) of GLP-1 agonist treatment. For DPP-4 inhibitors, the researchers found 23 cases of pancreatitis reported with 24,196 PYO and 34 cases of pancreatitis reported from the 2 endpoint trials.

The authors of the study concluded there were no significant differences in terms of pancreatitis incidence between incretin-based drugs and their comparators. They cautioned that even with the pooled data from all pharmaceutical companies, the number of pancreatitis events was still relatively small. In their opinion, the relatively small sample size neither proved nor disapproved an association between incretin-based therapies and pancreatitis.

Nevertheless, the data indicated a non-significant trend toward a slightly elevated risk of pancreatitis with GLP-1 agonists. For the DPP-4 inhibitors, no consistent trend from the clinical trials was noted by the study; however, the authors cautioned the available data was inconclusive.