Do Incretin-Based Drugs for Diabetes Cause Pancreatitis?

Both GLP-1 receptor agonists such as exenatide (Byetta, Bydureon) and DPP-4 inhibitors such as sitagliptin (Januvia) lower blood glucose as a result of their effects on incretin hormones, and both have been implicated in post-marketing reports of pancreatitis occurring in patients being treated for type 2 diabetes. Post-marketing reports by themselves cannot prove cause and effect, but the labels of all the drugs in both of these classes now carry prominent warnings about the possibility of acute and chronic pancreatitis and even pancreatic cancer occurring in patients who use them.

The FDA and the European Medicines Agency (EMA) decided to look further. In a report published in the February 27, 2014 issue of the New England Journal of Medicine, they described the results of their investigations, which included re-analysis of hundreds of toxicology studies in thousands of animals, including some that had been treated with doses much higher than those used clinically and some rodents that had diabetes. The agencies found no convincing evidence of pancreatitis. The FDA also looked at data from 41,000 patients participating in more than 200 clinical trials and found some increases in amylase and lipase levels (means were still within normal limits), but no evidence of an increased incidence of pancreatic disease. Both agencies agreed that current data did not support a causal relationship between use of incretin-based drugs and pancreatitis or pancreatic cancer. But the warnings stayed in the package inserts.

Now we are preparing an article on 2 new combinations of drugs (canagliflozin/metformin and dapagliflozin/metformin) for treatment of type 2 diabetes, and the article will include a table listing the advantages and adverse effects of all the classes of drugs for this indication. When we sent the article out to reviewers, it included pancreatitis as an adverse effect of GLP-1 agonists and DPP-4 inhibitors. Several reviewers objected on the grounds that both the FDA and EMA have said that there is no evidence to support a causal relationship. But can we just ignore a warning in the package insert? We welcome your comments.

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Comments

  1. Mark Nabavi says:

    It is quite surprising !! There is a reversal of roles here. Usually, the drug manufacturers try to ignore/antagonize/not welcome, the recommendations made by regulatory authorities. Why is it the reverse here ???

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