https://diabetes.acponline.org/archives/2014/03/14/1.htm

FDA finds no link between incretin-based drugs, pancreatic complications

Data do not support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, concluded a review by U.S. and European regulatory agencies.


Data do not support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, concluded a review by U.S. and European regulatory agencies.

Researchers from the FDA and the European Medicines Agency (EMA) outlined how they conducted comprehensive evaluations in response to postmarketing reports of pancreatitis and pancreatic cancer in patients using incretin-based drugs. Their conclusions appeared in a Feb. 27 Perspective in the New England Journal of Medicine.

The FDA reevaluated more than 250 toxicology studies completed as part of all marketing applications for incretin-based drugs. The studies, conducted in nearly 18,000 healthy animals, found no overt pancreatic toxic effects or pancreatitis. The EMA conducted a similar review and found no drug-induced pancreatic tumors in rats and mice that had been treated for up to 2 years with incretin-based drugs, even at doses that greatly exceed the level of human clinical exposure.

To gather data that might more closely match the drugs' uses in humans, the FDA required drugmakers to conduct 3-month pancreatic toxicity studies in a rodent model of diabetes. Three studies submitted to the FDA found no treatment-related adverse effects on the pancreas.

Clinical safety databases reviewed by the FDA included data from more than 200 trials, involving about 41,000 participants, more than 28,000 of whom were exposed to an incretin-based drug. In these trials, 15,000 patients received a drug for 24 weeks or more, and 8,500 received a drug for 52 weeks or more. EMA conducted a similar review. Small imbalances in the incidence of pancreatitis were reported in premarketing trials, but a pooled analysis of data from 14,611 patients with type 2 diabetes in 25 clinical trials of sitagliptin showed no compelling evidence of an increased risk of pancreatitis or pancreatic cancer.

The agencies also looked at 2 cardiovascular outcome trials: the Saxagliptin Assessment of Vascular Outcomes Recorded (SAVOR) trial and the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. There were similar rates of acute pancreatitis in the treatment and placebo groups in both trials. There were also similar rates of pancreatic cancer in the drug and placebo groups in the SAVOR trial, with no incidence of pancreatic cancer in either group in the EXAMINE trial.

The FDA and the EMA agreed that the data do not currently support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer. “Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal,” the Perspective concluded.