In a review published Thursday in the NEJM, the FDA and European Medicines Agency said that recent assertions regarding a causal association between incretin-based diabetes therapies and pancreatitis or pancreatic cancer "are inconsistent with the current data." Both the US and European regulators began separately reviewing the drugs, which include GLP-1 analogues and DPP-4 inhibitors, last year after study data linked the medicines to an increased risk of pancreatitis and pancreatic-duct metaplasia in patients with type 2 diabetes.
The EMA's Committee for Medicinal Products for Human Use announced in July last year that current findings do not confirm the previous concerns over an increased risk of pancreatic adverse events. FDA official and lead author of the NEJM paper Amy G. Egan said that due to the "intense interest" in the issue, the agencies had been sharing their reviews and findings, and decided "that a joint publication would best convey this consensus of opinion."
The regulators noted that they reviewed a number of clinical trials and animal studies, including some new rodent studies that the FDA asked drugmakers to conduct, as well as others that the agency performed itself. The analysis also comprised results from two cardiovascular outcome trials, including the SAVOR study, which investigated AstraZeneca's Onglyza (saxagliptin) in 16 492 patients with type 2 diabetes. The other trial, called EXAMINE, looked at Takeda's Nesina (alogliptin) in 5380 patients with type 2 diabetes.
According to the FDA and EMA, the reported rates of acute pancreatitis in the SAVOR and EXAMINE trials were low, with similar rates of events in the drug and placebo groups. In addition, the reported incidence of pancreatic cancer was five and 12 cases, respectively, in the drug and placebo groups in the SAVOR trial, with no incidence of pancreatic cancer in either group in the EXAMINE trial.
The regulators noted that they "have not reached a final conclusion at this time... although the totality of the data that have been reviewed provides reassurance." The agencies indicated that pancreatitis will continue to be considered a risk associated with incretin-based drugs until more data are available, with both the FDA and EMA continuing to probe this safety signal. The regulators added that "the current knowledge is adequately reflected in the product information or labelling."
A number of the studies that suggested a link between incretin-based therapies and pancreatic adverse events were conducted by Peter C. Butler, chief of the division of endocrinology at the University of California, Los Angeles. In response to the FDA and EMA's findings, Butler said the commentary "provides very little information as to how they reached this conclusion," calling for the analyses to be made public. Meanwhile, Sidney M. Wolfe, senior adviser to the Public Citizen Health Research Group, which has petitioned the FDA to remove Novo Nordisk's GLP-1 agonist Victoza (liraglutide) from the market, said "I don’t know what purposes are served by giving false assurances of safety" in the review.
ISI Group analyst Mark Schoenebaum suggested that the safety concerns' effect on sales of the drugs, which also include AstraZeneca's Byetta (exenatide), Boehringer Ingelheim's Trajenta (linagliptin), Merck & Co.'s Januvia (sitagliptin) and Sanofi's Lyxumia (lixisenatide), was probably small.
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