Any pancreatic effect of the drugs could be directly related to the beneficial physiological changes they induce in the pancreas, Dr. Spranger wrote. GLP-1 agonists increase beta-cell mass in rodents, by enhancing beta-cell proliferation, inhibiting apoptosis, and enhancing stem cell differentiation in the ductal pancreatic epithelium.
"Although beta-cell proliferation may be beneficial with regard to progression of type 2 diabetes, similar trophic mechanisms in other cell types might be detrimental. Thus, the epidermal growth factor receptor system and the Src kinase have been implicated in the pathogenesis and progression of numerous malignant tumors, including pancreatic cancer; mechanisms increasing the activity of these pathways could promote tumor development or progression."
The observations raise safety concerns which should be heeded until proven unfounded, Dr. Spranger wrote.
More detailed data about the link between incretin-based therapies and pancreatitis should be forthcoming, as long-term prospective studies continue to collect a wide range of safety information.
"There are at least nine prospective trials looking at cardiovascular outcomes which are capturing a lot of other outcomes data as well – including pancreatitis," Dr. Handelsman said. "In a few years we might be able to identify the true risk. But a scare based on an observational study from one insurance database, from years ago, is not enough to change practice."
The Endocrine Society’s response to Dr. Singh’s study echoed that of AACE and ADA, and added that "an important but unanswered question is whether or not the morbidity and mortality from incretin-associated pancreatitis is the same as that of other causes of pancreatitis," in particular whether such cases would lead to an increased incidence of pancreatic cancer similar to that seen in some other causes of acute pancreatitis. The statement suggested that some of the ongoing trials "may also help elucidate the conflict between Singh’s finding of increased incidence of acute pancreatitis with these drugs and the four recent retrospective database analyses and 1 meta-analysis cited in Singh’s paper which found no such association."
Dr. Singh’s study was sponsored by Johns Hopkins University and the National Institutes of Health. He had no financial disclosures. Dr. Handelsman has been a consultant to numerous drug companies developing diabetes treatments. Dr. Spranger has lectured for or received consultant honoraria from Eli Lilly and NovoNordisk.