European drugs agency clashes with scientists over safety of GLP-1 drugs

Despite concerns raised by some scientists that a particular class of antidiabetes drugs known as glucagon-like peptide-1 (GLP-1) based drugs may have adverse effects on the pancreas, the European Medicines Agency has said that it had no new concerns about the drugs on the basis of the “presently available data.”

These drugs, which are also called incretin mimetics, are of two types: GLP-1 agonists, such as exenatide, liraglutide, and lixisenatide; and dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin and saxagliptin.

A recent BMJ investigation found evidence indicating a potential risk of unwanted effects of the GLP-1 based drugs on the pancreas.1 This evidence included unpublished evidence of increases in size and abnormal changes in animal pancreases, raised pancreatic enzyme concentrations in humans, and pancreatitis in early clinical trials.

The investigation also highlighted safety signals for pancreatic cancer from the adverse reporting database from three different agencies.

However, after its own investigation of “presently available” non-clinical and clinical data, the European drug regulator said that the evidence did “not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines.”

The BMJ asked the agency what data it had reviewed and what it meant by “pancreatic adverse events.” At the time of the BMJ going to press the agency had not responded to the questions and said that a full report would be available later this week. (See bmj.com.)

The agency’s investigation into the safety of the GLP-1 based drugs was triggered by a study conducted by University of California at Los Angeles and the University of Florida, subsequently published in Diabetes.2 The US Food and Drug Administration has also announced an investigation but has not concluded it.

The small UCLA and University of Florida study analysed the pancreases of eight organ donors who had been taking an incretin mimetic for at least a year (seven taking sitagliptin and one exenatide), 12 pancreases from other people with diabetes who had been taking other classes of treatment, and 14 pancreases from people without diabetes.

The pancreases in those who had taken incretin mimetics were on average 40% larger, with more precancerous changes. In addition, seven of the eight patients who had been treated with a mimetic had α cell hyperplasia, three expressed α cell derived microadenomas, and one had a grade 1 α cell derived neuroendocrine tumour that was “not appreciated in life.”

After a review of the publication and consultation of a panel of experts, the European Medicines Agency said that the study had a number of methodological limitations and potential sources of bias.

“Most importantly, [there were] differences between the studied groups with respect to age, gender, disease duration and treatments, which preclude a meaningful interpretation of the results,” the agency said.

The BMJ had previously highlighted the uncertainty surrounding the mechanism of action of the GLP-1 based therapies. The drugs stimulate β cells and suppress glucagon made by the α cells, which the UCLA and University of Florida study suggested might lead to α cell hyperplasia.

Evidence of α cell hyperplasia has come from various models and sources. Whether this evidence is applicable to GLP-1 based treatments is subject to fierce debate.

However, the European Medicines Agency said that although clinical trials had not shown an increased risk of pancreatic cancer, the “number of events is too small to draw final conclusions.”

The agency said that there was still some uncertainty over the drugs’ mechanism of action. “Some uncertainties remain in respect to the long-term effect of these medicines on the pancreas and more data collection efforts are under way,” it said.

The agency also said that a small number of cases of pancreatitis had been reported in clinical trials. In addition, a significant number of cases had been seen in spontaneous reports, although these needed to be interpreted cautiously, it said.

“All these medicines already carry warnings in their product information,” the agency said, adding that the labels would be “harmonised” across the class.

Merck, the manufacturer of sitagliptin, sent the BMJ a statement. “Nothing is more important to us than the safety of our medicines and the people who take them. We appreciate the important role that the EMA [European Medicines Agency] and its CHMP [Committee for Medicinal Products for Human Use] play in monitoring the safety of medicines in Europe,” said Michael Rosenblatt, Merck’s executive vice president and chief medical officer. The statement pointed to different studies included in Merck’s review of the safety profile of sitagliptin.

After conducting their own review, the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation have said that people taking these drugs—or those who may consider taking them—should be informed of all that was currently known about their potential risks and advantages so they could make the best possible decisions about their treatment and care, in consultation with their healthcare providers.

In a joint statement in June this year they said, “At this time, there is insufficient information to modify current treatment recommendations.”

The European Medicines Agency said that several studies were “planned or ongoing, including large outcome studies which are aimed at increasing the ability to understand and quantify risks associated with these medicines, including the occurrence of pancreatitis and pancreatic cancer, and the potential value of additional studies will also be considered.”