Regulatory Focus™ > News Articles > Diabetes Drugs Taken by Millions May be Less Safe than Currently Believed, Reports BMJ

Diabetes Drugs Taken by Millions May be Less Safe than Currently Believed, Reports BMJ

Posted 10 June 2013 | By Alexander Gaffney, RAC

A class of diabetes drug taken by millions of patients around the world may be considerably more dangerous than originally though, owing to the reticence of pharmaceutical companies to share data and make public the results of some of their studies, claim investigators with the British Medical Journal.


The class of drugs, known as glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors, have already been the subject of ongoing and intensifying safety concerns from US and EU regulators since the 2007 approval of Byetta (exenatide), a GLP-1 injection intended to treat type-2 diabetes.

By August 2008, FDA had already received dozens of reports associating the drugs with acute pancreatitis, and subsequently issued a warning to healthcare professionals saying some of these cases could potentially be severe. In particular, FDA said it had received reports of six cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta, two of which were fatal.

By September 2009, FDA's concerns had spread to DPP-4 inhibitors, which include the diabetes drugs Januvia (sitagliptin) and Janumet (sitagliptin/metformin), which exhibited nearly identical trends to those seen in some Byetta patients. In both cases (GLP-1 and DPP-4), FDA advised providers to be vigilant and aware of the signs and symptoms associated with pancreatitis, and to discontinue the drugs if pancreatitis is suspected.

In 2013, FDA once again issued a warning to healthcare providers, saying it had become aware of still more potential risks to patients taking GLP-1 and DPP-4 incretin mimetics, including a general increase in the risk of cancer.

While the risks of pancreatitis remained relatively stable, FDA said the list of drugs associated with those risks had grown to include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto).

Based on what FDA called an "examination of a small number of pancreatic tissue specimens taken from patients after they died," it said it is concerned about "potential pancreatic toxicity" associated with the drugs. These associations are not yet conclusive, FDA added in its statement. Accordingly, the agency said it intends to study the issue in further depth and participate in a June 2013 meeting being run by the National Cancer Institute (NCI) on the association between pancreatitis, diabetes and pancreatic cancer.

Shortly after FDA's March 2013 warning, the European Medicines Agency (EMA) announced that it, too, would begin an investigation into the drugs, led by its Committee for Medicinal Products for Human Use (CHMP) and Pharmacovigilance Risk Assessment Committee (PRAC).

An Extensive Investigation

Though the drug's risk of pancreatitis is now well known, the British Medical Journal argues that the true risk to patients may be considerably more pronounced than previously known.

Writing in the June 2013 edition of the BMJ, Deborah Cohen, BMJ's investigations editor, said she had "reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to unwanted proliferative or inflammatory pancreatic effects."

Cohen also said she found no evidence that companies had conducted "critical safety studies" or released raw data that could have put some of the associated safety problems to rest, "posing serious questions about the safety of this class of drug."

And, as Cohen's piece explains, in case after case manufacturers have withheld certain data from regulators, raising questions about whether those data contain signals about pancreatic risks associated with the drug that would establish a more definitive causal link.

"All drug licensing is about balancing benefits and risks," wrote Fiona Godlee, editor in chief for BMJ in an accompanying editorial. "But instead of engaging in open debate about legitimate and important scientific questions, the manufacturers have been unwilling to share their data. Meanwhile patients and doctors have not been kept properly informed about the uncertainties surrounding these drugs."

"The debate would be much easier to resolve if all the information was placed in the public domain so scientists, doctors and ultimately patients could make up their own minds," she added.

BMJ: Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?


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