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Hyperplasia from GLP-1 drugs is “not a surprise,” say researchers

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f2025 (Published 27 March 2013) Cite this as: BMJ 2013;346:f2025
  1. Deborah Cohen
  1. 1BMJ

A week after the US Food and Drug Administration announced that it was to review unpublished data from a group of unnamed researchers linking certain antidiabetes drugs with pancreatitis,1 the findings have been published in a specialty journal, Diabetes.2

The FDA’s statement said that glucagon-like peptide-1 (GLP-1) based drugs used to treat type 2 diabetes could raise the risk of pancreatitis and precancerous pancreatic lesions and induce pancreatic duct metaplasia.

However, the findings in the small study go further than the US agency suggested.

Studies have previously shown that GLP-1 based drugs may cause pancreatic inflammation and focal proliferation in the exocrine pancreas in rodents. And a 2011 study published in Gastroenterology showed increased signals in the FDA’s adverse event reporting system of pancreatitis and pancreatic cancer in patients who used this class of drugs.3

So researchers from the University of California at Los Angeles and the University of Florida analysed a series of sections from pancreases from organ donors with type 2 diabetes who had been treated with a GLP-1 based drug for at least a year (sitagliptin (seven patients) or exenatide (one patient)) or with another antidiabetes treatment (12 patients) and 14 non-diabetic control patients.2 They matched participants in the two treatment groups for sex and BMI.

The pancreas mass from samples from people treated with the GLP-1 based drugs was on average 40% bigger than that from people with diabetes not taking GLP-1 based drugs, and this was associated with exocrine proliferation. Seven of the eight patients who had been treated with a GLP-1 based drug had α cell hyperplasia. Three of the eight samples expressed α cell derived microadenomas, and one had a grade 1 α cell derived neuroendocrine tumour that was “not appreciated in life.”

No neuroendocrine tumours or glucagon producing microadenomas were detected in the non-diabetic controls or the diabetic patients treated with other drugs.

The authors say that the finding should not come as a surprise: one of the properties of GLP-1 based treatment is to suppress the release of glucagon by α cells. Studies have previously shown that decreasing the availability or action of glucagon induces proliferation of pancreatic α cells.

“These findings lend additional weight to concerns regarding the effects of long term GLP-1 related therapy with respect to both unintended proliferative actions on the exocrine pancreas and now also a possible increased risk of neuroendocrine tumors,” the researchers wrote.

“In addition to the surveillance previously recommended for the potential association of GLP-1 based therapy and pancreatic cancer risk, the current data imply that surveillance for a possible increased risk of pancreatic neuroendocrine tumors is warranted.”

At the end of February a study in JAMA Internal Medicine showed that the risk of acute pancreatitis in people who took the GLP-1 based drugs exenatide and sitagliptin was twice that in people who took other antidiabetes drugs—although the absolute increase in risk was small.4

The FDA told the BMJ that it was taking the findings seriously but viewed them only as hypothesis generating and not as providing conclusive causal evidence of an increased risk of pancreatic cancer. It said that it has asked the companies for further evidence from ongoing clinical trials and epidemiological studies.

The European Medicines Agency said that it was currently investigating the information provided by the researchers to determine the need for possible further regulatory action.

The BMJ asked several companies, including those that make or market GLP-1 based drugs—such as Merck, Novo Nordisk, Lilly, BMS, and Boehringer Ingelheim—whether they thought this was a class effect. The BMJ also asked whether they had studied the effects of glucagon suppression on α cell hyperplasia and the effects of GLP-1 based drugs on the exocrine pancreas. None answered the questions directly.

However, a spokeswoman for Novo Nordisk said that the study did not include its drug, liraglutide.

She added, “The number of patients included in the study is small, and the groups are seemingly not well matched in relation to age at diagnosis, duration of diabetes, BMI, and concomitant medication.”

A spokeswoman for Lilly said that no drug related pancreatic tissue damage or toxicity was seen in an extensive non-clinical safety programme.

A spokesman for Merck said that the results of a meta-analysis involving 33 881 patients found “no association” between the use of the drugs and pancreatic cancer,5 and nor had any epidemiological studies found an increased risk, he added.

Notes

Cite this as: BMJ 2013;346:f2025

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