BMJ Digs Deep Into Incretins and Pancreatic Cancer Debate

June 10, 2013

The issue of pancreatitis and pancreatic cancer associated with so-called incretin mimetic therapies for type 2 diabetes has been downplayed by the pharmaceutical industry, according to a new in-depth investigation by the BMJ.

Also regulators, including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have not acted as aggressively as they could have regarding these concerns, says Deborah Cohen, MD, investigations editor of the BMJ, in a feature article published online today.

She acknowledges, however, that the 2 agencies are currently reviewing the issue following research published in March in Diabetes.

The controversy — most recently addressed in a series of articles published in Diabetes Care last month — will also be discussed in a Dispatches documentary: "Diets, Drugs, and Diabetes," to be aired on the United Kingdom's Channel 4 this evening.

Pieces of a Jigsaw Together Indicate Cause for Concern

The investigation begins by relating the story of how the concerns about pancreatitis and pancreatic cancer began to arise among the scientific community with regard to a new class of type 2 diabetes drugs, the glucagonlike peptide-1 (GLP-1) agonists and dipeptidyl peptidase (DPP-4) inhibitors. Abnormalities were first observed in the pancreas of rats given the DPP-4 inhibitor sitagliptin (Januvia, Merck), by Peter Butler, MD, from the University of California, Los Angeles, work that he subsequently published in 2009. Dr. Butler later found abnormal changes, including precancerous lesions, in the pancreases of eight organ donors taking GLP-1–based drugs compared with patients taking other antidiabetic drugs.

The BMJ and Channel 4 Dispatches have reviewed thousands of pages of regulatory documents obtained under the Freedom of Information Act and discovered data pointing to "unwanted proliferative or inflammatory pancreatic effects" of these drugs that have not been published, it claims.

Also, despite published reports that indicated concerns, pharmaceutical companies have not performed certain critical safety studies, nor have regulators requested them yet, the investigation has found. And access to raw data that might help resolve doubts about the safety of these drugs has been denied, it alleges.

"On their own, the individual pieces of unpublished evidence may seem inconclusive — increases in size and abnormal changes in animal pancreases, raised pancreatic-enzyme concentrations in humans, reports of thyroid neoplasms and pancreatitis in early clinical trials — when considered alongside other emerging and longstanding evidence, a more worrying picture emerges, posing serious questions about the safety of this class of drug," says Dr. Cohen.

"Should we be worried about this?" asks Edwin A.M. Gale, MB, Bchir, emeritus professor of diabetic medicine at Southmead Hospital, Bristol, United Kingdom, in an accompanying editorial in the BMJ today. "Very much so," he responds.

And editor in chief of the BMJ, Fiona Godlee, MD, says: "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 of the information were placed in the public domain so scientists, doctors, and ultimately patients could make up their own minds."

Michael Elashoff, PhD, a statistician and former FDA reviewer who was one of the researchers who expressed concerns about this issue in Diabetes Care last month, says the implications are clear.

"These drugs are being used by hundreds of thousands or millions of patients, and if the safety hasn't been adequately studied, then there are a lot of people at risk of some very serious side effects of the drugs," he tells Dr. Cohen.

US NIDDK to Discuss Topic Later This Week

The US Institute for Safe Medication Practices has also recently called for "further investigation" into the signal for pancreatic cancer with these drugs and said further studies of their long-term effects on human pancreatic and thyroid tissues are needed.

"Meanwhile, we recommend updating the prescribing information to include stronger warnings based on the adverse-event data now available," the institute concluded in April.

And later this week, the subject will be discussed during a National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Workshop on Pancreatitis, Diabetes, and Pancreatic Cancer.

At the same time, hundreds of people in the United States are suing manufacturers, alleging that these drugs cause pancreatitis and in some cases pancreatic cancer.

The concerns relate to a number of widely prescribed GLP-1–based therapies, the 2 injectable GLP-1 agonists, exenatide (Byetta, Amylin/Lilly) and liraglutide (Victoza, Novo Nordisk), and the oral DPP-4 inhibitors sitagliptin, saxagliptin (Ongylza, AstraZeneca/Bristol-Myers Squibb), and linagliptin (Tradjenta, Boehringer Ingelheim/Lilly).

Newer entrants to these drug classes are also on the horizon, including the GLP-1 agonist lixisenatide (Sanofi), recently approved in the European Union but not yet available in the United States, and the DPP-4 inhibitor vildagliptin (Galvus, Novartis), which is available in Europe but not the United States. Another DPP-4 inhibitor, alogliptin (Takeda), was recently approved by the US FDA in January 2013.

The market leaders in these drug classes, sitagliptin, in the case of DPP-4 inhibitors, generated sales of about $4.1 billion last year, and liraglutide, a GLP-1 agonist, had revenue of $1.7 billion.

This means "there is much at stake for the companies and the organizations and doctors who depend on their support," Dr. Cohen observes.

"Have doctors and patients been adequately warned?" she wonders.

"While the debate continues about pathophysiology and mechanisms of action, questions remain about whether the companies and regulators have done enough to get to the bottom of these safety concerns," she concludes.

Patients Should Not Stop Diabetes Meds, Says UK Charity

UK media reports this morning detailed the BMJ investigation and how diabetes drugs "taken by thousands of Britons may contribute to the causes of pancreatic cancer."

But the charity Diabetes UK urges calm. Simon O'Neill, Diabetes UK director of health intelligence, said in a statement provided to Medscape Medical News: "The European Medicines Agency is currently investigating findings from an independent study that has suggested there may be a link between use of GLP-1– and DPP-4–based therapies for type 2 diabetes and pancreatitis and pancreatic cancer.

"Diabetes UK does not currently advocate any change in the use of GLP-1– and DPP-4–based treatments for patients with type 2 diabetes and will await the findings of the EMA research. In particular, patients should not stop their medication, unless advised by their doctor."

And Andrew Boulton, MD, from the University of Manchester, United Kingdom, and current president of the European Association for the Study of Diabetes (EASD), told Medscape Medical News: "These agents — both GLP-1 analogs and DPP-4 inhibitors — have been used extensively across the world to treat type 2 diabetes, and their efficacy is clear. Weight loss on the GLP-1 analogs is usually seen, with a beneficial effect on glycemic control."

However, "a slightly increased risk of pancreatitis is well recognized, and these data published by Butler need to be confirmed, in my view, by other investigators (independent of the pharma industry) and subjected to rigorous peer review," he added.

"In the meantime, until these precancerous changes are confirmed and their relevance to humans clarified, it is important not to generate unnecessary anxiety in our patients with type 2 diabetes," he concluded.

Dr. Cohen and Dr. Boulton have reported no relevant financial relationships. Dr. Gale has provided expert testimony in litigation concerning exenatide.

BMJ. Published online June 10, 2013. Abstract Editorial

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