The escalating controversy over the safety of the diabetes drugs known as incretin therapies — glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors — got even more heated Monday with a new investigative report by British reporters working for the medical journal BMJ and “Dispatches,” a documentary TV show on Britain’s Channel 4.
The investigators say they have uncovered unpublished data that link the drugs to “unwanted proliferative or inflammatory pancreatic effects.” They also report that drug regulators in both the United States and Europe have been slow to respond to research that suggests these drugs, which have been on the U.S. market since 2006, may be less safe than their manufacturers claim.
The investigation underscores how difficult it is for patients and physicians alike to be able to assess the benefits and risks of drugs when drug companies are able to withhold crucial data from independent scientific review.
It also raises questions about who should bear the burden — patients or the drug companies — while scientists and regulators attempt to resolve safety concerns about drugs already on the market.
Incretin therapies are taken by millions of people with diabetes. Global sales are reportedly $9 billion a year.
‘New darlings of diabetes treatment’
As BMJ investigations editor Deborah Cohen notes, incretin therapies, which lower blood sugar, have “been touted as the ‘new darlings of diabetes treatment’ — the biggest breakthrough since the discover of insulin nearly a hundred years before.”
Because the drugs have also been found to suppress appetite, drug manufacturers are hoping that the drugs will also soon receive FDA approval to be marketed to people without diabetes as an aid to weight loss.
But concerns about potential serious side effects — most notably, an increased risk of pancreatitis (inflammation of the pancreas), pancreatic cancer and thyroid cancer — have been surfacing with increasing frequency and are causing some in the medical community to wonder if incretin therapies should be widely prescribed.
This year alone, three separate reports have raised red flags about the safety of the drugs. In February, researchers at Johns Hopkins University reported that people who took two GLP-1 drugs, sitagliptin (Januvia) and exenatide (Byetta), were twice as likely to be admitted to the hospital for acute pancreatitis than people taking other classes of anti-diabetic medications.
In April, the non-profit Institute for Safe Medication Practices published an analysis of Food and Drug Administration (FDA) data that showed physicians were reporting an increasing number of cases of pancreatitis, pancreatic cancer and thyroid cancer among patients taking five different incretin therapies.
Also this spring, Dr. Peter Butler, chief of the division of endocrinology at the University of California, Los Angeles (UCLA), published a small study involving donated pancreases from people who had died of a non-pancreas-related disease. He found that the pancreases of people who had taken incretin therapies were more likely to have pre-cancerous abnormalities than those of people whose diabetes was being treated with another class of drug or who did not have diabetes.
Butler has been raising concerns about incretin therapies since 2008, when he and his UCLA colleagues found, to their surprise, that rats given sitagliptin developed enlarged pancreases and cellular changes thought to be a precursor to cancer.
Data remains hidden
Of course, none of these studies’ findings is proof that incretin therapies cause pancreatitis or cancer. As Cohen notes in her BMJ article, the drugs’ manufacturers contest all of the findings and strongly defend the safety of their products.
“Merck, for example, told the BMJ that independent observational studies and a meta-analysis of clinical trials involving 33,881 patients found no association between DPP-4 inhibitors and pancreatic cancer,” writes Cohen. “Bristol-Myers Squibb says that ‘post-marketing data does not confirm a causal relationship between saxagliptin or exenatide and pancreatic and/or pancreatic cancer.’”
Regulators — the FDA and European Medicines Agency — have also taken the position that there is no causal link between this class of diabetes drugs and potentially life-threatening changes to the pancreas, although both agencies announced in March that the issue is now under review.
But, according to the BMJ/Channel 4 investigation, the drug companies may not be revealing all that they know about this class of diabetes drugs:
In the course of this investigation, the BMJ has reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to unwanted proliferative or inflammatory pancreatic effects.
The BMJ has also found that, despite published reports that indicated safety concerns, companies have not done critical safety studies; nor have regulators requested them. And access to raw data that would have helped resolve doubts about the safety of these drugs has been denied.
On their own, the individual pieces of published evidence many 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. But when considered alongside other emerging and long standing evidence … a more coherent and worrying picture emerges, posing serious questions about the safety of this class of drug.
Needed: an open debate
“All drug licensing is about balancing benefits and risks,” states BMJ editor-in-chief Dr. Fiona Godlee in a press release that accompanies the investigative report. “But instead of engaging in open debate about legitimate and important scientific questions, the manufacturers have been unwilling to share their data … [and] 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 adds.
You can read the investigative report in full on the BMJ website. The report is accompanied by several related articles and editorials, including one (scroll down) on the drug-company pushback that has been leveled against Butler and two by Mayo clinic-associated physicians: “Helping Patients Make Sense of the Risk of Taking GLP-1 Agonists” by endocrinologist Dr. Victor M. Montori, and “Incretins and Neoplasia” by internists Thorvadur Halfdanarson and Rahul Pannala.