Diabetes Drugs Linked to Pancreas Disease

Six relatively new diabetes drugs have been linked in recent studies to an increased risk of pancreatitis and pancreatic cancer. These drugs are exenatide (BYETTA, BYDUREON) and liraglutide (VICTOZA), both of which are injected, as well as sitagliptin (JANUVIA, JANUMET, JANUMET XR, JUVISYNC), saxagliptin (ONGLYZA, KOMBIGLYZE XR), alogliptin (NESINA, KAZANO, OSENI) and linagliptin (TRADJENTA, JENTADUETO), which are taken orally.

The drugs are used, preferably along with diet and exercise, to lower blood sugar in adults with type 2 diabetes. They work by mimicking the effect of a hormone called GLP-1, which the body produces naturally to stimulate the release of insulin in response to a meal. More than 12 million prescriptions were filled in the U.S. in 2012, and the number is rising.

In April 2012, Public Citizen’s Health Research Group (HRG) asked the Food and Drug Administration (FDA) to ban one of the bestselling of these drugs, liraglutide, because pre-approval studies indicated that the drug caused pancreatitis in humans and thyroid cancer in animals at doses similar to the human dose. This evidence prompted several FDA reviewers to be so concerned about human thyroid cancer and other toxicity that they recommended it not be approved. HRG is in the process of drafting an additional petition to ban the other five drugs in this dangerous family. All six drugs are categorized as Do Not Use on WorstPills.org.

Pancreatitis

A recent study matched 1,269 diabetic patients hospitalized with acute pancreatitis to 1,269 “control” diabetic patients without pancreatitis, matching them by age category, sex and diabetes complications. Patients using either exenatide or sitagliptin, the only GLP-1 drugs used frequently enough to be examined at the time of the study, were 2.24 times more likely to be hospitalized because of acute pancreatitis than diabetics not using these drugs.[1]

Since these drugs came on the market and are being more widely used, a large and growing number of cases of pancreatitis have been reported to the FDA.

The risk has increasingly been acknowledged by the drug companies: In the year following HRG’s petition to ban liraglutide, the labels for the six GLP-1 drugs have been amended to contain statements on pancreatitis. One example appears on the label of saxagliptin:

Patients should be informed that acute pancreatitis has been reported during postmarketing use of ONGLYZA. … Patients should also be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.

A recent letter to U.K. physicians from saxagliptin’s manufacturers went even further, stating:

A review of reports of pancreatitis from post-marketing experience revealed that signs of pancreatitis occurred after the start of saxaglitpin treatment and resolved after discontinuation, which is suggestive of a causal relationship [emphasis added]. Moreover, pancreatitis has been recognized as an adverse event for other DPP-4 inhibitors [referring to other -gliptin drugs, such as sitagliptin, alogliptin and linagliptin].[2]

Liraglutide’s label states:

Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with VICTOZA. After initiation of VICTOZA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).

Finally, bestselling sitagliptin’s label states:

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA should promptly be discontinued and appropriate management should be initiated.

Pancreatic cancer

In addition to pancreatitis, recent evidence from both animal and human studies has increasingly pointed toward an additional — and similarly unacceptable — risk of pancreatic cancer with these same drugs.

A recent study from the University of California, Los Angeles (UCLA), found that brain-dead organ donors who had used exenatide or sitagliptin were much more likely to have abnormal, premalignant cell growth (or, in one case, a tumor) in their pancreas than nondiabetics or those using other diabetes drugs. This same study reviews evidence from previous studies documenting the capacity of these drugs to stimulate the same type of premalignant change in animal pancreases.[3]

Another recent article, coauthored by one of the UCLA study researchers, reviewed cases reported to the FDA of pancreatic cancer in diabetics. Such reports were much more common in diabetic patients using liraglutide, exenatide, sitagliptin or saxagliptin than in diabetics using other, older diabetes drugs. The article concludes that “a plausible mechanism links GLP-1-based therapy with acute pancreatitis — and a potential risk of pancreatic cancer — in individuals with type 2 diabetes.”[4]

What You Can Do

If you and your doctor are choosing a new drug to treat your adult-onset diabetes, do not use any of these six drugs (or the others in the box below). Do not stop using drugs until you talk to your doctor. Bring along a copy of this article.

An unhealthy lifestyle is behind most cases of adult-onset diabetes. For these patients, a diet and exercise plan is preferable to taking risky drugs.

References

[1] Singh S, Chang H, Richards T, et al. Glucagonlike peptide 1–based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: A population-based matched case-control study. JAMA Intern Med. 2013 Apr 8;173(7):534-9.

[2] Bristol-Myers Squibb/AstraZeneca EEIG. Direct healthcare professional communication on the association of saxagliptin (Onglyza) with serious hypersensitivity reactions and acute pancreatitis. http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con146917.pdf. Accessed July 24, 2013.

[3] Butler A, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 62:2595–2604, 2013.

[4] Butler P, Elashoff M, Elashoff R, et al. A critical analysis of the clinical use of incretin-based therapies. DiabetesCare. 2013 Jul;36(7):2118-25.