DPP-4 Inhibitors Cause Abnormal Cell Proliferation and Pre-cancerous Changes in the Pancreas

Page Changed: DPP-4 Inhibitors Januvia, Onglyza, Trajenta, Combiglyze, Janumet, and Jentadueto


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Januvia was the first of a family of diabetes drugs that works by increasing the levels of GLP-1 in the bloodstream. Newer drugs in this family include Onglyza and Trajenta, as well as combination drugs which mix the incretin drug in the same pill as metformin. These drugs are Janumet, Combiglyze, and Jentadueto. GLP-1 is an incretin hormone that stimulates insulin secretion. Another kind of incretin drug, which includes Byetta and Victoza are artificially sythesized molecules that behave just like GLP-1 in the body but last longer. The DPP-4 inhibitors are quite different. They are pills that cause the GLP-1 your body secretes on its own to rise to a higher than normal level by
inhibiting the action of DPP-4. DPP-4 is an enzyme (a.k.a. protease) which when it is left to its own devices, chops up GLP-1 and another hormone, GIP. When DPP-4 is inhibited, GLP-1 does not get chopped up and remains active in the body. When GLP-1 is active, it stimulates insulin secretion when blood sugars rise.

The Fatal Flaw with These Drugs: They Cause Abnormal Cell Growth and Pre-cancerous Tumors in the Pancreas

For several years the FDA has been getting reports that drugs in both families of incretin drugs were causing pancreatitis, a painful inflammation of the pancreas that can destroy large portions of it and lead to full-fledged Type 1 diabetes or even death. They recently decided to study the issue, though, in typical FDA fashion they merely asked for more research without warning doctors to take patients off these dangerous drugs. A study run by a big mail order pharmacy, Medco, which analyzed its patient's medical records appeared to suggest that Byetta and Januvia were not causing pancreatitis. Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin: A retrospective observational pharmacy claims analysis. Rajesh Garg et al. Diabetes Care Diabetes Care November 2010 vol. 33 no. 11 2349-2354

However, this was a relatively short study, and it was run under the auspices of a commercial organization that profits from selling this very expensive drug.

A far more conclusive, and damaging, study was conducted by highly regarded researchers at UCLA's Medical School. They carefully autopsied the pancreases of people with diabetes who had died of strokes and head injuries. About half of these people had been taking an incretin drug for at least a year. All but one were on Januvia, the other was on Byetta. The most troubling finding of this study was that all the people with diabetes who had taken these incretin drugs for a year or more had very abnormal findings when their pancreases were examined. The abnormalities included the presence of an abnormally high number of both beta cells and alpha cells--more than three times greater than normal and the fact that these cells were arranged in "eccentric" islets that were proliferating into the pancreatic ducts in an unusual way.

The people taking these incretin drugs were also found to have tiny glandular tumors scattered throughout their pancreases.

The pancreases of none of the people who had had diabetes but had not taken these drugs displayed any of these abnormalities.

The proliferative changes observed were of the type associated with pancreatitis. Most of the tumors found in people taking Januvia were adenomas--a type of glandular tumor that starts out benign but can over time turn cancerous. They also found a 1 cm neuroendocrine tumor in the pancreas of one patient who had been taking Januvia.

The scientists explain in their study that it is very likely that exposure to abnormally high levels of GLP-1 or to GLP-1 mimics is what is causing these changes, citing animal research which illuminates the mechanism involved. This means any incretin drug, be it a GLP-1 mimic or a DPP-4 inhibitor will cause these dangerous changes.

They also point out that people on these drugs despite having more than three times more beta cells than normal people were still diabetic, suggesting that the newly created cells were not functioning normally. In fact, they observed that that many of the cells found showed signs they had been secreting both insulin (secreted normally by beta cells) and glucagon (secreted normally by alpha cells) . This kind of secretion pattern is characteristic only of immature cells found only in fetal tissue. It is never found in normal adult humans.

These abnormalities are very serious. More importantly, they have also been found in animals treated with these drugs, so though this is only one human study, its findings should be taken as confirming that yes, the dangerous changes seen in animals taking these drugs also occur in humans.

Since the kind of tumors found here are undetectable until they cause pancreatitis or cancer, they are very worrisome. The researchers point out in their discussion of their findings that when there is any suspicion that a person has one of these benign pancreatic tumors the treatment is immediate surgery. But what they don't mention is that suspicion that such a tumor is present only arises when it is causing clear-cut symptoms.

Unfortunately, the first symptom of spreading tumors in the pancreas is an increase in blood sugar. Since doctors consider rising blood sugars in people with diabetes to be normal, the are unlikely to suspect a tumor until other, more troubling symptoms emerge at which time it may be too late to save the patient's life.

All DPP-4 Inhibitors Will Cause the Same Abnormal Growths Because They All Raise GLP-1

In addition, during the testing of one of the newer of these drugs, Onglyza, problems with thyroid tissue also emerged, suggesting that it not only causes abnormalities in pancreatic glandular tissue but also in thyroid gland tissue.

Bottom line: All incretin drugs are hazardous to your long term health no matter what their short term benefits.

The study is found here:

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. Alexandra E Butler et al. Published online before print March 22, 2013, doi: 10.2337/db12-1686. Diabetes March 22, 2013

You can read another discussion of what this study found HERE.

These findings are so disturbing and the potential for harm so large, that I can see any reason to take any drug in this family.

The rest of this page describes more about these drugs and what people taking them report. I include them for historical purposes, but urge you not to experiment with these drugs now that we know what they do to the pancreas. Whatever their benefits, it seems foolish to take any drug that could cause abnormal cell growth in your pancreas and stimulate the growth of undetectable tumors that could over time turn cancerous or cause pancreatitis requiring surgery that could damage your pancreas and take away what limited function it still has.