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

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DPP-4 Inhibitors Januvia, Onglyza, Trajenta, Combiglyze, Janumet, and Jentadueto
The image I've chosen for this page is the Roman god, Janus, whose prime characteristic of facing in two directions seems very appropriate for the similarly named drug Januvia, which can be extremely effective and extremely dangerous.

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 synthesized 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 cnewly 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.

Flaws in Studies Purporting to Refute Dr. Butler's Findings

As soon as Dr. Butler's study came out, there was a rush to publish studies that supposedly refute it, funded, not so surprisingly by the companies who are earning billions of dollars from these highly profitable drugs.

A good example is this one:

UPDATE 2-Doctors get good and bad safety news on diabetes drugs

This study claimed to find no sign of pancreatic disease with Onglyza, but there are several reasons to discount this finding:

1. The study only lasted 2 years, which is far too short a time for the changes in pancreatic architecture discovered by Dr. Butler to result in overt pancreatitis.

2. Cancers also take much longer than 2 years to cause symptoms. Pancreatic cancer, in particular, is almost always symptom free until it is too late for any treatment to keep the patient from dying within a few months. The patients in Dr. Butler's study who took Januvia and died with small precancerous tumors in their pancreases and abnormal cells throughout their pancreatic tissue had no symptoms suggesting anything was wrong with them.

The only cases of pancreatitis or pancreatic cancer which were evaluated in this study were those that produced symptoms.

There is no way to study the cells of a living pancreas without destroying it, which is why Dr. Butler was forced to study the pancreases of people who have died of head injuries.

Any study that assures you that these drugs are not damaging the pancreas which does not examine pancreatic tissue is not conclusive. (And remember, that there are several studies of huge databases of people who are taking these drugs that have already found a small rise in the numbers of cases of pancreatitis among people taking them.)

Given how cancers progress, it will take 10 years or more for the pancreatic tumors these drugs are capable of growing to cause the epidemic of pancreatic cancer deaths that I fear is coming. By the time the deaths appear, it will be too late to do anything.

Until someone shows you 10 years worth of data that show no significant increase in cases of either pancreatitis or pancreatic cancer in people taking any incretin drug, be very skeptical of studies claiming they are safe.

The British Medical Journal looked into this issue and found disturbing signs of suppression of evidence suggesting this is a very real problem: Discussed here: Medcscape: BMJ Digs Deep Into Incretins and Pancreatic Cancer Debate.


The actual BMJ review is found here:

Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?

Onglyza Found to Increase the Incidence of Heart Failure

The drug company that ran the study of Onglyza discussed in the previous paragraph was attempting to show that Onglyza decreased heart attack deaths. What they found instead was that though Onglyza did not cause more heart attacks, but it didn't decrease their number either.

Even more worrisome was their unexpected finding that Onglyza increased the incidence of heart failure, a weakening of the heart muscle that is almost always fatal within a 5 year period.

Quoting the Reuters report: "The co-principal investigator on the Onglyza study, Dr. Deepak Bhatt, said he believed the heart failure issue seen with Onglyza was very likely a class effect common to all DPP-4s."



Historical Content about These Drugs Including Suggestions that they May Promote the Growth of Cancers

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.

How Effective is Januvia?

In 2008 the drug companies spent more money marketing Januvia to doctors than they did on any other drug prescribed for a non-psychiatric condition. Not so surprisingly, there were more new prescriptions written for Januvia than for any other new drug.

Though commonly accepted practice guidelines state that patients newly diagnosed with Type 2 diabetes should be started on Metformin and possibly Insulin, the marketing onslaught has led to Januvia or the combination drug, Janumet (Januvia and Metformin) being prescribed to a very large number of people newly diagnosed with type 2 diabetes.

This is disturbing, because the data about Januvia's effectiveness is underwhelming. Data from the studies conducted by the manufacturer as part of the drug approval process for Januvia found that that in a group of people with Type 2 Diabetes whose A1c was 8%, Januvia decreased the A1c by a measly .6%. When Januvia was added to Metformin or Avandia, the studies found Januvia got only about half of patients taking the combined drugs to an A1c near 7%--which as you have seen elsewhere in this site, is a blood sugar level high enough to produce significant diabetic complications. Anecdotally, many people who were doing very well with Byetta report that when their doctors switched them to Januvia, they saw their blood sugar control deteriorate. This should not be surprising, since the way that Januvia works results in much lower GLP-1 levels than are present with the injected Byetta.

In addition, Januvia, when it is effective, results only in increased insulin secretion. In people with Type 2 diabetes, insulin resistance is often a more serioud problem than decreased insulin secretion, and it is important to address the insulin resistance before stimulating more insulin secretion.

The only safe drug for decreasing insulin resistance is currently Metformin. However, combining Januvia and Metformin doubles the amount of gastric distress caused by Metformin alone because one impact of raising GLP-1 is that the valve at the bottom of the stomach shuts down, preventing stomach contents, and metformin, from moving through the system.

People who have combined Metformin and Januvia by taking two different pills have found it is important to take the metformin an hour or two BEFORE the Januvia so that the metformin gets digested before the Januvia shuts down stomach emptying.

A very expensive pill that combines Januvia and metformin is marketed under the name, Janumet. Unfortunately, I have heard from several people with Type 2 Diabetes who report that when they experienced stomach problems with Janumet their doctors moved them to plain Januvia--and took them OFF metformin, depriving them of the proven cardiovascular effects of metformin and it's ability to lower insulin resistance and leaving them taking only the very expensive Januvia ($4 a pill!) that does nothing but slightly increase their insulin production.

VERY Serious Concern - Januvia's Impact on Inflammation

When Januvia came out, I tried it and found it did a very good job at controlling my blood sugars. This was to be expected, as I have a form of diabetes that responds extremely well to drugs that stimulate the beta cell to produce insulin.

Then, after I'd been taking Januvia for a few weeks, I cut my finger while cooking. It seemed to take forever for the wound to heal. At the same time I noticed that I was getting sore spots on my fingers in the places where I was using my lancet to test my blood sugar. This was unusual. I'd been testing 6-8 times a day while using insulin and my fingers never hurt. Suddenly they were red and sore all the time.

I posted about this experience and my concern about slowed wound healing on the Januvia blog at The Diabetes Monitor Blogs Almost immediately someone chimed in that they had also noticed slow wound healing which went away when they stopped the Januvia. A nurse reported to me by email that she noticed very slow healing after gum surgery while taking Januvia which appeared to improve after she stopped the drug. She also summarized her experience on the Januvia and Galvus Blog. Anther person taking Januvia reported significant white blood count changes after starting Januvia. Yet another person reported coming down with pinkeye after starting Januvia.

Further research turned up the information that DPP-4 the enzyme inhibited by Januvia does more than get rid of GLP-1 in the gut. That same enzyme turns out to be used throughout the immune system, where it is involved in the control of inflammation.

A study which measured the concentrations of DPP-4 in both mice with an induced autoimmune arthritis and people with rheumatoid arthritis found that the lower the DPP-4 levels, the higher the degree inflammation . (CD26 is another name for DPP-4.
Circulating CD26 Is Negatively Associated with Inflammation in Human and Experimental Arthritis. Nathalie Busso, Nicolai Wagtmann, Christian Herling, Veronique Chobaz-Pclat, Angelika Bischof-Delaloye, Alexander So and Eric Grouzmann. American Journal of Pathology. 2005;166:433-442

The manufacturer's Prescribing Information for Januvia does not discuss the changes in immune system function caused by the drug except to say that
Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.
A helpful email from a leading DPP-4 researcher who sent me some publications about Januvia not available on the web, suggests that the problem caused by Januvia re wound healing is that it causes more persistent inflammation while wounds are healing. This is because another function of DPP-4 is to get cut up and get rid of cytokines, which are the substances that cause inflammation.

So by inhibiting DPP-4 we may be allowing cytokines produced by other processes to persist. The impact of this on our bodies is not well understood, and unfortunately, the drug approval process included no requirement that the other impacts of DPP-4 inhibition be studied

Apparently, some of the impacts are very severe. In Sept, 2008 I received an email from a reader (which has been passed on to the FDA by her physician) that stated,
Within a week of starting Januvia, I was experiencing severe bilateral hip pain and stiffness. It became difficult to rise from a seated position, I developed a visible limp and my gait was disturbed. Despite discontinuing Januvia after three months of use, these symptoms have continued and I am unable to exercise, have difficulty sleeping because of pain and the quality of my life has seriously deteriorated. I discovered that I am not alone in developing these problems after taking Januvia and am very concerned that others may be harmed by this medication and they and their physicians are unaware of the possible connection with the medication.
Clearly, this makes Januvia a very poor choice for anyone who has other inflammatory conditions. It also raises the question of whether inflammation in the arteries--known to be associated with heart attack and stroke--might be worsened in people taking Januvia.

Obviously, if you suffer from any inflammatory conditions, Januvia is probably a poor choice of medication for you. If you begin to notice joint pain after starting Januvia, discontinue it immediately.<

Rash and Skin Side Effects

After posting this page and citing the problems I'd noticed with Januvia, I received two anecdotal reports of an allergic rash reaction to Januvia during the first six months it was on the market.

In October of 2007, six months later, the manufacturer added the following information to their FDA-approved prescribing information.
These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome.
This confirms that swelling, rashes, and peeling skin may indeed be side effects of Januvia. Stevens-Johnson syndrome is a terrible immune-system related problem where large portions of skin may separate from the body. It is very much like having a 3rd degree burn. It can be fatal, and survivors may be left with lifelong scars and blindness. In the course of my research into Stevens-Johnson syndrome I found some blogs that included photographs of Stevens-Johnson victims and they are some of the most disturbing images I have ever seen.

If you experience a rash while using Januvia, take it seriously and do not let your doctor tell you, as people have reported to me, that Januvia doesn't cause a rash.

To track all studies involving the various functions of DPP-4 throughout the body as they are published visit this page:

DPP-4: Information Hyperlinked over Proteins.

Other Common Januvia Side Effects


There are two other common other side effects experienced by people taking Januvia which doctors may not be aware of.

Sinus Headache

Sinus headaches that increase in their frequency as the months go on are a very common side effect of Januvia and probably are another impact of the rising level of cytokines caused by inhibiting DPP-4. When I took the drug for three months, I eventually was having sinus headaches almost every day. They stopped shortly after I discontinued the drug.

Bloating

Because GLP-1 causes the stomach valve to stay shut, delaying stomach emptying, Januvia can cause upper abdominal bloating. This can become worse the longer the drug is taken. My own experience was that the bloating lasted for several weeks after I stopped the drug. It was very uncomfortable.

Anorexia

Because GLP-1 gets into the brain, raising GLP-1 levels can have an impact on hunger. (This may be why for some people Byetta is so effective as a weight loss aid. While I was taking Januvia I lost interest in food in a way that was quite unusual for me.

FDA Adds Pancreatitis Warning to Januvia Labels

In September of 2009, the FDA is adding this information to the Prescribing Information for Januvia:
Eighty-eight post-marketing cases of acute pancreatitis, including two cases of hemorrhagic or necrotizing pancreatitis in patients using sitagliptin, were reported to the Agency between October 16, 2006 and February 9, 2009.
You can read the entire FDA Safety Warning here:
Information for HEalthcare Professionals - Acute pancreatitis and sitaglipitn (marketed as Januvia and Janumet).

The manufacturer of Januvia is dismissing this as being due to the population taking Januvia having at least "risk factor" for pancreatitis--diabetes! But this sentence from the FDA warning strikes me as clarifying the risk: "Furthermore, 47 of the 88 cases (53%) resolved once sitagliptin was discontinued."

Doctors are advised to warn patients prescribed Januvia of the symptoms of pancreatitis so they can be taken off the drug.

If you are on Januvia, has your doctor warned you about the symptoms of pancreatitis? If not, ask your doctor why. The doctor probably doesn't know of this latest issue with Januvia, as they usually don't know of the others, either.

Could the DPP-4 Inhibition Caused by Januvia and Onglyza Promote Cancer?

In the course of reading up about the other functions of DPP-4 in the body, I discovered that the suppression of DPP-4 appears to be involved in the transformation of skin cells (melanocytes) and prostate cells into malignant cancer cells.

Some research suggests that the tumor cells in these two cancers fend off the immune system cells that usually kill them by turning off the expression of DPP-4.

As one study (cited below) states "downregulation of DPPIV is an important early event in the pathogenesis [development of the illness] of melanoma." The study explains that
Malignant cells, including melanomas and carcinomas, frequently lose or alter DPPIV cell surface expression. Loss of DPPIV expression occurs during melanoma progression at a stage where transformed melanocytes become independent of exogenous growth factors for survival." [I.e. when cells stop expressing DPPIV when they start to turn into viable tumor cells.]
Furthermore,
Reexpressing DPPIV in melanoma cells at or below levels expressed by normal melanocytes induced a profound change in phenotype that was characteristic of normal melanocytes.
In short, turning DPP-4 expression back on stopped the cells from behaving like cancer cells.

A similar effect was observed with ovarian cancer cells. The researchers state,
We investigated the correlation between DPPIV expression and progressive potential in ovarian carcinoma. We demonstrated that ovarian carcinoma cell lines with higher DPPIV expression were less invasive.[emphasis mine]
As I'm a melanoma survivor, this ed me to stop taking Januvia immediately despite its excellent effect on my blood sugars. I cannot afford to play around with any chemical that might be turning off the immune system response which keeps melanocytes from turning malignant

Several months after I raised this issue here and on my blog Dr. Mark R. Goldstein published a letter in the high impact journal,Annals of Internal Medicine flagging this issue and citing more studies linking DPP-4 inhibition with colon and prostate cancer.

DPP-4 Inhibitors and Cancer Mark R. Goldstein, Ann Int Med. Sept 21, 2007.

Don't Drug Companies Have To Prove Their Drugs Don't Cause Cancer?

Most people assume that the testing drug companies are required to do rule out the approval of drugs that cause cancer. This, unfortunately, is based on a misunderstanding of how the required cancer testing for new drugs works. Cancer screening for new drugs involves two tests. One is the Ames test, which looks to see if the substance causes mutations in bacteria and the other is a test where rodents are given huge doses of the drug and observed to see if they develop cancers.

The Ames test is helpful for identifying substances that cause mutation in DNA but the Ames test doesn't identify drugs that promote cancer by damaging the mechanisms that the body uses to kill cells that have developed cancerous characteristics.

In fact, it is known that throughout our lives each of us develops many cancerous cells. Usually our immune system recognizes these cells and attacks them before they can grow into tumors. It appears that DPP-4--the enzyme that Januvia inhibits--is part of the system that kills these rogue cells, so you would have expected that the drug approval process would have required further testing to make sure that Januvia did not make it easier for malignant cells to develop into full fledged tumors. This kind of testing was never done.

The other cancer test that is a routine part of the new drug approval process is to see if rodents given very high doses of the drug develop cancer. According to the Januvia Prescribing Information Rats fed a very high dose of Januvia (60 times the normal amount) did develop liver cancer, though mice did not.

Rodents are very different from humans and their incidence of melanoma, ovarian, and prostate cancer--the cancers linked with DPP-4 inhibition is unknown. What is known is that none of this testing conclusively proved that DPP-4 inhibition does not promote cancer.

There are hints in the human trials used to approve Januvia that it might have increased the incidence of cancer. You can read about this evidence in this blog post:

Diabetes Update: More Evidence Connects Januvia to Cancer.

The acceptance testing for Januvia lasted less than two years. Cancers take a lot longer to develop to where they are detectable. Unfortunately, as explained in the blog article, the way that the drug manufacturers have reported cancers obscures the significance of the findings and there is no study under way to track the incidence of cancer in people taking Januvia. Dr. Goldstein estimates that it is probably causing an extra 30,000 cases of cancer a year, based on the huge number of new prescriptions being written for Januvia and the excess cancers hidden in the acceptance testing data. But because doctors prescribing Januvia have no idea that it might be causing cancer, they are not likely to link a new case of melanoma or prostate cancer to a diabetes drug they prescribed their patient three years before.

Januvia is not any more effective than other, safer, drugs for diabetes, and the impact it has on most people's blood sugar is not worth the risk of causing any additional cancers.

Research Connecting DPP-4 and Cancer

Recent research links DPP-4 inhibition to melanoma, prostate cancer, ovarian cancer, neuroblastoma, and lung cancer.

I have corresponded with the author of several of the studies cited below who responded to my letter asking whether Januvia's suppression of DPP-4 was a concern with these words:
I agree that use of DPPIV inhibitors to treat diabetes patients needs
further studies. Inhibiting DPPIV function in general(according to ours and others research) may not be a great idea. I believe that decrease or loss of DPPIV may be associated with cancer initiation or progression.

We have shown that loss of DPPIV is indeed associated with melanoma, prostate and lung cancers. Importantly our work has shown that restoring DPPIV can suppress the tumor growth. I have not conducted any detailed studies with DPPIV inhibitors including Januvia, in particular. DPPIV has multiple functions. It is not known if Januvia blocks all of its functions. This warrants more studies with this drug.


The extent to which DPP-4 is implicated in the development of cancer is made clear by the conclusion of a study about prostate cancer published in 2008, that concludes,
... these data suggest that the degradation of CXCL12 by CD26/DPPIV may be involved in the metastatic cascades of PCa [prostate cancer], and suggests that inhibition of CD26/DPPIV may be a trigger of PCa metastasis.[emphasis mine]
CD26/dipeptidyl peptidase IV regulates prostate cancer metastasis by degrading SDF-1/CXCL12. Sun YX et al. Clin Exp Metastasis. 2008;25(7):765-76.

Here are some more studies that link DPP-4 and the immune system's cancer fighting abilities. I urge you to look at these abstracts before taking Januvia:

Suppression of neuroblastoma growth by dipeptidyl peptidase IV: relevance of chemokine regulation and caspase activation.
Arscott WT, Labauve AE, May V, Wesley UV. Oncogene. 2008 Nov 3.

Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation.
McGuinness C, Wesley UV. 2008 Jan 1;13:2435-43.

Dipeptidyl peptidase IV in tumor progression. Kikkawa F et al. Biochim Biophys Acta. 2005 Aug 1;1751(1):45-51. Epub 2004 Oct 22.

Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells. Wesley UV et al. Int J Cancer. 2004 May 10;109(6):855-66.

A Role for Dipeptidyl Peptidase IV in Suppressing the Malignant Phenotype of Melanocytic Cells. Umadevi V. Wesleya, Anthony P. Albinoa, Shakuntala Tiwaria, and Alan N. Houghtona. J. Exp. Med. Volume 190, Number 3, August 2, 1999 311-322.


Dipeptidyl peptidase IV (DPPIV) inhibits cellular invasion of melanoma cells. Pethiyagoda CL, Welch DR, Fleming TP. Clin Exp Metastasis 2001, 18:391-400
(Not available online)

Dipeptidyl peptidase IV (DPPIV) inhibits cellular invasion of melanoma cells. Pethiyagoda, C.L.; Welch, D.R.; Fleming, T.P.. Clinical and Experimental Metastasis, Volume 18, Number 5, September 2000, pp. 391-400(10)

Prolonged Survival and Decreased Invasive Activity Attributable to Dipeptidyl Peptidase IV Overexpression in Ovarian Carcinoma. Hiroaki Kajiyama, Fumitaka Kikkawa2, Takahiro Suzuki, Kiyosumi Shibata, Kazuhiko Ino and Shigehiko Mizutani. Cancer Research 62, 2753-2757, May 15, 2002

Januvia Causes Precancerous Changes in Human-derived Pancreatic Duct Cells

A study published in July 2009 found evidence that while Januvia improved pancreatic beta cell function in the short term, it did so while producing pre-cancerous changes in the pancreatic duct cells.

You can read the abstract of this study here:

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes: Interactions With Metformin Aleksey V. Matveyenko et al. Diabetes. doi: 10.2337/db09-0058 Diabetes July 2009 vol. 58 no. 7 1604-1615

This study was conducted in human islet amyloid polypeptide transgenic (HIP) rats which have had human genes inserted into their pancreata. The HIP rats were treated with Januvia, or metformin, the combination of sitagliptin plus metformin, or no drug as controls for 12 weeks.

It found that "Metformin more than sitagliptin [Januvia] inhibited -cell apoptosis [cell death]. Metformin enhanced hepatic insulin sensitivity;"

But when Januvia was added to the mix, there was a small improvement in insulin sensitivity and in beta cell function. Note that "beta cell function" is only a measure of insulin secretion. It is not a sign that more beta cells are growing, only that existing beta cells are pumping out more insulin.

In fact, the finding, reported above was that beta cells survived better in the transgenic rats given metformin alone compared to those given Januvia.

But any benefit that might have come from increased insulin secretion was cancelled out by a very troubling finding. Here is the way the researchers report it:
sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. -Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis [emphasis mine].
"Metaplasia" is defined this way in Mosby's Medical Dictionary, 8th edition. 2009, Elsevier:
the reversible conversion of normal tissue cells into another, less differentiated cell type in response to chronic stress or injury. With prolonged exposure to the inducing stimulus, cancerous transformation can occur.

Is Januvia for You?

If the above is not enough to deter you from trying Januvia, it is worth noting that the reports posted online on the diabetes.blog.com Byetta Blog from people who had been getting good results from Byetta whose doctors moved them to Januvia are not encouraging. This is not a surprise. The amount of GLP-1 analog in a Byetta shot is much higher than the amount of naturally produced GLP-1 you achieve by taking Januvia and blocking the breakdown of that naturally produced GLP-1.

Whatever the cause, Januvia does not appear to work for most people who had good but not great results from Byetta. Januvia won't work unless your body is making a lot of GLP-1 on its own and it also requires that your beta cells be able to secrete additional insulin in response to GLP-1 stimulation and that your cells are not so insulin resistant that they can't respond to that additional insulin secretion.

Also, Januvia is being described as being weight-neutral (i.e. not causing weight gain) based on two studies, one of which actually did show a slight gain of weight in those taking the drug. This might make it a worse choice for many people with Type 2 diabetes than Byetta, since Byetta, when it works, causes weight loss. So Byetta would probably be a better choice for an incretin hormone-based treatment for Type 2s who need to lose weight.

Though Byetta was recently linked to a tiny number of cases of Pancreatitis (about 6 in hundreds of thousands of people taking the drug) the number of excess cancers attributed to Januvia was much higher per number of people taking the drug than the cases of Pancreatitis.

Does Januvia Regenerate Beta Cells

One reason that doctors are putting patients onto Januvia is that they are being told by drug marketing reps that Januvia rejuvenates beta cells. This is not backed up by any research findings in humans. The data being used to defend this claim in Byetta is discussed on this site's
Byetta
page and is of very poor quality. There is no evidence that Januvia does anything except stimulate insulin secretion and perhaps, because of its impact on another hormone, GIP, it may also decrease glucagon secretion by the pancreases Alpha cells. Anecdotally, it appears that when people stop Januvia, their blood sugars go back to whatever state they were in before they started the drug, which does not suggest that any change has been made to the state of the beta cells.

Incretin Drugs Are Not Likely To Work if Sulfonylurea Drugs Don't Work for You

If you have found that you respond strongly to a relatively low dose of a sulfonylurea drug such as Amaryl or glipizide (the sulfonylurea drug found in Glucovance) you may respond strongly to Byetta and, though it is less likely, Januvia. If you have no response to these drugs, it may indicate that stimulating your beta cells with raised levels of GLP-1 isn't going to produce insulin because you no longer have enough functioning beta cells.

However, I hear from far too many people who are walking around with dangerously high blood sugars who inquire about Januvia, hoping to add another pill to their regimen to avoid going on insulin. This is a tragically misguided approach.

Insulin works. And if you are already on a lot of oral medication and are still going over 250 mg/dl after meals, you probably should start out with insulin, get your blood sugars down to a safer, more manageable level to save whatever functioning beta cells you still have left, and then see if Byetta or Januvia can improve matters for you. Neither of these drugs will help if your beta cells are dead, and the research we cite on our Organ Damage page makes it clear that prolonged exposure to blood sugars over 150 mg/dl kills beta cells dead. Only insulin, dosed properly, is 100% guaranteed to lower blood sugar.

Historical Information about Other DPP-4 Inhibiting Drugs


Onlyza and Tradjenta- Just like Januvia, But Worse

When the FDA approves a new drug it requires no proof that the drug is more effective than similar, existing drugs, only that it is better than placebo.

Onglyza, approved August 1, 2009.
is the brand name for Saxagliptin, which alert followers of drug news remember as the Januvia clone developed at the same times as Januvia whose release has been blocked due to its ability to cause "skin lesions" some of which necrotized (i.e. died and fell off) in monkeys.

I have read through the Prescribing Information for Onglyza and cannot see any benefit it offers in comparison to Januvia, the other DPP-4 inhibitor currently on the market.

Setting aside for the time being the advisability of controlling your blood sugar by turning off a tumor suppressor gene Onglyza offers nothing not offered by Januvia.

Both inhibit the expression of the DPP-4 gene for a full 24 hours--which means that if your body was fighting a new, very small DPP-4 sensitive tumor, like ovarian cancer, melanoma, prostate cancer or lung cancer, the drug would keep DPP-4 from killing off the tumor cells.

1. Feeble impact on blood sugar: Onglyza lowered A1cs that averaged 8% by .5%, which does not bring them anywhere near a safe level even by the anemic standards of the ADA. When the highest dose of Onglyza was compared to a placebo, it allowed only 14% more of those taking it to achieve 7% A1cs.

To better understand how "Effective" it is, consider what that A1c really meant: Onglyza lowered the average fasting glucose in those who took it from 171 mg/dl to 162 mg/dl (9.5 mmol/L) to 162 mg/dl (9 mmol/L). It lowered the average two hour post-meal blood sugar reading from a damaging 278 mg/dl (15.4 mmol/L) to an equally complication-guaranteeing 235 mg/dl (13 mmol/L).

So my immediate question would be: Why take this drug which is likely to cost 3 or 4 dollars a day to "achieve" blood sugars that are still high enough to lead to amputation, blindness and kidney failure when for the same money or less you could use insulin to get normal blood sugars?

2. Negative impact on the immune system. Inhibiting the DPP-4 gene, which produces an enzyme that rids the body of GLP-1 by chopping it up, lowers blood sugar because GLP-1 lowers blood sugar. However DPP-4 is used by the immune system for other functions most doctors know nothing about. Januvia's initial testing showed that it caused changes in white blood cell counts which the drug company dismissed as being of unknown significance.

Onglyza has a stronger impact on your immune system's white blood cells. In the prescribing information we read:
There was a dose-related mean decrease in absolute lymphocyte count observed with ONGLYZA. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with ONGLYZA 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical studies. Similar effects were observed when ONGLYZA 5 mg was given in initial combination with metformin compared to metformin alone. There was no difference observed for ONGLYZA 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count =750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to ONGLYZA although some patients had recurrent decreases upon rechallenge that led to discontinuation of ONGLYZA.


Translated into English, this means than in 1 person in 100 who take it, Onglyza lowers the white blood count to a dangerously low level.

If your doctor prescribes Onglyza without requiring that you have a blood count periodically, you can be sure the doctor has not read the prescribing information. Few doctors do.

3. Onglyza conflicts with common drugs and grapefruit juice Because of the way it is removed from the body Onglyza may build up in the blood stream when taken with common yeast medication, ketoconazole, as well as with erythromycin, calcium channel blocker verapamil, and grapefruit juice. Onglyza levels also rise in people with poorly functioning kidneys. The manufacturer says that dose must be cut back in people using these drugs. Whether busy doctors will know this and warn patients about lowering the dose when needed is another story.

4. Onglyza raises the peak Concentration of Sulfonylureas and TZDs. This makes it more likely people whose doctors prescribe this new drug with a sulfonylurea drug will experience hypos. Onglyza also reduces the peak concentration of metformin.

5.Side effects The main side effects reported with Onglyza are the headache and runny nose that are also found with Januvia and which result from the inhibition of the immune system these drugs cause. Over time, my experience with taking Januvia for several months was that the headaches increased in intensity in a way that made me glad to stop taking the drug.

However, Onglyza also causes other immune reactions: As reported, "Hypersensitivity-related events, such as urticaria [rash] and facial edema [swelling] in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients."

Januvia also turns out to cause rashes, including, very rarely, the life threatening Stevens-Johnson syndrome where people's skin peels off the body. It is significant, though that rash did not appear as a side effect of Januvia until after the approval testing was complete. That Onglyza produced such a high rate of rash during testing seems to suggest that it has a higher potential to disrupt the immune system.

6. No evidence that this or any other DPP-4 inhibitor preserves beta cells I mention this because the drug reps are selling these drugs to doctors claiming, based on weak animal evidence that these drugs preserve beta cells. No drug can preserve or regenerate beta cells when blood sugars are rising over 140 mg/dl for long periods of time, because sustained high blood sugars cause glucotoxicity--poisoning of beta cells. With the many years that BMS has been testing Onglyza you can be sure they have run every test they could find to demonstrate beta cell preservation and the complete lack of any cite to this in the prescribing information suggests they could not find it.

Why Take Onglyza?

Nothing in the prescribing information suggests any advantage in taking Onglyza compared to Januvia, while at the same time suggesting strongly that Onzglya's impact on the immune system is stronger than Januvia's. No research was done into whether Onglyza increases the incidence of tumors in those who take it, and because of the very small numbers involved in the clinical trials and the way the drug companies bury tumor incidence (combining benign and cancerous tumors in one category, as in the Januvia trials), that data is not likely to emerge.

Nevertheless, just about every newly-diagnosed person with Type 2 I've heard from from 2010 on was prescribed Onglyza. Why? Because it's new and the drug company that makes it did a saturation marketing campaign targeting diabetes-ignorant family doctors.

Onglyza is now being being marketed as Kombiglyze, a pill that combines Onglyza and Metformin. Easily swayed doctors are therefore prescribing to newly diagnosed patients only the very expensive combo pill instead of the extremely cheap generic Metformin pill. Don't let your doctor prescribe this combo drug.

Most people newly diagnosed with Type 2 will do just as well taking only generic metformin (starting with a small dose and working up as the body gets used to it) especially if they combine metformin with the technique described here: How to Get Your Blood Sugar Under Control. It really works. Even for people who have had diabetes for as long as a decade.

Tradjenta and Jentadueto

As of Summer 2011 there is yet another FDA-approved DPP-4 inhibitor drug available that is very similar to Onglyza. It is named Tradjenta in the U.S. and Trajenta elsewhere. Based on its prescribing information, which you can read HERE, it shares with Onglyza the characteristics that it makes very little change in blood sugar, costs a fortune, and causes the same significant immune-system related side effects--most notably the permanent sinus headache/runny nose that is a result of DPP-4 inhibition in the sinues--as well as raising the risk of pancreatitis.

In patients whose A1cs averaged 8.1% and whose fasting blood sugar averaged 178.4 mg/dl Trajenta lowered A1c to a still dangerous average 7.5% and lowered the fasting blood sugar to a rampantly damaging average of 165.1 mg/dl.

Trajenta is now being sold in combination with metformin, in a drug called Jentadueto.

If you are newly diagnosed and have not taken metformin before, don't don't let your doctor put you on this brand new, untested, extremely expensive, ineffectual combination drug. The practice guidelines published by all the major bodies who issue such guideliness recommend starting with plain metformin, which is a cheap generic drug that is highly effective and whose safety has been proven over 50 years of prescribing,unlike these new drugs that even in the acceptance testing gave hints that they may promote cancers and pancreatitis. The FDA has mandated follow-up reporting, but the history of follow-up reporting for other dangerous drugs is that it is useless as it is voluntary and relies on doctors recognizing the connection between the drug and the patient's disease. Very few doctors know anything about the relationship of any of the DPP-4 inhibitor drugs to cancer so when a patient develops a cancer after a few years of taking one of these drugs they are very unlikely to report that cancer as a side effect of the diabetes drug.

You can also lower your blood sugar far more than you will with these new, untested drugs, just by following the advice you'll find HERE.I have heard from hundreds of people who have done just that without any drugs except generic metformin--or no drugs at all.

If you feel that despite the risks you want to take a DPP-4 inhibitor Januvia appears to be the one that lowers blood sugar the best, though it doesn't do all that good a job of it and will end up giving you significant side effects.

 

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