Januvia

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 is a diabetes drug that works by increasing the levels of GLP-1, an incretin hormone that stimulates insulin secretion. Another diabetes drug, Byetta, is an artificial, injected, form of GLP-1. Januvia is quite different. It is a pill that causes 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.

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-Péclat, 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 ß-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. ß-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].

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.