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 for me was both extremely effective and extremely worrisome.

Januvia is a new drug which works on the incretin hormone system in a different way from Byetta. While Byetta provides a synthetic version of GLP-1, Januvia allows GLP-1 secreted by your body naturally to rise to higher than normal levels by inhibiting the action of DPP-4, an enzyme which removes GLP-1 and another hormone, GIP, from the body.

I was initially skeptical that Januvia was worth taking, given its very high expense ($5 a pill) and the study data that the manufacturer supplied with the press releases which made it sound like it produced very little improvement in blood sugar overall--the study data showed that in people whose A1c was 8%, Januvia decreased the A1c by a measly .6%--bringing it to a level significantly higher than even the dangerously high 7% recommended by the ADA. Added to Metformin or Avandia, the studies found Januvia got only about half of patients near 7%.

My Own Experience with Januvia

In reading initial reports online from people trying Januvia I noticed an interesting pattern. The drug either worked very well for them or not at all. This made me rethink the statistics in the Prescribing Information and wonder if that .6% decrease in A1c was the result of averaging the results of many people who experienced a 0% decrease in A1c with a few who achieved a much larger decrease.

Having noticed how many people with health histories similar to my own were doing extremely well on Byetta, I'd been wanting to try an incretin hormone drug, but had avoided Byetta because of the possibility of developing antibodies to the injected proteins and a disinclination to be nauseated. I got some samples of Januvia from my endocrinologist early in January of 2007 and started taking it.

Initial Results

My initial results were extremely impressive. I stopped taking my low dose insulin and was getting almost the same normal blood sugars with Januvia as I had been with low dose insulin--without having to worry about hypos. (Note: I continued to take 1500 mg of Metformin.)

I found I needed to eat some carbohydrate with each meal to stimulate the release of insulin while taking Januvia, but once the insulin was secreted, since it was being secreted in a normal physiological way it worked quickly. I found myself at 99 mg/dl (5.5 mmol/L) one hour after eating 30 grams of pastry several times and was in the very normal 80s an hour later!

I found that in my body a carb intake of 20-30 grams was handled very well by Januvia. Above that level it took three hours to get to a fasting level of 85 mg/dl (4.7 mmol/L). For reference, I have never been able to get my fasting blood sugar below 100 mg/dl even with a very low carb diet, unless I was using insulin at meals. The ease of use of the Januvia, a once a day pill, was a huge plus compared to insulin.

Keep in mind when reading this that I have an unusual kind of diabetes where I am not insulin resistant and where I am also abnormally sensitive to drugs that stimulate insulin secretion. I can lower my blood sugar at meal time significantly with 2-5 units of insulin.

Side Effects

Stomach Side Effects

I experienced the following side effects while taking Januvia.

Increased heartburn
Delayed stomach emptying and very annoying upper abdominal bloating after meals .
Worsening constipation.
A lack of appetite verging on anorexia after 2 months on the drug. It allowed me to diet at a low calorie level I'd always found intolerable in the past, however, it was not pleasant and became increasingly worrisome as time went on.

Sinus Headache

After a few months on Januvia I started noticing that I was having far more sinus headaches than I ever had had before. In the past, they were a very occasional thing. Headache is one of the few symptoms that was reported on the Januvia prescribing information. At three months, I was having one headache every 3 days, some lasting for 6 hours. The headaches were one reason that even though I knew it meant going back to insulin, I wasn't that reluctant to stop Januvia. The sinus headaches went away completely over the next month after I stopped it.

How Long Until Januvia Takes Effect?

For those who have asked how long it takes for Januvia to take effect, I saw an almost immediate improvement in blood sugars. By two weeks the blood sugar lowering effect was only a bit stronger though my feeling of well-being had increased significantly.

When I stopped Januvia, it took exactly one week for its effect on my blood sugars to fade out completely.

So I'd say based on my own experience, that if you don't see significant effects after taking Januvia for a month, this might not be the drug for you.

A VERY Serious Concern - Januvia's Impact on Inflammation

After I'd been taking Januvia for a few weeks I cut myself (not very seriously) while cooking. But 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 where I was testing my blood sugar. This really was unusual. I'd been testing 6-8 times a day while on insulin and my fingers never hurt. Suddenly they were getting red and sore.

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 on Januvia reported significant white blood count changes after starting Januvia. Yet another person reported coming down with pinkeye after starting Januvia. Yes, these are anecdotal reports, but given that we know that DPP-4 plays an important role in the immune system, and the lack of any in-depth studies about the impact of inhibiting DPP-4 on the immune system conducted as part of the approval process for Januvia they are troubling.

I had read some discussion online that since Januvia turns down the immune system, it might be extremely useful for people with diabetes who have inflammatory conditions like artery disease, gum disease, arthritis, and of course, inflammation of the beta cells. I also saw a study that found high levels of DPP-4 in people with Multiple Sclerosis.

However, 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 way of referring to DPP-4.

http://ajp.amjpathol.org/cgi/content/full/166/2/433
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 changes in immunity 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 persistant inflammation while healing the wounds. 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.

Rash and Skin Side Effects

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 serious immune-system related problem where large portions of skin may separate from the body. It can be fatal. If you experience a rash while using Januvia, take it seriously and do not let your doctor tell you, as people have reported hearing, to me, that Januvia doesn't cause a rash. Because Januvia messes with DPP-4 a vital component of the immune system it is capable of stimulating serious immune sytems reactions.

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

http://www.ihop-net.org/UniPub/iHOP/bng/87784.html
Information Hyperlinked over Proteins [DPP-4]

Could Januvia Promote Cancer?

In the course of reading up about the other functions of DPP-4 in the body, I ran into another very serious concern about what its long term side effects might be, in particular whether Januvia might promote cancer.

It turns out 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 may be able to 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 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 information was a shock, and led 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 kills the off individual melanocytes that might become malignant!

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. A big part of cancer screening is the Ames test, which looks to see if the substance causes mutations in bacteria. This test s helpful for identifying substances that cause mutation in DNA.

Unfortunately, what the Ames test doesn't do, is identify drugs that promote cancer by damaging the mechanisms that the body uses to kill cells that have developed cancerous characteristics.

In fact, throughout our lives each of us develops many cancerous cells, but 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 does this, 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.

However, rodents have short life spans and being, as they are, covered with fur, and living in labs, they are unlikely to be as susceptible to melanoma as people are.

With this in mind, it is worth noting that the drug approval testing for a Rheumatoid Arthritis drug, Anakinra, that also causes a serious drop in DPP-4, showed more cases of melanoma developing in the test population than were "expected." The total number of cases of melanoma were small but percentage wise, the increase was troubling. The Prescribing Information for Akinra (Kineret) says, "There were 3 melanomas observed in study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known."

RA is a serious, severe, crippling disease where the additional risk of promoting cancer may be outweighed by the benefits of the drug, but 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.

It is also worth noting that the preapproval drug testing for Kineret lasted longer than the testing for Januvia which was unusually short.

More Research Connects Januvia with Colon and Prostate Cancer

A letter from Dr. Mark Goldstein that was published in the journal, Annals of Internal Medicine in September of 2007 ciltes additional research which connects DPP-4 inhibition with the promotion of colon and prostate cancer.

You can read Dr. Goldstein's published letter here:

DPP-4 Inhibitors and Cancer

Because the research has not been done to investigate the effect of Januvia's inhibition of DPP-4 on cancer, we'll only know if it promotes cancer after many hundreds of thousands of people have taken the drug for a decade or more.

However, if you are a melanoma cancer survivor, or for that matter, any kind of cancer survivor who may still have malignant cells in your body Januvia--no matter what it's effect on your blood sugar--looks like a poor choice of therapy. You don't want to gamble with anything that inhibits the mechanism your body may be using to keep them under control

Research Connecting DPP-4 and Cancer

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.
http://www.jem.org/cgi/content/abstract/190/3/311

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

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
http://cancerres.aacrjournals.org/cgi/content/abstract/62/10/2753

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)
http://www.ingentaconnect.com/content/klu/clin/2000/00000018/00000005/00335541

Is Januvia for You?

Despite my good blood sugar results while taking Januvia, it may not be the best choice for most insulin resistant people with Type 2 diabetes. 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.

I am very insulin sensitive, so Januvia doesn't need to stimulate my body to make much insulin. If you need more insulin, you may not get good results with Januvia.

Also Januvia is being described as being weight-neutral (i.e. not causing weight gain) based on two studies, one of which showed 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 as Byetta, when it works, causes weight loss.

For the time being, it looks like Byetta would be a much better choice for an incretin hormone-based treatment for Type 2s who need to lose weight.

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

Since posting this page I've received a lot of email from people who would prefer to take Januvia rather than Byetta and want to know my opinion of which is best.

My suspicion is that 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 by adding 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.