June 23, 2007

Januvia and Melanoma

UPDATE (April 2, 2013): Before you take Byetta, Victoza, Onglyza, or Januvia please read about the new research that shows that they, and probably all incretin drugs, cause severely abnormal cell growth in the pancreas and precancerous tumors. You'll find that information HERE.

Original Post:

Because this blog was one of the very first to discuss Januvia, I get a lot of visitors who find this site via a Google or Technorati search on the term "Januvia." So I thought I'd post a bit more about my major concern about this new drug.

Whatever it does for blood sugar, the big problem I see with Januvia is that the testing that the FDA required before they approved it for use did not look at what the other effects might be of its new and very powerful mechanism.

As a result, Januvia has gotten the undeserved reputation of having very few side effects. This has gotten a lot of doctors prescribing it, despite its cost, which is among the very highest for any diabetes pill, ever.

But the problem is that Januvia uses a new and not well-understood mechanism. It works by keeping an enzyme from being produced. This enzyme, DPP-4, stimulates the removal of another substance, GLP-1, from the body. Since GLP-1 can stimulate insulin release, allowing GLP-1 to build up can cause more insulin to be produced by the beta cells, lowering blood sugar.

That's good, and in a person who still has living beta cells that are capable of secreting more insulin than they do, DPP-4 inhibition lowers blood sugar, though the amount it will lower it depends on how insulin resistant the person is and how much excess capacity their beta cells have left.

But here's the problem: DPP-4 isn't just used to keep GLP-1 levels from building up. It is used throughout the body for many other functions, many of which involve the immune system and brain. Even more important, scientists do not yet fully understand these functions of DPP-4.

This means that they also don't know what the effect of inhibiting its action will be. And even more importantly, the testing that the FDA required of Merck before approving Januvia did not look into the effect of inhibiting this enzyme in other parts of the body.

This is not trivial. There are cancers, most notably melanoma, in which researchers have found that the cells become malignant when they stop producing DPP-4. When DPP-4 production is restored to these cells, they stop being malignant. That would suggest, at a minimum, that the testing for Januvia should have looked to see what the impact of artificial, drug-induced inhibition of DPP-4 would be on these particular kinds of cells and whether inhibiting DPP-4 for a long time would lead to more melanomas developing. This was not done.

The standard drug acceptance process involves using some standard cancer tests. But these tests do not involve looking at the effect of removing DPP-4 on the specific kind of cell that responds to DPP-4 suppression by turning cancerous. The cancer screens look for the ability of a drug to cause tumors in rats (which, by the way, Januvia did do at very high doses.) They look at the effects of a drug in a test tube culture to, to see if the drug messes up the DNA in a way that leads to cancer.

But what we are talking about here is a drug that doesn't cause cancer by messing up a cell's DNA. Instead, what it might do, is disable the enzyme the body uses to get rid of cancerous cells once some other mechanism has made them malignant.

With melanoma, the mechanism that turns cells cancerous is working on all of us--sunshine. But most of our bodies get rid of cancerous cells before they have a chance to grown into large invasive tumors. How they do this apparently involves the use of DPP-4--which is the substance Januvia inhibits. So you can see that the standard cancer testing should not reassure you that Januvia doesn't cause cancers to grow out of control.

This really worries me. Especially since so few people know about the relationship of DPP-4 and melanoma. I do, because I'm a melanoma survivor. And I can tell you right now that the reason you don't see people wearing "beat" melanoma ribbons, and going on melanoma runs, and painting and singing about how much they grew spiritually through fighting melanoma the way you do with breast cancer, is because most people who fought melanoma are dead.

Whenever I tell someone I have had two surgeries for melanoma they tell me about some relative or friend who had it, was told they'd be fine, and then died of it. I'm very lucky my melanoma was in a very visible spot and that a doctor saw it early enough for me to be able to have it removed before it had penetrated through the bottom layer of the skin and into my bloodstream. Once this happens, your chances of survival plummet.

Even though I'm supposed to be fine, I am not allowed to donate blood or organs because there is a good possibility that melanoma cells are floating around in my body which would seed themselves in the person who received my tissues and kill them.

That's how nasty melanoma is, and why it really troubles me that there have not been any specific studies to see what the effect of Januvia's form of DPP-4 inhibition is on melanocytes.

Januvia was approved after a very short trial--barely two years long--and melanoma can take quite a few years to develop to where anyone would notice a melanoma lesion and consider it abnormal. I had actually shown my lesion to a skin doctor 4 years before it was biopsied and found to be melanoma. But the first time I showed it to the skin doctor, he only inspected it visually and told me it was "nothing to worry about." It was about ten times larger by the time a doctor did consider it something to worry about. Before that, I foolishly assumed it was nothing because the skin doctor had told me that.

So unless every single suspicious patch of pigment on every participant in the Januvia trials was biopsied, we have no idea whether or not they had developed very early cell changes leading to melanoma during the brief, two year trial.

Even worse, there is a form of melanoma which develops inside the body, in melanocytes that live in the linings of organs, and which is only detected when it has spread throughout the body and created tumors large enough to be observed as large lumps. If study participants developed this kind of melanoma, it would only be detectible on full body CT scans, which, of course, they were not given.

When I first read up on this, I asked quite a few doctors about it, and they had no information about it at all. Then I started emailing the researchers who had published about Januvia and DPP-4 inhibition. Eventually one, (whose name I promised to keep private) told me that my concern was real and that the research simply has not been done to answer the question about the possible melanoma risk.

You can be sure, with the pills selling for $6 each, that Merck is not about to do that research any time soon. This is, after all, the company that suppressed the heart attack data on its drug, Vioxx, and which is now selling another drug that research shows is equally dangerous, Arcoxia, despite data that shows it kills tens of thousands of people who would have lived had they used Ibuprofen, a drug that works just as well as Arcoxia.

So if you are thinking of taking this drug, give it some serious thought. Is it really worth the risk Januvia represents to get a .5% lowering of your A1c? And if your doctor tells you there are no side effects, do ask the doctor what they know about the effect of DPP-4 on melanomas and why they are sure inhibiting DPP-4 with this drug is safe when no research has been done to look into this.


Anonymous said...

Thanks for this information. I don't know why my endo didn't tell me this when I asked about the risks associated with Januvia. Now I know it's probably because he's on the payroll for this drug.

That being said, my A1cs for the last 2 1/2 years have ranged between 5.5 and 6.1 using diet and exercise alone for control. Just this week, I started taking Januvia and I've had a dramatic drop in my blood sugar readings, which now range between about 77 and 114. I have noticed some tiredness and sniffles but nothing major in the way of side effects. Sitll, I live in the Southwest, lead an active outdoor lifestyle, and skin cancer is a serious concern.

I don't know what to do. Maybe I'll try cutting the pills in half and taking a smaller dose to see what effect that has.

Jenny said...

Doctors only know what is in the "prescribing information" that the FDA requires drug companies to publish. The PI claims that the drug is almost completely side effect-free.

The problem I've highlighted is one that hasn't been investigated since the FDA did not require any research into it. Hence no need to mention it.

So your doctor is going on information he thinks he can trust. The problem is, that as we've seen in the past decade, the FDA approval process can miss some major problems with new drugs, especially those who were approved after only a few thousand people took them for a relatively short time.
Doctors are very busy and deal with literally hundreds of diseases and drugs so they don't have the time to do the detailed research that those of us who have a disease can and must do.

When I shared my concerns with my endo she agreed that it was a concern, especially since I am only 4 years from my melanoma surgeries.

Anonymous said...

I'm a nurse working in Wound Care and we are seeing more and more Januvia patients with non healing wounds. We knew nothing about this effect until I started researching on the internet. Thanks for the information regarding melanoma.

Jenny said...

PLEASE report the nonhealing wounds associated with Januvia to the FDA post marketing Adverse Event reporting system at:


Anonymous said...

The wound I had on my leg was not
healing and the family doctor just
kept the same treatment for it. I
went to the ER and a specialist told
me to go to a skin specialist for it.
She prescribed the topical cream
Biofine and it is healing. However
my doctor of Endocrinology wants me
to start on Januvia. I am concerned
after reading this. I've been working
with a nutritionist for six months
who has helped me lower blood sugar levels. I am doing better
and working towards more weight
loss exercise was at a stand still
after the leg ulcer.

Sweety said...

My father is diabetic from last 7 years. Since beginning he is on insulin. Recently he has also undergone heart CABG surgery (just 3 months back). Since then it is taking time to adjust the insulin doses to get his sugar levels under control. It was almost under control a month back (with Humalog regular and Lantus insulin doses). But as soon as he started taking medicine for Cholesterol control, fasting sugar again went high. Now doctor has suggested him to take Januvia 100mg 1 tablet daily along with Glimulin twice daily and lantus at bedtime for controlling fasting sugar. I am really concerned for making this switch based on these blogs. Jenny, please provide some of your views.

Jenny said...


My views are all clearly laid out on this blog and This page on the main Blood Sugar 101 web site.

It wouldn't be right for me to comment on any one patient's situation. The data are on the site for you or, ideally, your father, to read and make your own decisions.

You can suggest that your father try this strategy first:
How to lower your blood sugar. It may solve the problem without new drugs.