December 8, 2008

More Research Shows Januvia and Glinides Inhibit Tumor Suppressor Gene DPP-4

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:

I spent some time this week scanning IHOP for the latest academic research about the impact of DPP-4 inhibition.

This IHOP has nothing to do with pancakes. It's a database that links to all research references related to specific genes.

Two new studies grabbed my attention and should be of great interest to anyone taking Januvia. These studies looked at the impact of inhibiting DPP-4 on the growth of two different kinds of cancers.

This is important because the way Januvia lowers blood sugar is by inhibiting DPP-4. It does this because DPP-4 is a protease (an enzyme that chops up protein chains) that, among other things, destroys a hormone, GLP-1, that helps control blood sugar levels. When you inhibit DPP-4, GLP-1 levels to rise and blood sugars drop.

But none of the drug industry-sponsored testing for the safety of Januvia looked at the other things that DPP-4 does. Fortunately, some academic researchers not-funded by drug makers are doing this and what they are finding should make any sane person stop taking Januvia.

Because it turns out that DPP-4 is also a tumor suppressor. And when you inhibit it, cells that have become cancerous get a "get out of jail free" card.

One study of prostate cancer cells studied in a culture medium concluded
By inhibiting CD26/DPPIV, invasion and metastasis of PCa cell lines [prostate cancer] were enhanced in in vitro and in vivo metastasis assays. Together, these data suggest that the degradation of CXCL12 by CD26/DPPIV may be involved in the metastatic cascades of PCa, and suggests that inhibition of CD26/DPPIV may be a trigger of PCa metastasis. [emphasis mine].
This is serious stuff. What it is saying is that if you have a prostate cell that had become cancerous and then inhibit DPP-4 that will be able to invade tissue and really take off.

Here's the abstract of that study:

CD26/dipeptidyl peptidase IV regulates prostate cancer metastasis by degrading SDF-1/CXCL12.

The other study involved melanoma cells and had this to say,
Previously we have demonstrated that DPPIV abrogates growth factor independence and functions as a tumor suppressor gene in melanomas ... Further more, 5-AZA-Cdr induced increases in DPPIV levels correlated with growth inhibition and apoptosis in melanoma cells. All together these findings suggest that frequent downregulation of DPPIV expression in melanoma can be attributed, in large part, to aberrant promoter hypermethylation and this loss of DPPIV may be a critical event contributing to melanoma development. [emphasis mine]
What this is saying is that if you increase DPP-4 levels, melanoma cells experience apoptosis, a fancy word for cell suicide. If you inhibit DPP-4, these cancerous cells will continue to grow.

Here's the abstract of that article:

Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation.

All this suggests, loud and clear, that if you want to raise GLP-1 levels it is much safer to use Byetta. Byetta is a synthetic, long-lasting form of GLP-1 which does not have any impact on your DPP-4 levels.

Another, older study points to another interesting conclusion. Metformin raises GLP-1 levels without inhibiting DPP-4.

Enhanced secretion of glucagon-like peptide 1 by biguanide compounds.

Even more interesting, another study that came up on the IHOP DPP-4 search suggests that another diabetes drug family also inhibits DPP-4. That family is the "glinide" family which includes Prandin and Starlix.

You can read the research that found this connection here:

Effects of antidiabetic drugs on dipeptidyl peptidase IV activity: nateglinide is an inhibitor of DPP IV and augments the antidiabetic activity of glucagon-like peptide-1.

Here Starlix was the drug the researchers found to have the strongest inhibitory effect on DPP-4. (Note, this statement has been corrected since this post was first made.)

But if you want to use a pill to inhibit DPP-4 there is one huge advantage to using Starlix or Prandin rather than Januvia. Is this: they have a much shorter half life in the body. The half-life of Prandin is 1 hour. The half life of Starlix is 1.5 hours. That means that if you take these drugs at meal time, they do their job and go home. So while they inhibit DPP-4, they do so for only a short period, after which the DPP-4 gene can express and produce DPP-4 again.

In contrast, the half life of Januvia is 12.5 hours and the Januvia prescribing information states, "In patients with type 2 diabetes, administration of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period." Since Januvia is taken daily, this means that it inhibits DPP-4 all the time.

Ask yourself this: Do you want to permanently inhibit the activity of a tumor suppressor gene?

I don't think so. Particularly not when you realize that all the studies attesting to the safety of Januvia did not examine its impact on tumor growth. You can read more about how the safety studies avoided this issue in this old blog post:

More Evidence Connects Januvia to Cancer,

UPDATE Later the same day:

In response to an email in which I asked for more clarification about the implications of the research cited above for people taking Januvia, the researcher who authored one of these studies wrote the following:
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.
Januvia is Merck's most profitable drug. You can be sure that they have not and do not plan to do any studies that could kill this particular golden goose. Even if failure to do this research might kill YOU.

11 comments:

Scott said...

I am hopeful (but not naive to think it is guaranteed) that the FDA's use of "surrogate endpoints" as the sole criteria for approving diabetes drugs has finally come to an end. This began last year with the FDA's review of its criteria, and Steve Nissen at the Cleveland clinic was a big factor in pushing for expanded criteria.

We are already seeing this with the delay given the Amylin/Lilly's Byetta LAR, but also with a number of other drugs that big pharma had planned on being given a rubber-stamp approval have since been delayed for more information. The reality is that reduced HbA1c does not guarantee improved patient outcomes, but with that as the primary requirement, a number of questionable drugs were approved.

Let's hope more conservatism in reviewing drugs will be the mantra in coming years.

Jenny said...

Scott,

While the issue you raise is a step in the right direction, the reason LAR wasn't approved is because of a problem already identified with Byetta--the possibility of pancreatitis. As I understand it, the problem with a longer acting drug is that it makes it impossible to cease taking the drug if pancreatitis appears.

But the problem with Januvia is different--it is that testing HAS NOT BEEN DONE to check out a major problem indicated by basic research.

I just heard from one of the researchers whose papers I cited that inhibiting DPP-4 with a diabetes drug does sound like a very bad idea, but that NO research has been done to see if these drugs inhibit the anit-tumor activity of DPP-4.

No drug company will fund that research, and researchers are too dependent on drug companies for grants to undertake it on their own.

So we really need another level of questions to be asked during the approval process.

The Old Man and His Dog said...

Nice blog! You are one of the reasons I am now on Byetta and off of Januvia. Thank you for caring.

uwak said...

this medicine still need test and test....cause still new, some report say that the power to control blood glucose more low than su

Ween said...

I am pretty certain that lowering my glucose to normal decreases my chance of developing blindness, kidney failure and amputation. Diabetes is the leading cause of these scourges. So what is wrong with the FDA using lowering of glucose or lowering of HbA1c as a "surrogate" marker of benefit. To Dr. Nissen at the cleveland clinic I say: I am blind and on dialysis (and my leg has been cut off), but thank goodness I did not have a heart attack because he saved me from taking Avandia. To Jenny: I am now blind and on dialysis and my leg has been cut off, but thank goodness my prostate cancer did not spread because I did not take Januvia.

My point (in case you missed it) is, who gets to decide what risks we should take when we take a pill or are prevented from taking a pill? Should the FDA decide that Januvia worsens the risk of prostate cancer and thus ban it? or should I decide if I want to take the drug and lower my risk of retinopathy, nephropathy and neuropathy?

Jenny said...

Ween,

If Januvia allows a cancer to go metastatic you won't live long enough to go blind or get amputations.

It takes at least 10 years for severe diabetes complications to develop.

Melanoma or ovarian cancer that has gone beyond stage 2 usually kills within a year. Since melanoma develops in the linings of the digestive system, not just the skin, it can be undetectable until it is at stage 4.

The survival statistics for prostate cancer are misleading because there are two kinds--a slow growing form most people survive and a fast growing form that kills within two years. Do you really want to risk turning a slow growing cancer you could live with to one that will kill you in two years?

If there were no other ways of lowering blood sugar, one could argue that there is a place for these dangerous drugs. But the point is that THERE ARE OTHER SAFER TREATMENTS that are equally effective. Neither Januvia or Avandia/Actos do much for blood sugar control. They cause about a .5% drop in A1c overall. Neither is powerful enough to lower the kinds of blood sugars that lead to blindness and amputation to a safer level.

Only cutting down on carbohydrates and adding insulin can drop a 10% A1c (which is the kind of level at which complications accelerate) to even the anemic 7% A1c at which point they still occur but less frequently.

Anonymous said...

Jenny,

This is off subject, but how can I open a thread about the DOT's senseless discrimination against commercial drivers who need to take injectible insulin?

I am more than willing to discuss this discrimination at leangth with you, but please don't post my email address. It is don-ej-jones@my180.net. This address is for your use only in contacting me.

Thank you.

stant7 said...

I don't get it. Reviewing Merck literature they quote 2 year rat cancer studies and it seems reasonable. I'd welcome your comments. Here is the link to the reference:

http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf

Jenny said...

Rat studies have failed to find cancer relationships with many drugs and chemicals that are linked to cancer in humans.

The human findings in the clinical trials DID point to excess cancers--that is what Dr. Goldstein's letter in Annals of Internal Medicine pointed out. It isn't a huge number, but then the number of cases of melanoma aren't huge overall.

Another drug,. Anakinra, which also impacts DPP-4 levels produced a couple more cases of melanoma than "expected" in clinical trials, but was still approved. The problem is that 2 or 3 extra cases per thousand when applied to many hundreds of thousands turn into a lot of people who might not have died.

And with Januvia, they did NOT track the incidence of the individual kinds of cancers known to respond to DPP-4. That's another problem with the rat study. The rise in cancer is relatively small and it takes thousands of subjects to see it.

But for those of us who are cancer survivors or men over 50 most of whom harbor cancerous cells in the prostate this is an issue. And because doctors aren't aware that there is a link between DPP-4 inhibition and cancer, they don't report prostate or melanoma deaths in Januvia patients, so there is no way of learning that the number of such deaths has risen.

LocalGP said...

Thanks Jenny for the excellent and critically important inputs. I am practicing in a region (non US, non European)where this Drug (Januvia) has established itself as safe (no hypoglycemia)option in diabetes. My worry is that GPs are widely prescribing it as almost first/second option in Diabetes, and tragically even public health institutions are dispensing it freely. This is happening in an area of the world where the official poverty line (income per day) is lower than the cost of one tablet of Januvia; and a large section of the population is below poverty line. in addition to the legitimate and profound concern about cancers and diversion of cost to an ineffective drug; I personally feel that it may actually be associated with more frequent episodes of hypoglycemias (needs discreet, independent reaprraisal).

Jenny said...

LocalGP,

I'm pretty sure that the mechanism by which Januvia lowers blood sugar should not cause hypos because the insulin secretion should stop when blood sugar is under the threshold where 2nd phase kicks in. It may cause "false hypo" in people who are used to high blood sugars.

The main side effects people have reported to me are severe rashes, joint inflammation that does not resolve when the drug is discontinued, headache, nasal congestion and severe constipation. These are all in line with what the drug does. If you read up on DPP-4 on the gene database you'll see that it does also act in the sinuses.

But I hear you on the criminality of prescribing a drug that expensive when there is a safer, very cheap alternative available. And don't get me started on why there isn't generic insulin available at a cost people can afford.