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

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.