July 19, 2007

How Januvia Works

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:

This blog has been getting heavy traffic from people searching for information about Januvia, and I'm also getting a lot of mail on the topic.

Much of it shows that doctors do not understand the way that this new incretin drug works to lower blood sugar and are therefore prescribing it inappropriately. As a result, a lot of people who are taking Januvia report seeing very high blood sugars. Let's look at why this might be and what it tells them about their true medication needs.

The main way that Januvia lowers blood sugar is by raising the level of a substance, GLP-1, which is produced in the gut and has the ability to do several things.

1. GLP-1 stimulates the beta cell to secrete insulin in a manner very similar to that of the sulfonylurea drugs like Amaryl and Glipizide (sulfs). What is different about using Januvia to do this, is that GLP-1 only causes your beta cells to secrete insulin when blood sugar rises to a certain level (for me, it was 120 mg/dl). Thus with GLP-1 stimulation you don't have the problem you have with sulf drugs of insulin being produced all the time, even when there is no glucose coming into the blood stream, and so Januvia does not cause hypos as sulf drugs do.

2. GLP-1 also affects the speed of stomach emptying. This is why larger doses of artificial GLP-1, Byetta, causes vomiting and very slow stomach emptying. The levels of GLP-1 Januvia causes are much lower than those you get with Byetta, so the digestive symptoms are milder, but they are most definitely there.

If you already have digestive problems or slow stomach emptying, Januvia may make them worse. I found the stomach symptoms didn't really kick in until my third month on Januvia, but then it seemed like my whole digestive system pretty much ground to a halt.

3. GLP-1 also affects hunger in the brain. There are GLP-1 receptors in the brain and one of the things they do is down-regulate hunger. So if you end up with a lot of GLP-1 in your system, you may end up with a near-anorexic attitude towards food. Again, I developed this the third month I was on Januvia when I found myself not wanting to eat.

Januvia does NOT create GLP-1. What it does is keep the body from destroying the GLP-1 your body makes on its own by inhibiting an enzyme called DPP-4 whose job, in the gut, is to chop up DPP-4. Januvia will only raise GLP-1 if your body can make GLP-1. Many people with diabetes do not apparently make much of it anymore.

Even more importantly, GLP-1 controls blood sugar by stimulating the beta cells to secrete using a mechanism very similar to Sulf drugs. If you are no longer responding to high doses of a drug like Amaryl or Glipizide it is very unlikely you will have any response to Januvia, because when active, it is doing the same thing these drugs do, but less strongly.

By the same token if Byetta has not given you normal blood sugars, adding Januvia isn't likely to help that much. A shot of Byetta is a very large dose of a GLP-1 analog. If that isn't stimulating insulin production, Januvia isn't likely to help. In theory it would keep that injected GLP-1 active longer, but since Byetta is active for 2 hours already, and you inject it at meal time, if it isn't lowering blood sugar by 2 hours, keeping it around more isn't likely to do much.

I had a very good response to Januvia's stimulation of my beta cells, because I have an oddball form of diabetes that is known to be exquisitely sensitive to stimulation by sulfs. A tiny dose, of Amaryl, caused me to hypo. But most people with Type 2 diabetes are not very sensitive to sulfs. The typical dose they take may be 50 times higher than what I was taking. Even with these much larger doses their blood sugars are much higher than normal. So because they do not respond well to strong beta cell stimulation their response to Januvia will probably be much weaker.

If Sulf Drugs Arnen't Normalizing Your Blood Sugar Januvia Won't Either


If your beta cells are dead or are no longer secreting insulin in response to Amaryl or Glipizide they will not be able to respond to GLP-1.

I cannot tell you how many people have written to me that their doctors prescribed Januvia along with the sulf drug they were taking even though it had stopped working very well.

Januvia is, not surprisingly, doing nothing for them. This is as you'd expect it to be. If the sulf isn't stimulating insulin secretion, Januvia won't either because GLP-1 stimulates the SAME part of the beta cell.

Paying $6 a pill for a drug that is not going to be able to do anything for you is just plain stupid. Doctors who prescribe Januvia along with Sulfs clearly have not read up on how the drug works.

The Dream of Beta Cell Regeneration


Doctors are telling many patients, based on claims made by the drug reps and NOT published in any of the legally required documents which receive FDA scrutiny, that they should keep taking Januvia because it will "regenerate" their beta cells.

The lab research this is based on is rodent research where rodents who took various incretin drugs ended up with more beta cell mass--though not anything near normal beta cell mass.

But applying some critical thinking to the few studies that hint at this, it is important to realize that what the research may really show is that when the drug does restore normal blood sugar levels as it does in people with relatively mild diabetes, beta cells stop dying from being poisoned by the very high blood sugars. That this can happen has been proven by a lot of research. Prolonged exposure to blood sugars over 150 mg/dl appear to kill beta cells. So lowering the blood sugar can indeed preserve beta cells from destruction and perhaps help some of them reproduce.

This means, however, that if your blood sugars are over 160 mg/dl all the time while you take Januvia or Beytta, you are still exposing your beta cells to the poisoning effect of high blood sugar and they are not likely to regenerate.

If you are taking Januvia and not seeing the dramatic lowering of blood sugar which some people see, or not seeing any lowering at all, you should not keep taking it in the hope it will rejuvenate your beta cells. The high blood sugars you are maintaining are guaranteed to kill more of them, to say nothing of what those high blood sugars are doing to your retinas, nerves, and kidneys.

Other Known Effects of Januvia


Inhibiting DPP-4 affects many other functions this enzyme performs around the body. (Note: In research studies, DPP-4 is also referred to as "CD26")

Among those are:

1. Regulation of the Immune System. DPP-4 inhibition has shown some ability in early studies to turn down autoimmune responses, which would be good news for people with autoimmune diseases like Rheumatoid Arthritis and Multiple Sclerosis, and early research shows it may end up being useful for these conditions.

NOTE: While I had read about DPP-4 inhibitors being used to treat RA and MS, I just stumbled upon a study that found that the LOWER the DPP-4 level the greater the inflammation in Rheumatoid Arthritis in both mouse and human models. Here's the reference:

Circulating CD26 is Negatively Associated with Inflammation in Human and Experimental Arthritis

However, if you do not have an overactive autoimmune system, inhibiting DPP-4 may still lower your immune response. This may not be a good thing if you need to fight infection. Pfizer notes in the required label information that Januvia raises one kind of white blood cell, but comments only that the significance of this is "insignificant." I had my blood tested before and after taking Januvia for 3 months, and sure enough, it had raised just that part of my white blood count.

2. Headache and sinus problems are an early side effect with Januvia that the company also mentions. It is not known what causes them. The increasingly frequent sinus headaches that would not quit all day long were one reason I stopped taking Januvia. It is possible that some inflammatory change in the sinus is at fault.

If you have a non-autoimmune problem with your immune system, be very cautious with Januvia, because it's effect in down-regulating the immune system is not understood and many doctors are blissfully unaware of it, mostly because the articles that discuss this and other effects of incretin drugs, like raising blood pressure, are only available in full to subscribers to the expensive journals that publish them.

3. Mood. Some studies of people undergoing treatment for cancer that raised DPP-4 found that high DPP-4 caused massive depression. Lowering DPP-4 may therefore improve mood.

4. Fighting Cancerous Cells. Raising DPP-4 with radical cutting edge treatments that affect interleukins appear to be effective in several cancers. Suppressing IL-1 to treat rheumatoid arthritis with the drug Anakinra has been shown in one study to raise the incidence of melanoma. I have written at length elsewhere in this blog why I am concerned that inhibiting DPP-4 may be dangerous for people who are melanoma survivors. While not causing melanoma, DPP-4 inhibition may handcuff the mechanism the immune system uses to get rid of metatastic cells once they appear. Prostate cancer is another form of cancer where DPP-4 seems implicated in the body's natural defenses.

The acceptance testing for drugs involves tests that look at whether they cause cancerous changes in cells in the test tube. They also look at whether the drugs cause cancer in rodents, but it's worth remembering rodents live short lives.

What the testing does not look at is whether a drug might cause cancer by crippling the mechanism that the body uses to fight cancer. Since this may be what Januvia does, it has not been looked at.

Melanoma may take much longer to develop than the lifespan of a rodent. My lesion took more than 6 years to become bad enough that a doctor noticed it and demanded a biopsy. It was present 6 years earlier but a skin doctor had dismissed it as normal pigmentation. On biopsy, it was melanoma. Therefore, I know that a 2 year trial is not long enough to show the impact of this drug on melanoma. Because DPP-4 inhibition has been linked with the progress of melanoma this is a very serious issue that has gone unexamined.

And it is worth noting that high levels of Januvia did cause tumors in rodents. The Prescribing Information states: "There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily."

I do not know whether rodents get melanoma. Since they are completely covered with fur they do not get the dose of damaging radiation that we hairless monkeys get.

Bottom Line: Januvia works best in people with VERY early diabetes or genetic forms of diabetes that are hyper sensitive to sulfonylurea drugs.



Even more important, the impact of suppressing DPP-4 on all the many other functions of this enzyme throughout the body and brain are not at all understood and may involve breakdowns of the immune system that could be dangerous. If you are a melanoma survivor, as I am, and may still have melanoma cells in your body, you should not take this drug until its effect on the immune system is better understood. The same may be true for Prostate cancer.

It's up to you if you want to try it. For some people with early Type 2 diabetes it's effects on blood sugar are dramatic, though if you are like me, the side effects may eventually outweigh the benefits of better blood sugar control.

But don't expect it to work well if you are not doing well on Byetta or Sulfonylurea drugs because it is uses a much weaker form of the same mechanism these drugs use.

If your Beta Cells ARE Dead


If your beta cells are dead and your blood sugar does not come down to normal levels with Januvia or Byetta, it is time to move on to the one drug that, dosed correctly, always works. Insulin.

More about Januvia with scholarly citations is on this page on my Main Diabetes Web Site: http://www.phlaunt.com/diabetes/15332388.php Byetta and Januvia.

10 comments:

Anonymous said...

If all it took to get beta cell regeneration was normalized blood sugars, then any drug or insulin would do that. But they don't. Some drugs such as Byetta and Januvia do, while others don't. So you are wrong.

And you are also wrong or at least speculating when you say that sulfs and GLP-1 use the same mechanism to stimulate beta-cells.

Jenny said...

In fact, Anonymous, a recent study conducted by the Mayo clinic shows that a significant number of people with type 2 recover their beta cell function over a period of 12 years. So yes, drugs and/or insulin that provide blood sugars low enough to prevent glucose toxicity do appear to rejuvenate beta cells in people whose cells are not completely dead. This research is discussed on my main web site on the page "Do People with Type 2 Always Deteriorate."

And the information about how GLP-1 stimulate insulin is not speculative, but is based on several journal articles which are not available online which I was sent by the researchers who wrote them.

A British researcher who specializes in the MODY forms of diabetes told me that he was eagerly awaiting the release of incretin drugs in the UK because their similarities to sulf drugs in the way they caused insulin secretion suggested that they would work very well for many people with MODY. He was very interested in the very strong response I had to Januvia for that reason.

jim said...

Dear Jenny,
Thank you for sharing and caring! I am newly diagnosied early stage T2. With diet and execise alone, I am at 5.8 a1c. My body weight is good. My lipid numbers all good except for my HDL which is low.
Blood prssure under control. Have debated about using any meds at all. My eno has suggested, and I have taken for 1 month with no weight gain)Actos 15mg just to avoid beta cell deterioration. My interest suggested Januvia..if anything. I had volunteered for a study in Boston and a clamp was done indicating moderate IR (7). The doctor said metformin or only a med when I go out for larger tha usual meals. Confused here!
My real long term concern is long term beta cell function loss (obvioulsly) so given my early stage..Januvia? Actos? Metformin? Nothing?
Thank you, once again!
Jim

Jenny said...

Jim,

Who's confused is the doc who told you to only take metformin occasionally. It builds up in the blood stream and reaches efficacy in about a week! This is not obscure information, but should be known to anyone who prescribes the drug.

The A1c is not very informative in the range yours is in, because it is possible to have very high post meal numbers and normal fasting numbers and get that A1c. If your blood sugar is routinely going over 140 mg/dl you need to watch it.

Did the Actos modify your post-meal numbers? If it didn't, and if your post-meal response continues to get worse, it is possible you aren't a type 2 at all, being of normal weight. You should monitor it over the next six months closely.

At your A1c level, the post meal blood sugars are the most important thing. Metformin would be the drug of choice to start with, rather than Actos, as the claim that it rejuvenates beta cells has been disproven, though your doctor seems to have missed that study, probably because the drug reps who "educate" him on drugs didn't mention it!

jim said...

Dear Jenny,
My concern. While the net result of any of the drugs that cause the pancreas to produce (more)insulin, is a better BG, are we actually stessing the very beta cells that we want to preserve resulting in potential long term survival consequences to those very beta cells? I don't know if the answer exists. Here lies the possible rational for using drugs that lower insulin resistance. In theory these drugs not only lower the BG, but they do not stress the beta cells...in fact they alleviate stress to those very cells that we wish to retain. Therein lies a fundemental question with potential long term consequences. I don't know how theory translates into reality. So while lower BG can be achieved by different means, and a lower BG in and of itself may very well help retain beta cells, might we be causing some of those very same cells damage long term by using drugs that stimulate them to achieve the lower BG, while the lowering IR drugs may achieve the same lowering of BG (FOR SOME) without potential harm to the beta cells because they do not stress them?
Jim

Anonymous said...

Jim
Metformin is the best drug for insulin resistance. Metformin, Actos and Avandia do not stimulate insulin production.

I think lowering IR is better than stimulating more insulin production. I also think shooting insulin is better than stimulating insulin production. However,
I wouldn't think that taking a short acting ß-cell stimulator like Starlix(?) occasionally would be as bad for you as taking one of those long acting ones, like glyburide, every day. We aren't talking about occasionally like once a day, more like once a month.

Anonymous said...

Correction!! Januvia Reps are NOT Telling doctors that Januvia Regenerates the Beta Cells!!
Thanks

Vinod said...

Hi Jenny:

I stumbled upon your blog while researching on Januvia. I have type 2 diabetes and am on Metformin two 500mg tabs twice a day. Lately I have noticed my 1Ac go high and at 8.4mmol my doc added a 4mg Amaryl. Today is my third day of taking Amaryl and yesterday I saw a puff develop underside of my left eye. I have an itchy feeling on the left side of my face. The puff does not hurt me or anything like that. I do not know if it could be an allergic reaction to Amaryl. Have you come across any reaction like this before.

Today I saw my doctor who gave me Januvia and asked me to stop Amaryl. From your article I gather Januvia may not be a perfect fit. I am thinking whether I should go on Januvia. Would like to know your thoughts,

Thanks

Jenny said...

Vinod,

It isn't appropriate for me to tell anyone what meds to take as I am not their doctor. What I do is present the evidence I've found, which you will find on the Januvia page. You will have to make your own decisions based on the facts. Unfortunately, doctors often are not informed about any issues involving new drugs since they get their "education" from the sales reps of the drug companies.

The swelling from Amaryl does sound like it might be an immune problem.

Have you already tried Metformin? It is what the various doctors' organizations say should be the first drug prescribed. Insulin is also very helpful for many people with Type 2 and probably safer than the other oral drugs besides metformin.

dajaxon said...

I was on Amaryl but by the advice of my pharmacist, the doctor switched me to Januvia. That seemed to work OK - kept A1c levels around 6.9-7.1 while I was also taking 1000mg of Metformin. This started in late 2006. I then had SIADH July 2010 and was removed from ALL medication except for my Nephedpine (BP med). The endo doctor I consulted has suggested not taking januvia or simvistatin again. I'm not sure of the reasons. Is there some known interaction that could cause hyponatremia ... or is it possibly a low testosterone value (diagnosed recently). I'm confused how januvia was targeted. My A1C did drop to 6.2 when I lost 54 lbs. Now I'm back to same old issue with the weight gain.