March 25, 2013

Disturbing Study: Both Families of Incretin Drugs Appear to Cause Potentially Cancerous Changes in the Pancreas

Researchers just published a study in the journal Diabetes in which they autopsied the pancreases of 20 people with diabetes, 12 of whom were taking incretin drugs as well as those of 14 people without diabetes. Most had died of stroke or head injuries, leaving their pancreases in excellent condition.

The researchers wanted to see if, in fact, as claimed, the incretin drugs--the drugs that raise the concentration of GLP-1 or mimic GLP-1--cause an increase in the beta cell mass. These drugs have been promoted with the promise that they do, that they regenerate the pancreas. This is one major reason doctors prescribe them even when they appear to have no significant impact on their patients' blood sugars.

What the researchers found when they conducted rigorous studies of these pancreases found should make anyone taking any drug that increases the effect of GLP-1 completely rethink their drug strategy.

The study is Marked Expansion of Exocrine and Endocrine Pancreas with Incretin Therapy in Humans with increased Exocrine Pancreas Dysplasia and the potential for Glucagon-producing Neuroendocrine Tumors. Alexandra E Butler et al. Published online before print March 22, 2013, doi: 10.2337/db12-1686. Diabetes March 22, 2013

These Drugs Appear to Grow Lots More Beta Cells and Alpha Cells, But they Are Abnormal

What they found is this: These drugs do indeed appear to grow huge numbers of new beta cells and alpha cells in these people's pancreases. People with diabetes taking the incretin drugs had more than three times as much beta cell mass and alpha cell mass as people with diabetes not taking incretin drugs.

Unfortunately, the study also found that these cells were not growing in their normal patterns. They were found in  "eccentrically shaped islets" and "in association with duct structures."

These abnormal beta and alpha cells were only found in the people who had been taking incretin drugs for a year or more, not in people with diabetes. Moreover, the researchers comment that the structures found in association with the pancreatic ducts were of the kind that are found in people with pancreatitis.

Even worse, the researchers found "glucagon expressing microadenomas" in three cases. An adenoma is a benign tumor made of glandular tissue which has the capacity of turning malignant. None were found in the people with diabetes who were not taking incretin drugs.

A glucagon-expressing neuroendocrine tumor was also found in one of the patients taking Januvia.

The researchers point out that,
Moreover, since the standard of care of a pancreatic neuroendocrine tumor, because of the risk of conversion to malignancy, even if benign, is surgical resection [i.e. removal], patients exposed to incretin therapy would seem to be at increased risk of requiring pancreatic surgery.
Pancreatic surgery, even if it doesn't require the removal of your pancreas is very likely to damage it to the point where you become fully dependent on insulin. And that's the good outcome. The bad outcome is that they don't get all of the tumor, which converts to malignancy and you die of pancreatic cancer.

More importantly, the chances of doctors even noticing that one of these drugs is growing a tumore on your pancreas is nil--until it has grown to where it blocks ducts and causes extreme pain. The people autopsied in this study died of other causes unrelated to their diabetes or the health of their pancreases. The tumors they were carrying were unknown to their doctors.

The researchers that the causative factor here appears to be is the action of high levels of GLP-1 since both families of drugs caused the abnormal cell growth. Because of that, the same problems are almost certainly being caused by the newer incretin drugs, Onglyza, Victoza, Trajenta and any other DDP-4 inhibitor or GLP-1 mimic.

Since there were already troubling signs of pancreatitis and other kinds of adenomas associated with some of these newer incretin drugs while they were still in the testing phase, while it took many years for the possible association with pancreatitis to emerge with Byetta, these new drugs may be even more dangerous than Januvia and Byetta.

Talk to Your Doctor and Show Him or Her the Link to this Article Immediately

Tell them to hunt up the full text version. (I have read it.) It is compelling reading and should make any doctor not on the payroll of a drug company seriously reconsider prescribing any of these drugs. 

That said, I fully expect to see this result spun by the drug companies, because the study also found that these drugs increased beta cell mass, something the drug companies have been hoping would turn out to be true.

But as these researchers point out, these new beta cells appear to be immature beta cells that are not functional.  Some are expressing both insulin and glucagon, a characteristic of fetal human cells but not those of adults. And as they note, too. These people were all diabetic when they died, though they had 3 times as much beta cell mass as a normal person. Obviously, these beta cells were not the kind we want to fill our pancreases with.

And of course, the cost of this increase in  beta cell mass was to fill the pancreas with invasive structures made up of a kind of fetal beta cell that isn't usually found in adults. Cells that are clumping together into glandular tissues aaround the pancreatic ducts in ways that aren't normal and, long term, may be far from benign.

Since there is no way to monitor what is going on in your pancreas without opening you up and taking a slice or two, the cost of any beta cell mass growth is obviously much too high.


drjbo said...

Well, I am one week into a trial of Victoza now. Thought I would try and take the doctor's advice. This is VERY HARD FOR ME! Of course, I have had side effects, and am wondering how long these tumors took to form? She said I didn't have to stay on this forever, and thought it would help with weight loss. I have access to a health library, I just have to figure out how to get in. BTW, haven't lost an ounce, just nauseous with back pain, bad sleep patterns not to mention the other GI effects.

Ken said...

Wow ... this is BIG news, I think. A thought that this induces for me, as well, is that the Butler study and the (reasonably) well known strong negative correlation between pancreatitis / pancreatic cancer and T2DM are probably closely linked.
Jenny, I am a severe skeptic of the usefulness of drugs in general for the treatment of any chronic disease, but even I have wondered whether you might have been a bit too harsh in some of your opinions.
I'd say your instincts and judgements have been vindicated.
As (I believe) is most often the case, people taking prescribed drugs (in addition to the drugs themselves) for chronic/metabolic/Western diseases "of civilization" may possibly provide the most benefit as "human-model" study subjects (and hormone emulators/manipulators) even though this is obviously not the intent of the prescribing MDs or the drugs.

Jenny said...


This news shocked even me since I had been recommending Byetta for years, and had been swayed by the Medco study to think it was benign. My biggest problem with it had been how many people I had heard from who told me it didn't do anything for them-- result borne out by the manufacturer's own post-marketing data--and by the fact that over time that data showed it seemed to become ineffective, which to me seemed like proof it wasn't regenerating the beta cells.

Now this makes me wonder if perhaps the long term problem has to to with hyperactive alpha-cell secretion of glucagon, the hormone that opposes insulin and raises blood sugar.

drjbo said...

Well, Jenny. I only made it two weeks on the Victoza anyway. The first week I had to cut back on my work schedule because I couldn't function. Bad sleep, back pain and headache are not a good combo for a dentist treating patients. My endocrinologist had never had anyone with those side effects. I tried to stick it out because the blood sugar effects were so good...but anything that makes you feel that bad can't be good! I am trying to see if I can manage just on 2000mg of Glumetza which is working much better than the generic version for me. Funny thing is that I have found that I can tolerate white potatoes (which I have avoided for years) better than whole grain flours, brown rice and a bunch of other stuff I thought was GOOD for diabetics. The good news for me is that I can make my own low carb bagels(using Bob's Low carb bread mix and Carbylose), that keep my post prandials in the 120 range!

Jenny said...


I've noticed the same thing with potatoes, myself.

The headache is a known side effect of DPP-4 inhibitors and it is caused by the fact that the gene is also expressed in your sinuses, where inhibiting it has an effect not related to blood sugar. My guess is that many people get the headaches after starting those drugs but never connect them. Since doctors never seem to be aware of the known side effects of the drugs commonly described (documented over and over again in studies) they don't connect them with the drug but just prescribe another medication.

Glad the glumetza works for you!

drjbo said...

Thanks Jenny, I swear if it were not for your books and your website I would be a hot mess. :-) If I had been listening to the ADA my BG would still be very elevated. The latest issue of "Everyday Health" (which drug company owns that?) is still promoting whole grains as a "good" for for diabetes control. A carb by any other name...
I have taken your advice to TEST, TEST, TEST! I have found that a non-flourly "dessert" is often better then the whole-grains (especially the pasta) I was consuming. If you don't test, you don't really know what is elevating your BG levels. The prepared "low" carb pasta I just bought tasted great....but alas...2 hour post prandial 185! I am going to try making my own and will report back. Do you have a place to post recipes? My lo'carbels (low-carb bagels) are divine. :-)
Thanks a bunch for all of your efforts and research, Janet

Jenny said...

Yes, that is why I don't tell people what to eat, but tell them to test. There is quite a lot of variation from person to person in how much carb can be eaten, which makes it necessary to fond that individual level.

I provide a recipe page but it doesn't get much traffic. There are a lot of sites with huge low carb recipe collections out there. So I concentrate on the diabetes info which does get very good exposure.

Unknown said...

Took Onglyza off and on for a year. I now have an enlarged adrenal gland. Still awaiting the outcome of that CT, but I know that much. Will find out more in a few days.
I had the CT because of chronic pancreatic pain that started out as "attacks" from a couple of times a month to finally after 3 months of use without interruption, "attacks" 2-3 times a week. My PA put Onglyza on my allergies list.
In the meantime, I lost almost 50 lbs in 5 months due to illness. Loss of appetite, pancraetic pain, chronic diarrhea, then eventually, inability to move my bowels. Sever back pain from the pancreas, and severe chest pain sent me to the ER where I was worked up for cardiac pain. I was cardiac cleared, but told my amylase was very low.
Still seeking a diagnosis, but I lay the blame squarely on Onglyza. I'd had pancreatic issues in the past, and argued with the PA that prescribed it, she was calling me non-compliant, and I feared repurcussions from my insurance company.
I even took an article about the dangers of Onglyza, particularly in patients with a history, and she made me feel foolish.
I wish I had listened to my instincts, I fear not only damage to my pancreas that is irreversible, but also severe damage to my left kidney, though I have bilateral kidney pain.
I am currently off all diabetes meds, and control sugars strictly low to no carb. I can barely eat anymore, I have severe anorexia.
I would warn anyone taking Onglyza to consider a change, and anyone considering taking it, to select a different avenue. I have been suffering severely for about 6 months now, but the past 3 months have been unbearable.
I have been off Onglyza now, for 3 months, and simply zero improvement. I had none of these issues except a history of pancreatitis in my distant past.

21BeachRose said...

Its been 2 years since this report. My Dr just prescribed Januvia for me. I'm nervous now after reading this. Is there any more current information?

Jenny said...


The response to this disturbing study is discussed on this page: DPP-4 Inhibitors Januvia, Onglyza, Trajenta, Combiglyze, Janumet, and Jentadueto.

Big Pharma earns so much money from these drugs and has such a revolving door relationship with the FDA that it is very likely we will only find out the truth about these drugs when they go off patent and no longer are blockbuster cash machines.

That is what happened with statins. Within weeks of Lipitor going generic, we learned that taking it raised the risk of developing diabetes.

Januvia is under patent until at least 2010.