Januvia could trigger pancreatitis, pancreatic cancer

Just received this information from UCLA.

A new study from UCLA’s Larry L. Hillblom Islet Research Center finds that the Type 2 diabetes drug sitagliptin, sold in pill form as Januvia, could lead to a form of low-grade pancreatitis in some patients and a greater risk of pancreatic cancer in long-term users. The study was just published in the online edition of the journal Diabetes.

Popular diabetes treatment could trigger pancreatitis, pancreatic cancer
Drug's adverse effects negated when combined with older diabetes drug

A drug widely used to treat Type 2 diabetes may have unintended effects on the pancreas that could lead to a form of low-grade pancreatitis in some patients and a greater risk of pancreatic cancer in long-term users, UCLA researchers have found.

In a study published in the online edition of the journal Diabetes, researchers from the Larry L. Hillblom Islet Research Center at UCLA found that sitagliptin, sold in pill form as Januvia, caused abnormalities in the pancreas that are recognized as risk factors for pancreatitis and, with time, pancreatic cancer in humans. Januvia is marketed by Merck & Co. Inc. Sitagliptin is a member of a new class of drugs that enhance the actions of the gut hormone known as glucagon-like peptide 1 (GLP-1), which has been shown to be effective in lowering blood sugar in people with Type 2 diabetes. The study is available at http://diabetes.diabetesjournals.org/cgi/content/abstract/db09-0058v1.

“Type 2 diabetes is a lifelong disease — people often take the same drugs for many years, so any adverse effect that could over time increase the risk for pancreatic cancer would be a concern,” said Dr. Peter Butler, director of the Hillblom Center and the study’s lead investigator. “A concern here is that the unwanted effects of this drug on the pancreas would likely not be detected in humans unless the pancreas was removed and examined.”

An observed connection between Byetta, a drug used to treat Type 2 diabetes that is related to Januvia in its intended actions, and pancreatitis has already been reported, prompting a Food and Drug Administration warning. Amylin Corp., which markets Byetta, has suggested that since there is no known mechanism linking the cases of pancreatitis with Byetta, the association might be chance. The UCLA study suggests that there may indeed be a link between drugs that enhance the actions of GLP-1 and pancreatitis — by increasing the rate of formation of cells that line the pancreatic ducts.

In the study, researchers used human IAPP transgenic (HIP) rats to test both sitagliptin and metformin; metformin, a member of an older, different class of diabetes drugs in use since the 1950s, has recently been found to have anti-tumor properties. The researchers sought to determine how the drugs, both singly and in combination, affected islet disease progression in the pancreas — particularly how they affected beta cells in the pancreas’s Islets of Langerhans. Beta cells are responsible for releasing insulin in people with normal metabolism, but they don’t produce insulin in sufficient amounts in diabetes patients. HIP rats approximate both the islets and metabolism of people with Type 2 diabetes. The drugs were tested in 40 rats for 12 weeks.

The researchers found that the two drugs in combination had a synergistic effect that helped preserve beta cells, improved their function and enhanced insulin sensitivity in the test rats. With the sitagliptin alone, however, the rats had abnormally high rates of cell production in their pancreatic ducts; a few developed an abnormality known as ductal metaplasia, and one developed pancreatitis.

But the metformin, trade name Glucophage, seems to counteract sitagliptin’s adverse effect.

“The apparent protection against the unwanted actions of sitagliptin in the exocrine pancreas are intriguing and may offer a potential way of using the GLP-1 class of drugs safely,” Butler said. “The protective effect may have been either by the actions of metformin to decrease blood glucose values or its recently appreciated properties as a tumor suppressive agent.”

Butler noted that the present study was undertaken in rats and that it is possible the adverse effects observed would not occur in humans.

“Given these findings, it is probably sensible to use the GLP-1 class of drugs only with metformin until other data is forthcoming,” he said.

The National Institutes of Health, the Larry Hillblom Foundation and the Merck Research Foundation funded this study.

In addition to Butler, researchers included Aleksey V. Matveyenko, Heather I. Cox, Artemis Moshtaghian, Tatyana Gurlo, Ryan Galasso and Alexandra E. Butler, all of the Hillblom Center, and Sarah Dry of the department of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA.

The Larry L. Hillblom Islet Research Center at UCLA, established in 2004, is the first center dedicated to the study of the Islets of Langerhans, which include the insulin-producing cells in the pancreas. An understanding of the causes of islet cell destruction is key to finding a cure for diabetes. The center’s faculty members, recruited from around the world, provide leadership in the worldwide fight against the disease. The center is funded by a grant from the Larry Hillblom Foundation, which supports medical research in the state of California.

Inhibiting DPP-4 , which is what Januvia does, will promote several other cancers, most notably melanoma, ovarian cancer, testicular cancer and lung cancer.

Note that this study was funded by Merck, maker of Januvia, which is why they are still spinning the finding and suggesting metformin is protective. Long term, it isn’t going to be.

Januvia turns off a cancer supressor gene, (DPP-4). It does this because DPP-4 also cleaves GLP-1, so turning off DPP-4 lets GLP-1 levels rise.

But DPP-4 also helps the immune system fight cells that have become cancerous. Januvia suppresses DPP-4 round the clock. So if you get a single cancerous cell your body can’t kill it and it is free to reproduce.

It will be another five years until the data starts coming in showing the huge increase in cancers among people taking Januvia. By then Merck will have made it’s billions off the drug and they’ll move on.

Please, people. Don’t take Januvia. Byetta is MUCH, MUCH safer and for most people more effective.

Research study data supporting the Januvia/Cancer connection can be found here: http://www.phlaunt.com/diabetes/18538604.php

I don’t think that a study is inherently flawed simply because a drug manufacturer funds it. Drug manufacturers have funded far more valid studies than invalid ones.

I have yet to see any research that shows Januvia creates a situation in your body where “if you get a single cancerous cell your body can’t kill it and it is free to reproduce.” The Januvia research undertaken for drug approval did not show any statistically significant rise in cancers despite the effects on the DPP-4. This is a situation where the test tube results did not accurately predict the in vivo response, which is very common actually when it comes to drugs.

Finally, this particular study was only done in rats and the results have not yet been duplicated elsewhere, so it is a bit too soon to be sounding some huge alarm that taking Januvia is going to give you cancer.

The bottom line is that, like any medication, the risks should be weighed against the benefits. If Januvia allows you to maintain blood glucose control over the long-term and you understand the risks and know how to mitigate them with metformin then maybe it is the right drug for you. If worse glycemic control presents a lower overall health risk to you as an individual then don’t take Januvia.

There are many options out there without taking Januvia. For me, the side effects were awful and it also worsened my BG. I’d take insulin and or symlin any day before I would ever touch the stuff again.

As a Type 1 I can tell you I’m much more comfortable using insulin than I would be using any of the oral medications out there for Type 2. Symlin is more or less identical to human amylin so I have no issues with that one either.

I’m curious why many Type 2s don’t just skip right to the insulin. Maybe you or another Type 2 can shed some light on that one?

From discussions here, many Type 2s appear to balk at the idea of insulin because it somehow represents the end of the road. Oh no, I’ve “failed” at meds, diet, exercise & have degenerated to needing insulin. Oh dear, I must be a Type 1 now. I’ve had several intense discussions urging Type 2s to use insulin to help control, preserve beta cells & to spare them the very side effects from oral meds they’re concerned about. Brick walls instantly go up with some people at the mere mention of insulin. Also, it seems that endos are reluctant to prescribe insulin for Type 2s, so they’re not getting recommendations from their doctors.

That reminds me of when I was diagnosed with Type 1 and my very first question was “Am I going to have to take shots?”, not realizing that injections would be the very least of my worries. I know the analogy isn’t perfect but I suppose I understand the feeling of shots being the “worst thing ever” to some degree.

Funny how they think being a Type 1 is worse than being a Type 2. I would rather be a Type 1 knowing what I know about them both. But maybe that is just one of those “the devil you know” things.

I’m one of two tudiabetes members, that I’m aware of, currently on Januvia (if I recall correctly, the other member is on a combination of Januvia and one or more other diabetic drugs). I’d like to share my Januvia experience and what I think about the above study available at http://diabetes.diabetesjournals.org/cgi/content/abstract/db09-0058v1 . First, thanks Manny for forwarding the info from UCLA to TuDiabetes members. I intend to give it to my doctor, along with other info, prior to my next appointment in mid-May, regarding review of my current diabetes treatment: Januvia.

Notably, the new study from UCLA’s Larry L. Hillblom Islet Research Center “was just published in the online edition of the journal Diabetes” (that is, it isn’t a peer reviewed study; it’s merely the equivalent of a letter to a newspaper editor, please correct me if I’m wrong) and concludes: “The combination of metformin and sitagliptin had synergistic actions to preserve beta cell mass, beta cell function and enhance insulin sensitivity in the HIP rat model of T2DM. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.” (My emphasis added.)

Nevertheless, the study scares me. Frightening folks like me–I’ve read someplace before–is one of the things that kind of study is supposed to do, in addition to secure funding for more research, which is a good thing, or hurt a business, such as Merck.

Further, the above journal article says in part that Januvia “…may have unintended effects on the pancreas that could lead to a form of low-grade pancreatitis in some patients and a greater risk of pancreatic cancer in long-term users…” (My emphasis added.)

As everyone knows, the list of things that cause cancer is long, including toxic products, air pollution, and radiation to name a few. See http://www.care2.com/greenliving/what-causes-cancer.html# (What causes cancer?).
Also, sulfonylurieas (sp.?) (SFUs) and exogenous insulin have been documented to cause an increase in cancer too. Insulins been documented to increase breast cancer with a similar increase in colorectal cancer. See http://www.sciencedaily.com/releases/2009/01/090109173207.htm (High Insulin Levels Raise Risk Of Breast Cancer In Postmenopausal Women) and http://coloncancer.about.com/od/cancerresearch/a/10182004.htm (Insulin Increases Colorectal Cancer Risk), respectively.

What’s my point? Unlike Jenny and Cheri, I haven’t yet experienced any side effects on Januvia since starting it almost two months ago. I’m an “Other” type diabetic who didn’t mind injecting Levemir once a day until my fasting bs started increasing. Frankly, I find it’s easier to take a pill once a day than to use a flexpen.

The bottom line for me is: The complications of untreated diabetes are common knowledge; I need to take some diabetic treatment drug, but my options are limited by my history of pancreatitis 3X and subsequent pancreatic surgery. If I recall correctly, Jenny acknowledged that before in a reply to me. In addition to referring me to info about Januvia, I appreciate her suggestions of other diabetic drugs. On the other hand, I basically agree with Janson’s initial reply.

I don’t feel comfortable continuing Januvia beyond my next appointment if I have another option that works. It will be interesting to learn what my doctor recommends after considering my concerns, including the new study.

Really, injections are the least of our worries.

The reactions I’ve gotten when suggesting insulin to Type 2s have included: once I start on insulin that means I’m “stuck” doing this forever, I’m not ready yet, I’m not hopeless, I pray I don’t have to do that, I’m not that bad, etc. Negative, defensive. Also, misconceptions about insulin. Pointing out that insulin’s a lot more reliable than meds, will help in many ways, doesn’t shake people from their fear of insulin. I really think it’s a fear & not of needles. Guess there’s the dependence factor also.

My sentiments as well. Type 2 seems more difficult to me. I know what I’m working with being Type 1. Other than variations on a theme, I know what I have to take without dealing with the latest med, combos of meds, side effects & long term effects. That crap scares me.

Whichever is worse, both suck.

In answer to Jason’s reply: “I’m curious why many Type 2s don’t just skip right to the insulin. Maybe you or another Type 2 can shed some light on that one?”

I got the impression from my doc–when she recommended switching me from Levimer to Januvia–that oral treatment is an easier option than insulin/shot treatment, especially if one would need to inject multiple times a day.

I say this with out reading any further responses.

I am Type 2 and have been begging to be put on insulin. The doctors and health insurance is standing in my way. I have a mid grade insurance and little choice in doctors on the provider list and no extra money to go out of network. They had to run the course of all oral medications before my PCP could start insulin or send me to an endo.

I am now their but that is not with out incident. Dehydration and muscle deterioration (sp?) from metformin, Weight gain and bloating from Actos, severe hypos from glipizide. I am now having severe headaches, could this be from the Januvia/Actos/Levemir combo? I don’t know.

Lots of times Type 2’s don’t have a choice…I agree some do not want to move to insulin but I think there are many more that just don’t have a choice.

Yep, that’s the impression I’ve gotten from people–their doctors aren’t particularly supportive or encouraging about the insulin route. Swallowing a pill is easier, though not necessarily as effective, & doctors have real concerns about hypos with insulin. But when meds aren’t doing it, too many endos allow patients to have soaring BG without suggesting insulin.

I was corresponding with a Type 2 member about his out of control BG–high 200’s & 300’s. He was already at the highest dose of Metformin. Doc kept telling him to exercise & lose weight. Good advice, but not enough. He had to demand insulin. Seen this scenario too many times & it’s mind blowing.

Yikes Samantha, Januvia has not been tested with insulin–that meaning, specifically,Levemir, which you say you are taking in combination with other drugs.

Recently, I came across this study: Clinical trial: Januvia plus insulin
(National Institutes of Health) UPDATED 2007-06-06

This is a study to determine the safety and effectiveness of Januvia in patients with Type 2 diabetes who do not have effective blood-sugar control on insulin or insulin, metformin combination treatment. This international study is currently recruiting patients.

Samantha, Are you part of a study?

I just wrote about this very thing. Infuriates me! I’m so sorry. It’s absurd what you & others have to go through for proper treatment. Not even any out of the ordinary treatment. Curious because I’m Type 1, what do Januvia, Actos & Metformin cost per month?

Insurance companies–well, we sadly know about their dictates, but the fact that your doctor thwarted your efforts & wouldn’t refer you to an endo is horrible.

Gerri, Regarding the cost of Januvia: My doctor gave me my first month’s worth free (manufacturer drug rep sample) and I used a voucher printed from Merck’s website to get my second 30 day supply free; I haven’t paid yet. Under my insurance, a 30 day supply costs $25 copayment.

Thanks. I was wondering about the cost of oral meds relative to insulin.

In Canada for some obscure reason insulin was considered the last resort once your pancreas was dead. Metformin and the horrid sulphonyl ureas , the useless and possibly harmful avandia were pushed first. If you were an adult you were assumed to be type 2 no tests were necessary. If you were lucky and had extreme DKA at diagnosis they would possibly reconsider.

Nothing wrong with insulin the more so now with the modern ones fast acting and lantus and levemir are a great improvement or the bad NPH.

When my pancreas was still working and would have done smashingly on a few units of insulin per day I asked an Endo for some and he said" you do not want to touch that ■■■■ with a ten foot pole". Well now my pancreas is dead and I use over 100 units per day and with this very high amount getting fatter and fatter. And 10 lb away from death.

Metformin would be about $40.00 canadian at 2000 mg per day for a month. I use as much as possible in conjunction with insulin. Usually become so tired after 3 weeks that I can’t getout of bed. suspect it poison’s my liver but will ask GP for liver test after 3 weeks on the stuff to see if i am hypochondriac about this or if there is something detectable

A fast insulin novorapid is $65 canadian for 5 cartridges of 300 units each. Lantus $65 1000 unit vial and levemir maybe $100 for 5 cartridges of 300 unit each

Canadian dollars about 83 cents in real money, varies wildly of the course of the last 2 years. .

The above is my opinion.

To be fair it is important to note that some people like Dr. Unger consider than insulin is the last thing you should use to fight insulin resistance. He believes that adding insulin just makes the insulin resistance worst. Reading wiki " insulin oscillation" the saturation of the insulin receptors could possibly be made worst by a non-oscillating external supply of insulin.

Then again if you do not get rid of the insulin resistance successfully and help out the pancreas with external insulin it may well die.

Their is no doubt in my mind that with insulin resistance adding external insulin makes weight loss a nightmare.

The situation appears to be die if you don’t and die if you do. It would really be helpful if more was known about the disease.

Hi Anthony Holko, Your two above replies may explain why my doc seemed to want me off Levemir 4 units once a day at bedtime. I still don’t understand why she didn’t increase my Levemir to 8 units as before my surgery but with 4 units morning and 4 units evening–unless perhaps I would be at risk for severe lows. I’m not insulin resistant.
Best regards, Lucy