The answer is probably money, but more on that later.
I recently posted on the Lantus/cancer connection in my post A New Problem With Insulin: Cancer. The concern was triggered in a press release about a recent European report based on one earlier and three new studies which show a link between Lantus, a long acting insulin, and cancer. As I mentioned, I though it was interesting that more alarm has not been raised, particularly here in the US. Nissen's poorly done Avandia study got major press, and people stopped taking the drug (He was recently proven wrong- see here fore more info). Yet, for Lantus, the report is not about one study, but four studies that show similar findings that Lantus increases rates of cancer. In addition there are some biologically plausible reasons (more later) and a clear dose response. If you look at the criteria for causation, the Lantus/cancer connection seems to ring true. Yet, there seems to be not that much in the press and little public outcry to pull the medication from the market. This may be in part to the fact that the news cycle is now 24/7 Michael Jackson, but other medical stories, like the FDA and Tylenol, seem to be getting some attention, so this can't be the entire reason.
What do the experts say? The Europeans are making "an urgent call for more research". Yet, the US response is much more subdued. The official response from the American Diabetes Association (ADA) stated that findings from these research papers are conflicting and inconclusive, and cautioned against over-reaction until more information is available. A similar response can be found from The American Association Of Clinical Endocrinologists (AACE), the smaller but more academic group of diabetes specialists.
Where is the media attention on this? Where is the warning to patients? Why doesn't anyone seem to care?
MJ aside, here are some reasons:
1. The US experts don't want to say too much because of their ties to the drug companies. Both the ADA and AACE receive huge amounts of money from corporate sponsors, specifically the drug companies. In fact, back in 5/07 the experts issued a joint statement that had similar comments on the Avandia scare (which turned out to be correct). Sanofi-Aventis, the maker of Lantus, gives money to both of the ADA and AACE, and their members are unlikely to bite the hand that feeds them.
2. Though not all endocrinologists think alike, based on national and international diabetes recommendations, the expert guidelines recommend the use of insulin in type 2 diabetes much sooner than I would recommend. I have blogged in the past that I believe the endocrinologist making these recommendations may have a conflict of interest in that they have an incentive to make recommendations that will lead more patients toward insulin is because insulin use in type 2 diabetics is how they make their living. It is possible that the endocrinology experts are cautious about scaring the public about Lantus, because this may cause concern about all insulins, which they believe is the best treatment for diabetes.
3. The reason why Avandia drew more attention is because Dr. Nissen and some Congressmen were the ones making the noise, not the specialty societies. The Nissen meta-analysis on Avandia, from the data analyzed, to the publication, to the media frenzy had political motivations, whereas the Lantus studies do not. (See a timeline of the politics of the Avandia study in my post Diabetes Conspiracy )
What now?
Thanks to a comment on my previous post, I looked into the matter a little more. One of the problems with insulin is that is that it is related to insulin like growth factor (IGF-1) which has been shown to stimulate tumor growth. Regular human insulin has some affinity for the IGF-1 receptor, but Lantus has a much greater affinity, which is the likely reason more cancers were seen. There happens to be another long acting insulin on the market called Levemir that has very little affinity for the IGF-1 receptor (less than even human insulin) and is as effective as Lantus. In 2008, Lantus just missed the top 25 most commonly prescribed branded drugs at #26 with over 10.25 million prescriptions that year. Levemir came in at #170 with only 1.3 million prescriptions. Though I doubt this is public knowledge, I would guess that Novo Nordisk (the company that makes Levemir) is not giving nearly as much to these organizations as Sanofi Aventis (makers of Lantus), but I could be wrong. Since Levemir is a newer drug, is was not included in these studies and one can not rule out potential harm. That said, its low affinity for IGF-1 is reassuring. Thus, upon further reflection, I think that all diabetic patients who are on Lantus should talk to their doctor about insulin use, and if they need it, ask their doctor to consider switching them to Levemir.
Update: Via Med Page today, FDA just announced they were going to look into this. Not sure how much press this will garner. Certainly more valuable use of their time then trying to take down Tylenol.
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20 comments:
Dr Mintz,
It is disconcerning to me that there is a blog written by a doctor that cites studies and draws a conclusion that is flat out wrong. I have researched this topic thoroughly and have read the four studies you site. It is clear to me that you have not read them because you state that they show similar findings. This is not true. The German study, which had sever limitations being a observational insurance registry, retrospective study, showed no increase risk of cancer with Lantus, however when corrected for dose it did. The sweetish study, did not confirm the results of the German study as there was no overall incidence of cancer AND a dose dependant adjustment did not affect results. However there was an increased risk of breast cancer, but when you look at the numbers, it was 25 patients out of 114,000. The authors themselves said this finding was probably confounded due to selection bias. The Scottish study did not confirm either the German nor the Sweetish study, and showed that Lantus was not asso. With any increased risk of cancer, even breast cancer. The UK study showed no increased risk of cancer, tumor progression, or breast cancer in Lantus patients vs all otter insulin’s . It is obvious that there is no reliability to these studies, as they are not repeatable and are at the very best inconsistent. This is why the ADA released a statement saying just that and advised patients not to overreact and switch insulin’s. This is not to mention the safety studies done by Sanofi-Aventis regarding Lantus and Cancer, which were controlled, randomized long term studies which showed no increase risk of cancer. To get approval they had to do carcinogenicity studies in animals as well, something Levemir has not don (just look in their PI). On top of that you have 9 years of post marketing data that shows no increased risk.
As far as binding affinity, although one study (done by Novo- the Levemir people) reported increased binding affinity of insulin glargine for the IGF-1R and increased mitogenic potential in cells, most in vitro binding-affinity and cell-culture studies have demonstrated behavior of insulin glargine comparable to that of RHI for both IR and IGF-1R binding, insulin signaling, and metabolic and mitogenic potential. The study that Novo published also used insulin concentrations so high to bind and activate Igf1, that you would never see those doses in humans. Their theory is totally theoretical. What I do know is that when my son was switched to Levemir from Lantus he want from one shot to two shots a day, a higher dose of insulin, and had much more incidence of hypoglaucemia. Not a pleasant thing. We decided to get an insurance over-ride and switch back to Lantus. We all have to understand as well, that diabetics in general have a greater chance of developing cancer due to the damage of the disease. We have to be very careful to have well done, well-controlled studies to look into this topic because insulin is so important to minimizing the damage of high blood sugars in the first place. I feel much more confident in a drug like Lantus that does what it is supposed to do, has been on the market for 9 years, and has been used by millions of people, than to switch to Levemir that does not have that experience and is much newer to the market. Plus I have seen the results myself!
There was concern about Lantus before it was even approved because of its overwhelmingly, different than any other insulin, affinity for IGF-1 and yet it was approved. My friends mom was cancer free for over 18 years from breast cancer. Yet, when Lantus was added to her orals, her breast cancer returned. IGF-1 stimulation in former cancer patients is risky especially when the doctor can prescribe a less risky alternative. My friends mom is switching over to Levemir.
It was known prior to the approval of Lantus that IGF-1 stimulation could promote abnormal cell growth and that this insulin had a 600 times affinity for IGF-1. Google cancer, IGF-1, Lantus and you will get lots of information. Rob and Michelle, I have a friend whose mom was cancer free for over 18 years. Unfortunately, she also is a type 2 diabetic whose orals failed so she was put on Lantus about a year ago. Now, her breast cancer is back. In a person who has already had cancer, putting a person on a drug that has 600 times the affinity for IGF-1 than any other insulin is irresponsible. This type of patient already has a tendency to develop abnormal cell growth and there is no reason to select an agent like Lantus with its unbelieveably high affinity for IGF1 when there are other insulin choices. She called her doctor and had him change her to Levemir. But she already got the cancer back after being free for over 18 years and I am sorry, but we believe Lantus could have spurred its return.
Rob and Michelle,
I have read the studies. Though we will both agree that the studies don't prove that Lantus clearly causes cancer, my interpretation of the data and how that will impact my patients is somewhat different then yours. It is important to note that all of the problems were seen in patients on Lantus alone, and not Lantus plus short acting insulins. These patients were most likely type 2 patients. I am guessing your son is a type 1, so the data would not really apply.
I am posting a more detailed analysis on my blog.
Dr. Mintz,
I agree with Rob and Michelle Jacobson. When I first read your blog it seems so one sided and bias. Below is some information that will provide some balance.
To Marine Wife,
I'm sorry to hear that your friends breast cancer has returned but there are a couple of things to consider. As a breast cancer survivor your friend unfortunately will always be at risk for breast cancer and as a diabetic she is also at high risk breast, colon, pancreas cancer (thats minus any insulin).
I have been a nurse for over 10 years and have worked extensively with managing diabetes.
Someone mentioned IGF-1 receptor affinity, while it is true that Lantus has a high affinity to this receptor, the big question is what does that mean to patient's?
First of all there are three receptor chains IR (insulin receptor), IGF-1 (insulin like growth factor receptor 1), and IGF-2. These structural chains of IR and IGF-1 are very similar an almost identical. Any insulin will bind primarily to the insulin receptors and growth factors will bind to the growth factor receptors. There is very little binding of insulin to growth factor receptors and vice versa. Therefore if you understand this concept you will see that the high affinity of lantus means NOTHING in terms of activating and binding to the growth factor receptors. And it makes perfect sense to have a higher affinity to the growth factor receptors because it closely resembles the insulin receptors. It's not rocket science people!!!! In 1999 the FDA requested sanofi-aventis to conduct clinical trials to answer the questions concerning high affinity to the growth factor receptors of lantus and its possible link to cancer development. A study was conducted and completed and is available for your review by Dr. Rosenstock 2009, which confirm that when compared to NPH (human insulin), Lantus has no new safety concerns.
The only way in human beings to explore a possible link between growth factor receptor high affinity and any possible link to cancer is to study patients with diabetic retinopathy. There is a link between growth factor receptor high affinity and an increase in diabetic retinopathy. So if you take patients who do not have cancer and they are diabetics you randomize them on Lantus or NPH and you monitor them for four years looking for any type of tumor growth malignant or benign, then you will have a real scientific trial comparing apples to apples (patients were from USA and Canada, both groups were similar in age duration of diabetes and all other things being equal). That was the design of the Rosenstock trial which results showed no new safety concerns with lantus. Lantus is the only insulin thus far with this type of long-term safety data specifically looking at cancer.
Also some have suggested switching Lantus to Levemir. In head-to-head trials Levemir has been shown to be comparable to Lantus, especially at higher dosages and twice-daily administration. Levemir has been out for the past 4 years. Lantus has been out for the past 9 years. Lantus has 24 million patient-years. Based on all the information that I've shared with you it is clear why the FDA the ADA have agreed that Lantus is still safe and patient should not switch from Lantus to another insulin based on the evidence based trials available.
Dr Mintz,
Before you jump to conclusions and do exactly what Dr Nissen did with Avandia, you should read the recently published article titled:
Insulin Glargine and Cancer—An Unsubstantiated Allegation
Satish K. Garg, M.D.,1 Irl B. Hirsch, M.D.,2 and Jay S. Skyler, M.D., M.A.C.P.3
The 3 Arthurs of this editorial are well respected leaders in the diabetes field.
Here is the link:
http://www.liebertpub.com/mcontent/files/dia_2009_1705_Garg_3P.pdf
It is amazing to me that any of us can draw conclusions that there is not a heightened risk. I agree that the information is inconclusive but even the ADA states more research is warranted. This means they are not sure either. I do agree that patients should not panic. The risks of not taking insulin far out way any other risks of taking insulin. There is a viable alternative at this time if in fact a high IGF-1 binding affinity is linked to potential risks. To state that a high affinity to IGF-1 means NOTHING merely demonstrates pure ignorance. Even the most widely accepted experts in this area will state there could be something to this but the current data does not provide enough information to come close to drawing a conclusion. The bottom line is there is data out there questioning the link. We owe it to the patients to know the answer. How long this will take is unknown. If you are a diabetic take your insulin for sure. If you have concerns consider the alternative.
Dr. Mintz,
I have been a insulin dependent diabetic for 30 years. I would like to commend you first of all for coming forward with your interpretation of the findings on the lantus insulin.
I was on lantus for 30 days and ached all over and so did my husband (he is also insulin dependent)knowing my body, because I just am very sensitive to all medications, switched back to my other Humulin N and immedicately felt better and the body aches stopped.
I must say that I'm sorry that the people involved in PUSHING THIS
DRUG are so carelessly secure with other lives.
I would like to think that all Dr's and Health care professionals would care for me and others as they would care for their own families, that is if they loved them... Isn't that the oath taken when becoming a dr.?
KEEP UP THE GOOD WORK ,THERE ARE JUST A HANDFUL OF YOU OUT THERE THAT ARE WILLING TO GET THE TRUTH OUT TO THE PUBLIC.
Thank You!
I am a type 1 diabetic. I had been taking Lantus for over five years when I was diagnosed with colon cancer last year at age 36 with no family history of the disease. I read about the Lantus Cancer risk during my 10th round of chemo. My endo immediately took me off of Lantus as a precautionary measure. He did say that he probably would not do the same for his other patients but because I had cancer he wanted to play it safe. I'm looking for additional information on this possible link to cancer(or not). Please post any info or links you may have. Thanks.
BoulderB,
The link between Lantus and cancer is not definitive, but since there is pretty strong evidence and an alternative medicine available, I have tried to shed some light on the issue, since most of the major US "experts" seem to be blowing this off.
That said, the data seemed only to apply to type 2 diabetics, particularly people who took Lantus without other types of insulin. So, it's not certain this applies to you. In addition, since you are so young in getting colon cancer (the connection between Lantus and cancer seem to occur in folks over 50), which is usually seen in older individuals, the connection between your cancer and Lantus is also less likely. I do agree with your physician stopping the Lantus and switching to Levemir.
Dr. Mintz I appreciate your efforts in bringing more attention to this issue. It does seem that this has been largely ignored by the medical community or at least downplayed which is concerning. Do you know the percentage of type 1s vs type 2s that were involved in the studies? It would seem that type 1s would be more affected by this possible cancer link since they generally require larger doses of Lantus. I personally was taking close to 30 units per day. Being a young adult with colon cancer is very uncommon add to that no family history or genetic markers it raises even more questions about the cause. I realize that I will more than likely never have an answer as to what caused my cancer but I would like to know that is was not caused by Lantus. Thanks again for your efforts and any further info you can provide. On a side note I will be taking part in a young adult panel discussion on colon cancer on 3/22 on the Stupid Cancer Show. Please tune in if you can http://i2y.com/stupidcancershow/guests2010a.shtml
BoulderB
If you look at the press release in the original post you can see the actual studies. One of the problems with these types of studies is that you can't prove a definitive link. What they did is found folks with cancer who were taking insulin, and looked to see if they type of insulin mattered. Based on the methodology, it is impossible to determine who had type 1 and who had type 2. However, given the age and cancer, the vast majority of these patients were likely type 2. In addition, problems were usually only seen in patients taking Lantus as there only insulin, which would imply type 2 as well.
I have been diabetic for 29 years. In 2001 I was taken off of Ultra Lente and put on Lantus. This insulin worked great for me. However in 2008 I went to see my eye doctor and was told I had none to very little diabetic retinopathy and to come back in two years for another eye exam. Well in October of 2009 I was called in by my eye doctors office out of the blue to get a diabetic rental scan done. So from 2008 to 2009 I went from having no to little diabetic rentialopathy to have prolific diabetic rentinopathy, in just one year! As of now I have no other serious problem, but I am keeping a close eye on everything. My A1C's have always be in the 6.7 to 7.5 range, so I don't think I should be experiencing any type of diabetic retinopathy, and have been wondering if Lantus could cause it. I've gone thru many laser treatments on my eye to save my vision. By the way, I check my blood sugars at least 12 times a day, always have, sometimes more. I'd like to go back to using Ultra Lente, which I found much more safer. So does Lantus cause cancer? Who knows for sure. Why don't cancer doctors and eye doctors start questioning their patients to find out if they have taken Lantus insulin and see if it can be tied into cancer or diabetic rentinopathy. There should be national database for doctors to start inputting this data to track it. Then we'll find if it does or does not have a link to cancer or diabetic retinopathy.
Don't know whether or not Lantus causes cancer. Some troubling but inconclusive data exists, which is why I think Levemir is a safer alternative.
In regards to Lantus causing diabetic retinopathy, it should not do this. In fact, it should prevent this. It is possible that your retinopathy progressed because your diabetes was worse after you changed regemins. Even with at goal A1c's, there is still a chance of retinopathy.
Dr. Mintz,
I am wondering why you are so cavalier in recommending a newer insulin so brazenly especially when it lacks the aforementioned 24 million patient-years of experience? Insulin detemir has not been on the market long enough yet to know with what kind of cancer it might be associated...
I am also curious as to your thoughts on the reports that have actually shown that Lantus is associated with LESS risk of cancer than conventional human insulins.
In your comment back to Rob and Michelle, you correctly cite a potential difference between those with type 1 and type 2 diabetes, however, therein you create another paradox that clearly confounds your interpretation of the literature...If a patient with type 1 diabetes has been using Lantus for extended time (for example the people who were in the original HOE-901 trials), why would they not have higher rates of cnacer due to the prolonged exposure to such a "toxic" agent as you would have us believe Lantus is. You need to prove that chronic repeated exposure to Lantus would not increase the risk the same way that short-term high dose exposure would.
Further confusing your point: If you claim the cancer and retinopathy associations are real and due to increased IGF-1 receptor binding then you also need to explain how you conclude that the human body is anything like the test tubes and beakers and petri dishes that the in vitro studies were perform on. Please review the data again since you are missing the sections that have shown it is not the insulin level, but the metabolites (focus on M2), that are not seen in the in vivo environment because of alternative metabolism of the Lantus, that cause the increased binding and activation of the IGF-1 receptors.
Anonymous 12/1,
Lantus was approved in 2000, Levemir in 2005. There is not question Lantus has a bit more patient experience, but Levemir has been on the market for almost 7 years which even folks like Sidney Wolfe say is safe to use after that time period.
I will be the first to admit that the science behind the Lantus/cancer connection is weak. In fact, I am very hopefuly that I am wrong. I would like nothing more for there to be proof that Lantus does not cause cancer. However, since there is a concerning signal, a biologically plausible reason, and an alternative that should not have that same problem with nearly 7 years of expereince on the market; then I feel strongly that Levemir should probably be used instead. I don't really think this is cavalier.
Dr. Mintz,
Thank you for your recent points of clarification, but I encourage you to be careful in assuming that since Levemir has been on the market for 7 years it is probably safe...the 4 reports that raised the concerns with Lantus and the risk of cancer were published 9 years after Lantus had been on the market...just saying...
Oh my god, there's so much helpful info here!
I would just like to add, for anecdotal information, that my Dad died a horrible death from pancreatic cancer just 3 years after starting Lantus.
sue
I dont use Lantus because i feel bad menatly when i use it, but i think that the concern about igf-1, lantus and the connection to cancer is over exaggerative. People with typ-1 diabetes has much less igf-1 than other people due to the fact that the insulin gets transported to various tissues in the body without passoing from the pancreas through the Vena Porta and then further to the liver where insulin has an affinity for the igf-1 receptors, and from there gets transported to other tissues in the body. The fact that this is not the case in people without own insulin production means that the insulin thye inject raises igf-1 only modest compared to other people.
I therfore think that drugs that raises igf-1 is good for people with diabetes. The lower igf-1 levels found in general in people with type-1 diabetes explains why they have to use so much insulin compared to when the inject igf-1 peptide.
If you are worrying about igf-1 and cancer i recommend you to change your focus to dairy product which contains high levels of igf-1 and other hormoner such as estrogen sulfate. Dairy products has been proven to cause cancer.
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