Does the insulin Lantus (glargine) cause cancer?

7 07 2009

Last week my eyes were caught by a post of Kevin MD at his blog entitled

Does insulin cause cancer, and should you stop taking Lantus?”.

Kevin linked to the blog of Dr. Mintz, a board-certified internist, who had a strong opinion on this. Dr. Mintz  posted 3 blog articles on the matter, entitled: A new problem with insulin: cancer (June 29), Lantus causes cancer! Why doesn’t anyone seem to care? (July 1) and Lantus and cancer – A closer look is not reassuring (July 2). Dr. Mintz’s conclusion was based on 4 recent publications in diabetologica (1-4)6-7-2009 10-14-07 dr Mintz + foto

Alarming. Especially since Dr. Mintz is an expert, often prescribing insulins. Also, I’m suspicious  about any substance with an IGF (insulin growh factor)-like action, because I know from previous work in the lab that some tumor cells (i.e. prostate and breast cancer) thrive on IGF. On the other hand there have been several examples in the past, where retrospective studies initially “showed” drugs to cause cancer, which have later been invalidated by more thorough studies (i.e. statins).

“Lantus causing cancer” is a serious allegation, that might cause panic in those many diabetic patients using Lantus. Are fears justified and should Lantus be “banned”?

After reading the publications (1-5), news articles and some blogposts (i.e. a balanced blogpost at Diabetesmine, a blog of a patient) and a very thorough blogpost in Dutch), I rather conclude that the recent publications in Diabetologica, dr Mintz* refers to, do not support a causal role for Lantus in cancer. However, they still give reason for some serious concern in a subset of patients (explained below).

Now what is Lantus and what have preclinical and clinical trials revealed?

Insulin glargine (Lantus) is the first of the long-acting insulin analogues, introduced in 2001. This analogue is a so called designer molecule made by the recombinant DNA technique. It has three amino-acid substitutions, that cause a lower solubility of the insulin molecule  at the injection site, forming a depot from which insulin is slowly released (9, 10).  The advantage is that stable 24hr blood glucose concentrations are reached by a once daily subcutaneous injection without a blood glucose peak upon injection as seen with the short acting insulins. However, insulin replacement remains far from ‘natural’, “the insulin is injected in the wrong site (subcutaneously instead of intraportally), in shots (instead of a continuous low secretion associated with a prompt release in response to a meal, with a total lack of the physiological pulsatile secretion”).lantus pen + kineticsInsulins not only bind to the insulin receptor, leading to the intended glucose lowering, but also to the insulin growth factor receptor (IGF-R), which mainly induces cell proliferation. Importantly, glargine has a much higher affinity for both receptors than insulin. This can lead to a sustained activation of the IGF-receptor, resulting in enhanced cell growth.

Indeed, Preclinical Research has shown that only glargine showed a significantly higher proliferative effect on breast cancer cells compared to regular insulin among a panel of short- or long-acting insulin analogues (6) . Futhermore,  insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells (thus they stimulate cell division and prevent programmed cell death of cancer cells (8).

Experimental animal studies haven’t shown a tumorigenic or teratogenic potential of glargine, except for histiocytomas in male rat (Product information Lantus). Such studies don not examine tumor promoting properties (see below)

Clinical Studies (published in Diabetologica 2009)

Based on the insulin analogue characteristics and the in vitro results there was already concern about possible increased cancer risk of glargine. But the concern was boosted by a prominent diabetes researcher forecasting an “earthquake” event compromising the safety profile of Lantus,  and the subsequent publication of five studies in  the European journal Diabetologia, the Journal of the EASD (European Association for the of Study of Diabetes).

Except for one small study, which was a post-hoc analysis of a randomized study by Sanofi-Aventis itself [5], all other studies were retrospective. The Sanofi study didn’t find an increase in cancer, but given its small size (1000 patients), it is not  convincing enough to exclude a higher risk of cancer.

The first, German, study [1] was submitted a year ago, but because of the uncertainties and the expected high impact, researchers from other European countries were asked to replicate the findings before announcing them formally. Studies were carried out using databases from Sweden, Scotland, and the UK.

The German study (n= 127,031 patients, exclusively on human insulin or on one type of insulin analogues (lispro, aspart or glargine; glargine: n=23,855 ; mean follow-up time 1.63 years) found an overall increase in cancers, independent of the insulin used. After statistical modeling, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p<0.0001): with an adjusted HR of 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU, meaning that out of every 100 people who used Lantus insulin one additional person was diagnosed with cancer over the study period. The baseline characteristics were different between the groups. It was not possible to break the analysis down to type of cancer.

The Swedish and Scottish studies [2-3], both based on matching of national databases for cancer and diabetes, showed no overall increase in cancer, but an increased incidence rate of breast cancer in women using insulin glargine monotherapy (no other types of insulin or combination) as compared with women using types of insulin other than insulin glargine. Although this can be caused by chance, it is striking that both studies had a similar outcome. The enhanced risk was abolished in patients using glargine together with other insulins. These were mostly younger patients with diabetes type 1.

The fourth smaller study [4] found that patients on insulin were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. No harmful effect on cancer development, including breast cancer were observed: there was only a higher risk versus metformin, which has known anti-cancer properties.

In Conclusion:

  • Diabetes patients using insulin should never stop using insulin, as this is very dangerous.
  • Long term studies have shown ‘natural’ insulins to be effective and safe.
  • The reported studies do NOT show that Lantus can CAUSE cancer. Moreover, the time span (less than two years) is too short for any drug to cause cancer.
  • The enhanced risk was only observed for breast cancer (2-3) and/or if Lantus was used on its own, thus not with other insulins (1-3) or metformin (4). The association was clearest in type 2 diabetes patients. It is not clear whether the association reflects the effects of Lantus or the inherent differences between for instance diabetes I/younger  and diabetes II/older patients (also because the latter often use Lantus alone ). In addition, it should be noticed that diabetes patients already have a higher cancer risk (possibly related to overweight, often seen in type 2 diabetes)
  • At the most Lantus might promote existing cancer to grow and divide. Lantus might for instance provide a survival advantage of percancerous or cancerous cells. This would be consistent with its in vitro mitogenic effect on breast cancer cells.
  • On the basis of the current evidence there is no need to switch to other treatments when a long acting insulin is necessary to keep blood glucose under control. However, Lantus treatment could be reconsidered in diabetes II patients, with good control of blood glucose, for whom a clear benefit of Lantus has not been shown or  in patients with a higher cancer risk.
  • Levamir is considered as a good alternative by some, because this long acting insulin analogue lacks the greater affinity for IGF-R. However, absence of proof is no proof of absence: Levamir has only recently been introduced, it has not been included in these studies and clinical experience is limited.
  • More conclusive evidence is to be expected from analysis of the large combined analysis of the databases available worldwide, by EASD and sanofi-aventis. Results are expected within a few months.

Video-editorials featuring Prof. Ulf Smith, Director EASD, and Prof Edwin Gale, editor-in-chief Diabetologica (part 1 and 2)

*dr Mintz reformulated this in his last post, where he stated that “it is unlikely that Lantus actually causes cancer alone, because it takes years to develop most cancers. However, it is more likely that Lantus causes existing cells to grow and divide more rapidly.

Journal ArticlesResearchBlogging.org

  1. Hemkens, L., Grouven, U., Bender, R., Günster, C., Gutschmidt, S., Selke, G., & Sawicki, P. (2009). Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study Diabetologia DOI: 10.1007/s00125-009-1418-4 (Free full text)
  2. Jonasson, J.M., Ljung, R, Talbäck, M, Haglund, B, Gudbjörnsdòttir, S, & Steineck, G (2009). Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden Diabetologia (Free full text)
  3. SDRN Epidemiology Group (2009). Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group Diabetologia (Free full text)
  4. Currie, C., Poole, C., & Gale, E. (2009). The influence of glucose-lowering therapies on cancer risk in type 2 diabetes Diabetologia DOI: 10.1007/s00125-009-1440-6 (Free full text)
  5. Smith, U., & Gale, E. A. M. (2009). Does diabetes therapy influence the risk of cancer? Diabetologia (Free full text)
  6. Mayer D, Shukla A, Enzmann H (2008) Proliferative effects of insulin analogues on mammary epithelial cells. Arch Physiol Biochem 114: 38-44
  7. Arch Physion Biochem (2008), vol 1141 (1) is entirely dedicated to “Insulin and Cancer”, i.e. see editorial of P. Lefèbvre: Insulin and cancer: Should one worry?” p. 1-2
  8. Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H (2009) Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev 25: 41-49 (PubMed record)

Information about Lantus

9.  http://content.nejm.org/cgi/content/extract/352/2/174

10. http://products.sanofi-aventis.us/lantus/lantus.html

11. http://www.informapharmascience.com/doi/abs/10.1517/14656566.2.11.1891?journalCode=eop

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13 responses

7 07 2009
Twitted by PinkAdvocate

[…] This post was Twitted by PinkAdvocate […]

7 07 2009
Travis

I was unaware of links between exogenous insulin and cancer, but it’s quite well established that hyperinsulinemia resulting from obesity is a risk factor for certain cancers, especially colon cancer (the potential mechanisms are the same you discuss for Lantus). In patients taking exogenous insulin, are insulin levels kept higher, lower, or similar to those of a healthy person?

7 07 2009
Brief Grand Rounds from Argentina | Pharmamotion

[…] a librarian perspective, Laika sees that the results of some studies do not support a causal role for Lantus in cancer, but do give reason for some serious concern in a subset of […]

9 07 2009
Rajesh

A well written article. though lots of research has to be done to prove the claim, atleast it will help breast cancer patients who are also diabetic and use lantus. one way you kill them using chemo/radiation and on the same way u stimulate breast cancer cells to grow.
is immediate attention warranted to these subset of cancer patients??

8 05 2010
sukesh

r u sure lantus cases cancer…………………..pls reply….

12 01 2011
pa

it’s not conclusive don’t worry about it, and if your a guy even less to worry about as it causes breast cancer.

9 10 2011
Gina

I am certain. I took lantus for 2 years. in 2009 I ended up in the hospital. They never took me off latus. I continued to complain about the insulin and threatened to go to another doctor. They did not want to get in trouble and changed it. back in april to levemir. Now at that time I found a lump in my boob. It turned out to just be a cyst, and I had no Idea that Lantus might of caused it. When I heard about Lantus link to cancer. I realized it could have caused the lump.

18 07 2009
Bob

here are some points from a study by Kurtszals et al 2000 and, don’t seem to be disputed: using a baseline of 100% affinity to the IGF receptor for human insulin in our bodies, glargine or lantus has an affinity in vitro of 641% + – 51; lispro or humalog is 156 +- 16; aspart or novolog is 81 +- 9; detemir or levemir is 16; So, yes, there should be concern that the glargine has an affinity to the IGF -1 binding site that is over 700% when compared to our endogenous insulin. detemir, is a similar basal insulin and has much less of a question mark in this regard

21 08 2009
JP Marat

Given that there is a long-acting insulin (NPH) which has a very long historical safety record, and that both Lantus and Levamir offer at most a marginal benefit by elminating the peak in NPH’s therapeutic action, why would anyone keep taking Lantus or switch to the untested Levamir instead? Emphasizing the ‘distinction’ between Lantus promoting the development of established cancers and ‘causing’ new cancers is therapeutically nonsensical, since cells are undergoing precancerous changes all the time before they are suppressed by the immune system, and there is no way for anyone to know whether a particular patient has very early stage cancer or not, since it will show no clinical signs!

28 01 2010
Markus Lundqvist

Why can’t we have human ultralente insulins as before like Humulin ZN/Human Ultratard. I was very well controlled by these, yet it seems that all that Humulin and Novonordisk want is to poison us with these artificial analogs which,esp glargine (Lantus) and maybe determir (Levemir) because of the old human devil, making more and more money regardless of our health?!

26 03 2010
Jad

Hi
Can I ask what about Livemer? Does it as well as Lantuse?

18 11 2010
Bertha

I’m a breast cancer survivor for 13 years and started Lantus insulin 2 years ago and my cancer came back. I had a complete mastectomie and told my Dr. and he switch to Levemir but I found it very hard because my sugar levels are always very high now and don’t know what to do about it.

12 01 2011
pa

being a diabetic fucking sucks i hope everybody who was responsible for releasing lantus to the public without proper testing gets cancer and dies a slow painful death.

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