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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