Can Insulin Cause Cancer? By Daniel Trecroci

Richard K. Bernstein, MD, says that a potentially serious problem with eliminating Ultralente is the “long-term forecast of potential adverse effects” in people taking Lantus, as outlined by Ernst Chantelau, MD.

Chantelau is a professor in the department of endocrinology, diabetes and rheumatology at Diabetesambulanz MNR-Klinik in Dusseldorf, Germany. In a paper Chantelau co-authored with Jenny Hirst for the Insulin Dependent Diabetes Trust, he speculates that cancer may be a long-term side effect of taking Lantus.

Lantus was approved by the U.S. Food and Drug Administration in 2000. Chantelau says that before the European Medicines Evaluation Agency (EMEA) was asked to approve Lantus in Europe, “it was found to be highly mitogenic [causing cell proliferation] on in vitro testing with human osteosarcoma cells [cancerous cells from tissue surrounding bone].” Chantelau says that Aventis presented this information to the EMEA orally, and the EMEA decided it was “irrelevant.” Lantus was then approved.

Chantelau claims, however, that that “the mitogenicity of Lantus on osteosarcoma cells” was publicly disclosed in the June 2000 issue of the journal Diabetes. According to that study, which was conducted by Peter Kurtzhals, senior vice president of diabetes research for Novo Nordisk A/S, human cancer cells (not animal cells) in culture were studied to measure to what extent Lantus stimulated cell growth. Kurtzhals found that, “The combination of the B31B32diArg and A21Gly substitutions provided [Lantus] with a six- to eight-fold increased IGF-1 receptor affinity and mitogenic potency compared with human insulin.”

According to Bernstein’s translation of Kurthzhal’s finding, this means Lantus is much more likely to stimulate IGF-1 receptors than is human insulin. This is important, Bernstein argues, because other studies have drawn connections between IGF-1 and cancer. For instance, in the April 7, 1999, issue of the Journal of the National Cancer Institute, Harvard researchers found that circulating IGF-1 is related to future risk of colorectal cancer.

According to another study published in the May 1998 issue of the Lancet, Harvard researchers found a positive relation between circulating IGF-1 concentration and risk of breast cancer among premenopausal but not postmenopausal women.

“We know of at least two cancers that are accelerated by IGF-1,” says Bernstein. “IGF-1 is associated with cancer, and now we find out that Lantus behaves like IGF-1. So what are we to conclude? I’m certainly concerned, but I have no idea of the magnitude of potential risk, if any.”

Kurtzhals admitted to Diabetes Health that “increased IGF-1 receptor expression has been associated with some forms of cancer.” When asked if the data from his study is an indicator that Lantus may cause cancer in humans, however, Kurtzhals said, “These findings were made in cell lines, and there is no experience to project these findings to risk in humans…There is no evidence for an increased cancer risk in people taking Lantus.”

Taking the argument one step further, Chantelau also claims that when Lantus was later studied for its carcinogenic potential in another study (reported in the June 2002 issue of the International Journal of Toxicology), dosages were used that were much lower than those of the ill-fated insulin analogue B10Asp. B10Asp was an analogue insulin that never made it to market after clinical trials were stopped in 1992 when it was shown to promote breast cancer in rats.

“In short, this means that Lantus may have a similar carcinogenic potential as…B10Asp,” says Chantelau.

Ingo Stammberger of Aventis Pharma Germany in Hattersheim, Germany, was a lead researcher on the International Journal of Toxicology study. He told Diabetes Health that Lantus was studied in rat and mouse carcinogenicity studies and that in both studies, it “did not show a carcinogenic effect.”

Sanofi-Aventis spokespersons do not refute that Asp- B10 had been found to promote growth of mammary tumors in rodent toxicology studies.

“In the case of Lantus, the question was raised as to whether insulin analogues and Lantus may have specific growth promoting potential, which could be expressed as tumor-promoting activity in patients,” say Sanofi-Aventis spokespersons. “Asp-B10 was used as a comparator in the preclinical studies with Lantus and found to have a profile of receptor activation that is different from human insulin and from Lantus. Extensive investigation with Lantus has clearly established that there is no safety risk with the use of Lantus. This evidence includes preclinical in vitro studies on receptors and cell lines as well as toxicology studies in animals.”

Sanofi-Aventis adds that Lantus is the only insulin analogue that has been investigated in two-year animal toxicology studies.

“The two-year rodent carcinogenicity studies show no evidence of carcinogenicity.”

Nancy Bohannon says Lantus users should not look too deeply into Chantelau’s theories, because she claims the rats used in the studies were “very prone to certain types of cancer.” Bohannon adds that the researchers were using specially bred rats that didn’t have insulin receptors.

“Insulin binds to insulin like growth factor [IGF-1] receptors, and it binds to insulin receptors,” says Bohannon. “But if you have insulin receptors and IGF-1 receptors, it will bind to the insulin receptors and not the IFG-1 receptors. This was a specially bred strain that did not have insulin receptors, so the only thing to bind to was the IGF-1 receptors. And when you bind to the IGF-1 receptors, that can stimulate the formation of tumors.

” Bohannon says that you are never going to have humans who don’t have any insulin receptors, so she calls Chantelau’s claims “far reaching.”

Richard Bernstein, however, disagrees with Bohannon’s assessment.

“There is a law of physics that when you get down to molecular through subatomic dimensions, if it can happen, it will happen,” says Bernstein. “If you have IGF-1 receptors available, even though you have insulin receptors, insulin is going to bind to some of them. In chemistry, it is called the ‘law of mass action.’ Most of it will go to the insulin receptors, but a little of it will hit the IGF-1 receptors. So we probably should not use that as an argument that it can’t cause cancer.”

Stuart Brink says that in order to answer any questions about cancer risk, long-term studies in humans who have taken Lantus would need to be done.

“The current data do not suggest this is anything but a theoretical issue,” says Brink. “We just don’t know.”

Bernstein also agrees that “we just don’t know.”

Chantelau admits that the data gathered from rat studies do not tell us anything about the potential risk of cancer promotion.

“As we still don’t know whether insulin analogues are cancer-promoting or not, I and others have been asking for the investigation of insulin analogues on cancer tissues,” says Chantelau. “These studies are still lacking.”

Sanofi-Aventis disagrees, pointing out that Lantus has been “highly effective and well tolerated” throughout a comprehensive clinical trial program involving more than 2,000 patients treated with Lantus for up to 52 weeks, as well as clinical use since 2000 by more than one million patients with diabetes.

“The extensive preclinical safety data and clinical post-marketing data collected by Sanofi-Aventis indicate there is no carcinogenic safety risk with the use of Lantus.”

In addition, Sanofi-Aventis says mechanisms are in place to report any increase in cancer in patients.

“…We monitor possible adverse effects in our ongoing comparative trials of more than 15,000 patients.”

The results of the clinical safety evaluations are included in the prescribing information for Lantus. Since its market launch, this information has been continually updated by post-marketing surveillance under study and practice conditions and by Periodic Safety Update Reports.

For more information, see the section labeled “Carcinogenesis, Mutagenesis, Impairment of Fertility” on the prescribing label of your Lantus bottle.

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