Three Glargine Studies Find No Link to Cancer

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Untangling the Sticky Web of Diabetes and Cancer

On June 6, 2009, four articles about a possible link between the drug and incident cancer were simultaneously published. Although the authors were somewhat temperate in their conclusions, the lay press took this up with the screaming headline, "Insulin Treatment Causes Cancer!"

The public deemed insulin harmful to people with diabetes. And immediately, database scrutiny attempted to address this question.

Dr. James Meigs

Researchers want to know what we can learn about the usefulness of pharmacosurveillance databases for safety signals. And clinicians want to know if it’s safe to prescribe glargine.

If there is one take-home message from this group of studies, presented at the American Diabetes Association’s 2012 meeting – it’s "Yes. Glargine is safe and the benefits clearly outweigh the risks."

The other question is not so easy to answer.

Administrative databases can only tell us so much about patients and their experiences. Confounding is a crucial factor that often jeopardizes theses analyses. Missing data are the worst problem here. For instance, smoking status is typically missing in registry data. And yet smoking is common in diabetes and a huge risk factor for cancer. But missing smoking data do not equate to nonsmoking status. You can’t control for confounders that aren’t even measured.

Nor do these databases tell us much about exposure. Exposure time is easy enough to see in patients new to glargine. But we know nothing about prior exposure in those who switched to glargine. To accurately assess outcomes, we need to follow exposure with enough time to allow disease to develop in accordance with its natural history – which brings up another problem. Cancer has a very long latency. Its development can precede an exposure by years, creating the illusion that there is a relationship – when it was really present subclinically all along.

And finally – association does not imply causation. An association is just that – an association – until proven otherwise.

The punchline is this: It’s really hard to do these studies correctly. Cavalier publications of this or that exposure and risk are irresponsible and even harmful – particularly in the case of the glargine-cancer connection.

Insulin is lifesaving. We need it to treat diabetes. And we don’t want to limit our treatment options by prematurely worrying about signals coming up in poorly constructed studies.

Dr. James Meigs is director of the Massachusetts General Hospital’s clinical disease management research unit, in Boston. These remarks are taken from his presentation on the clinical implications of the findings presented by Dr. Boyle, Dr. Habel, and Dr. Stürmer. He had no financial disclosures.



Dr. Laurel Habel, a senior researcher at Kaiser Permanente, presented similar findings of no increased cancer risk from glargine exposure. Her study was based on Kaiser’s northern and southern California claims and coding databases. The study group comprised 115,000 patients with diabetes – 100,000 took NPH insulin, 27,000 took glargine, and 12,000 took both. The median follow-up time was 2.3 years for glargine and 3.6 years for NPH.

"We found no evidence of increased prostate or colorectal cancer for glargine users, whether they were new users or whether they had switched to it," she said.

In a time exposure analysis of breast cancer risk, those who had been on glargine at baseline had a "suggestion of a very modest increase in risk, of 1.6." after 24 months. Curiously, she said, there was no risk increase for patients who had been on glargine for at least 2 years after switching from another insulin.

"We can’t think of any biological reason why we would only see this in the new users, so it might be a case of confounding," she said. "None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer."

For prostate and colorectal cancers, there were no significant associations in any of the analyses, or in the time-dependent comparisons

Dr. Til Stürmer of the University of North Carolina at Chapel Hill presented the smallest study, but had results entirely consistent with those of his colleagues. Again, the comparison group of 52,553 patients was drawn from a large healthcare database. Median follow-up was 1.5 years for both the glargine and other insulin groups.

In looking at the relative risks of breast, prostate, colon. and all cancer, Dr. Stürmer found no significant associations with either new glargine users or those who switched medications. Compared with other insulins, glargine had a relative risk of 1.1 for breast cancer, 1.2 for prostate cancer, 0.9 for colon cancer, and 1.1 for all forms of cancer.

"In a subgroup looking at breast cancer stratified by time [0-6 months, 6-12 months, 12-24 months and longer than 24 months] the hazard ratios jumped around the null, but we only had 14 cancers in 4,000 person/years," he added.

All of the registry studies received support from Sanofi. Other than this funding, none of the presenters had any financial declarations relevant to their studies.


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