Insulin and cancer   (June 28, 2009)

I recently received an e-mail from an organization to which I belong, with the worrisome title "'Possible link' between taking insulin glargine and developing cancer." It went on to explain that the current issue of Diabetologia, the journal of the European Association for the Study of Diabetes (EASD), features four studies that point to a "possible link" between taking insulin -- especially insulin glargine (Lantus) -- and developing cancer. Diabetologia's website has a listing of involved studies, editorial comments, information for patients, and a press release from the manufacturer [Editor's note: hyperlink not working when checked March 2012].

The series of articles brings up all sorts of questions: Do other newer long-acting insulin analogs such as Levemir (insulin detemir) also share this association? If Lantus is associated with cancer, what kind of cancer? Does the administration of insulin cause a new cancer, or cause a pre-existing cancer to grow faster than if there had been no insulin therapy? None of these questions are answered in the studies that are published here.

The impetus for the claim of a link was a German observational study of 127,031 patients who were started on insulin therapy; the authors found a positive association between cancer incidence and insulin dose (bigger insulin doses = higher incidence of cancer) for all insulin types that they studied, which included human insulin and several insulin analogs (glargine/Lantus, lispro/Humalog, and aspart/Novolog/Novorapid). After rejiggling the numbers, they concluded that "the cancer incidence with glargine was higher than expected compared with human insulin." There were several interesting limitations to the study: patients simultaneously on both analog and human insulin were excluded; and most important, there was no mention of what cancers were found: were they typical of what might be expected in people with diabetes, or some unexpected tumor type?

The second study was in the UK, and involved 62,809 patients, came to the opposite conclusion about insulin analogs (such as Lantus): "Use of insulin analogues was not associated with increased cancer risk as compared with human insulin."

The third study was in Sweden, followed 114,841 patients on insulin, and concluded "No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurence [sic] of malignancies can be drawn from the results of this study."

The fourth study evaluated 49,106 patients in Scotland. The authors found that patients "receiving any insulin glargine ... had the same incidence rate for all cancers as those not receiving insulin glargine" and concluded that "insulin glargine use was not associated with an increased risk of all cancers or site-specific cancers."

There has always been a suspicion that insulin or insulin analogs might be causally associated with bad things. Since insulin is a "growth factor," cancer has been on the list. The possibility that insulin analogs could be associated with cancer was clearly indicated years ago, when one insulin analog (called B10Asp) was found to induce breast tumors in rats; further development of that analog was halted, and subsequent analogs have not had such an association.

Clearly there are associations that are overwhelmingly indicative of a casual relationship. For example, if you take too much insulin, your blood glucose will go too low. The causal association is supported by the understanding that hypoglycemia is merely an exaggeration of the anticipated effect of lowering blood glucose, and the close time relationship: the hypoglycemic effect occurs within hours of the administration of the insulin.

And some associations slowly become evident: tobacco is now firmly linked with lung cancer, although for years the evidence was argued. The causal relationship was difficult to sort out in part because the time frame between using tobacco and getting lung cancer was so long, measured in years. On the other hand, the location of the cancer seems to fit with where cigarette smoke would be, so it's not too big of a leap of logic to conclude that tobacco is causative of lung cancer.

With respect to diabetes, it's now understood that several types of cancer are more common: colon, pancreas, and breast. But whether taking insulin increases the risk of these malignancies (or perhaps of others) is much less clear, and these studies do not, in my mind, clarify the risk. I do agree with the editorial comment in Diabetologia: "With respect to insulin glargine, it is in no one's interest to mount a witch-hunt against this popular and widely used insulin . . . but it is in everyone's interest for the truth to be known. The evidence presented in this set of papers is sufficient to establish that there is a case to answer, but is entirely insufficient to bring in a verdict."

What should the patient who's presently taking Lantus do? The EASD states that "The EASD does not recommend that you stop taking insulin glargine (Lantus) on the basis of the evidence presented here, particularly if you have found it helpful in the management of your own diabetes. People with diabetes do, however, have the option of using long-acting human insulin or a mixture of long- and short-acting human insulin twice a day instead of the once-daily analogue. You may wish to consider this option if you already have a cancer, or, for women, if there is a family history of breast cancer."

The American Diabetes Association weighs in with the comment that "the data within these studies and between these studies are conflicting and confusing. Until more information is available, the American Diabetes Association advises patients using insulin not to stop taking it. For patients using glargine and considering switching to another form of insulin, the data in these studies make it unclear as to whether any one type of insulin increases the risk of cancer more than other types of insulin."

My advice: if you are on insulin, stay on your present insulin program. If you have a family history of cancer, or been diagnosed with cancer, or have a high risk of cancer for other reasons, the information is still very unclear whether to switch from one form of insulin to another. Remember that glucose control decreases your risk of diabetic complications, and that's well-proven, established fact.