Insulin glargine and cancer--an unsubstantiated allegation.

It has long been known that both obesity 1–4 and type 2 diabetes are associated with an increased risk of cancer. For type 2 diabetes, this has been particularly recognized with pancreatic cancer, colorectal cancer, and breast cancer. It has long been known that insulin can stimulate breast cancer growth in tissue culture. Many papers have examined the relationship between insulin and insulin-like growth factor (IGF) signaling in neoplasia and the possible effects of insulin in stimulating neoplasia via binding to the IGF-1 receptor. It is upon that background that recent events have erupted, bringing confusion to the situation. On Friday, June 26, 2009, the EASD (European Association for the Study of Diabetes) released on its website (http:==webcast.easd.org=press=glargine=glargine.html) and that of its journal Diabetologia (http:==www.diabetologiajournal.org=cancer.html) a series of papers, an editorial, a press release, a video statement, and patient information, all concerning a ‘‘possible link between insulin glargine and cancer,’’ as the press release was titled, or ‘‘Lantus insulin: a possible link with cancer which requires further investigation,’’ as both websites heralded. This triggered a global panic among patients with diabetes and those who care for them, as insulin glargine (Lantus , sanofi-aventis, Paris, France) is the most widely prescribed insulin in the United States, accounting for 37.5% of all prescriptions. Position statements have been issued by multiple organizations, including the American Diabetes Association, the American Association of Clinical Endocrinologists, the Endocrine Society, and the International Diabetes Federation, in addition to the original EASD statement. As a group, these statements asserted that there was only an unproven link between insulin glargine and cancer and advised patients to consult their physician before changing insulin. They urged further research. Unfortunately, the statements generally were unhelpful to physicians needing to make patient care decisions. This situation has prompted the authors to write this editorial assessing the papers, the data, and the circumstances and recommending a course of action. First, we should examine how it came to be that there were multiple papers appearing on-line addressing the relationship of insulin glargine and cancer. The editorial explains this and hypothesizes how insulin in general (and insulin glargine in particular) could increase cancer risk, specifically through an increase in binding to the IGF-1 receptor. The original article submitted was an examination of a German claims database carried out by The Institute for Quality and Efficiency in Health Care (IQWiG), a German group that makes healthcare recommendations and that previously took the position that insulin analogs offer no benefit over conventional human insulin. This raises questions as to the motivation of IQWiG in conducting the reported analyses. So, what did they find? First, it should be appreciated that the mean age of subjects in the analysis was 69.5 years. Because of the way the information was collected, there is no information available on their duration of diabetes, their degree of diabetes control (e.g., glycosylated hemoglobin), or their body mass index—all important information. Also, the types of malignancy found in these patients were not reported. Furthermore, in the German study, for all cancers, when insulin glargine is compared to human insulin the unadjusted hazard ratio (HR) is 0.85 (95% confidence interval [CI], 0.79– 0.93), indicating a significant 15% decrease in cancer with insulin glargine. A similar outcome is seen when adjusted for age and gender, namely, an HR of 0.86 (95% CI, 0.79–0.94). And, a similar finding was seen for all-cause mortality: an HR of 0.68 (95% CI, 0.65, 0.72). All of these HRs are statistically significant. An increased cancer risk for insulin glargine is only evident if there is further adjustment for dose of insulin. However, for that to be a valid adjustment, the subjects should have been classified by dose group when enrolled; instead, the investigators calculated an average dose over the duration of exposure. Moreover, any subject who changed insulin type during the study was removed from the analysis, resulting in a large number of exclusions. Further, there was a large imbalance in the proportion of subjects in the highest dose category—for glargine, this group was 13.5% of all subjects using glargine, whereas for human insulin it was 46.0% of subjects. Thus, in the highest dose group (>40 units daily), there were 103 events among glargine users and 2,075