Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study

Abstract

Aims/hypothesisSeveral publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study.MethodsData for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes.ResultsOf the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose–response relationships could not be identified.Conclusion/interpretationUsers of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2312-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies

“…1). Following our inclusion criteria, 16 cohort and 3 case-control studies were included in this systematic review (5)(6)(7)(8)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). All studies evaluated insulin glargine, with four studies also investigating insulin detemir (15,17,25,28).…”

“…One study examined duration of time since starting long-acting insulin analogs, and one examined mean daily dose (22,28). Four studies used time-dependent exposure definitions (15,17,20,24). All included studies evaluated cancer incidence as a primary outcome.…”

“…2) (5,8,(14)(15)(16)(17)(19)(20)(21)23,25,26,28). Four of 13 studies reported an association of insulin glargine and breast cancer (8,19,21,24).…”

“…However, residual confounding may have resulted due to the presence of unmeasured confounders. HbA 1c and diabetes duration were not accounted for in 15 of the 19 studies, resulting in likely residual confounding (7,8,(14)(15)(16)(17)(18)(20)(21)(22)(23)(24)(25)(26)28). In addition, residual confounding may have occurred in all 19 studies because none of these studies adjusted for time-dependent covariates, such as the addition of short-acting insulins or other antidiabetic medication (e.g., metformin), at all or appropriately (e.g., used a marginal structural model and inverse probability weighting to adjust for time-dependent confounders in the causal pathway).…”

“…These studies raised important concerns but were also criticized for important methodological shortcomings (9)(10)(11)(12)(13). Since then, several observational studies assessing the association between longacting insulin analogs and cancer have been published but yielded inconsistent findings (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Such discrepancies may be due to methodological limitations, including inadequate durations of followup between insulin initiation and cancer incidence, protopathic bias, detection bias, the inclusion of prevalent users, and time-related biases such as immortal time bias, time-window bias, and time-lag bias (29).…”