Glargine and Cancer: Can We Now Suggest Closure?

Abstract

The two publications on the pharmacokinetics of insulin glargine in individuals with type 1 and type 2 diabetes in this issue of Diabetes Care (1,2) provide additional explanatory evidence in support of the definitive findings in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) study in which exposure to insulin glargine for a median duration of 6.2 years did not increase the risk of any cancer (hazard ratio 1.00 [95% CI 0.88–1.13]) or death from cancer (0.94 [0.77–1.15]) (3). Soon after glargine’s long awaited and welcome introduction into clinical practice in 2000, questions were raised about its safety profile. This conception was based on the early finding that insulin glargine had an enhanced affinity to IGF-1 receptors when tested in a human osteosarcoma cell line (Saos/B10) with a preponderance of IGF-1 receptors and associated with increased mitogenicity (proliferation in an existing tumor cell line) (4). These findings were akin to those observed with the AspB10 insulin analog, the development of which had earlier been discontinued because of an increase in both benign and malignant mammary gland tumors in Sprague-Dawley rats after 12 months’ exposure (5,6); thus AspB10 was referred to as the “carcinogenic insulin analog” (7). In contrast, detailed extensive toxicological lifetime carcinogenicity studies of insulin glargine in animals (rodent and nonrodent), albeit at lower doses, revealed no carcinogenicity signal with insulin glargine when compared with human insulin (8,9). The risk was regarded as small by the European Medicines Agency safety working party because of the lack of effect on mammary gland proliferation, absence of mammary carcinoma, and rare tumors during the lifetime studies in animals. The higher insulin receptor affinity and consequent prolonged dephosphorylation due to the increased residence time of AspB10 on insulin receptors (4) along with a predilection for the …