Glargine and Cancer: Can We Now Suggest Closure?

The two publications on the pharmacokinetics of insulin glargine in individuals with type 1 and type 2 diabetes in this issue ofDiabetes 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 SpragueDawley 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 onmammary 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 insulin receptor IR-A isoform (10)may in large part account for the differential metabolic andmitogenic outcomes observed when compared with human insulin and insulin glargine. Di-arginyl insulin (ArgB31-ArgB32human insulin) is known to be an intermediate in the conversion of proinsulin to insulin. Insulin glargine (GlyA21-ArgB31ArgB32 human insulin) possesses glycine at A21 instead of asparagines, thereby adjusting its solubility at neutral pH for retarded release while lowering its propensity for aggregation. After subcutaneous administration, insulin glargine precipitates amorphously and is then slowly released according to zero-order kinetics. It has been documented for some time that insulin glargine is biotransformed both in the subcutaneous tissue and circulation (11). Sequential cleavage of the carboxyl terminus of the C-chain occurs via local and systemic converting proteases into the primary metabolite GlyA21 human insulin (M1) and also GlyA21 des-ThrB30 human insulin (M2) as described using high-performance liquid chromatography and a nonspecific radioimmunoassay. Biotransformation in serum occurs rapidly with ;70% of insulin glargine converted toM1within 30min of incubation (12,13). The metabolites M1 and M2 retain the full biological activity of human insulin and have substantially reduced IGF-1 receptor binding and mitogenic potency relative to human insulin (4). Whereas insulin glargine has a greater affinity to IGF-1 receptors than human insulin (10-fold) it has a 100fold lower affinity than native IGF-1 (14). This enhanced IGF-1 affinity is reversed by removal of the di-arginyl molecules. The primary (M1) and secondary (M2) metabolites are less metabolically active with reduced affinity to IGF-1 receptors and equivalent growth-promoting activity in Saos-2 and MCF-7 cell lines compared with human insulin (15). The early vital information on the biotransformation of insulin glargine (11) was seemingly ignored for many years, with research groups having chosen instead to focus on the in vitro IGF-1 binding properties of the parent compound insulin glargine. Therefore, little further development has occurred until the current articles by Bolli and colleagues (1,2). In the meantime, researchers have extensively explored the potential adverse clinical impact of insulin glargine ondiabetic retinopathy and cancer. Concerns relating to the development or progression of diabetic retinopathy by insulin glargine were alleviated when in both a meta-analysis of four phase 3 trials (16) and a randomized control trial over a 5-year period revealed no difference between NPH and insulin glargine (17). In September of 2009, four international communications relating to insulin and the risk of cancer were published together (18–21); three were instigated by the European Association for the Study of Diabetes to explore the validity of the first study carried out in Germany (18), which demonstrated a strong correlation between insulin dose and cancer risk and implied that insulin glargine carried a higher risk than human insulin. This lead to considerable anxiety among the insulin-treated diabetic population and the diabetes care community alike, which necessitated the regulatory authorities and diabetic associations to issue statements of reassurance. The findings of Hemkens et al. (18) were subsequently criticized because they used an unconventional and fundamentally flawed analysis that adjusted for insulin dosage, which meant that the conclusions were unsupportable (22). There was no excess cancer risk seen in a 5-year randomized control trial comparing NPH and insulin glargine (17) or when the combined randomized control trial experience of malignancies in studies using insulin glargine were evaluated (23). With regard to the general clinical question, the Consensus Report on Cancer and Diabetes by the American Diabetes Association and American Cancer Society concluded that further research was needed to clarify the relationship between exogenous insulin and increased cancer risk and the specific question relating to insulin glargine (24). Sandow (9) attempted to highlight the complexity of the relationship between the growth effects of insulin and insulin analogs while emphasizing the need for clarity regarding the meaning of mitogenicity under physiological and pathophysiological situations in relationship to insulin and insulin analogs. In hindsight, it is somewhat unfortunate that during the discussion of insulin glargine, after its introduction into clinical