Evaluation of the Carcinogenic Potential of Insulin Glargine (LANTUS) in Rats and Mice

Abstract

Insulin glargine (LANTUS) is a new, long-acting insulin analogue with a stable profile of action. The purpose of these studies was to evaluate the carcinogenic potential of insulin glargine in rats and mice. General toxicity studies were conducted in NMRI mice (3 months' duration) and rats (Wistar rats in the 3- and 6-month studies and Sprague-Dawley rats in the 12-month study) to determine the optimal dose of insulin glargine for long-term carcinogenicity studies. Based on these results, groups of Sprague-Dawley rats or NMRI mice (50 male, 50 female) received a daily subcutaneous dose of 2, 5, or 12.5 IU/kg of insulin glargine or 12.5 (mice) or 5 IU/kg (rats) of the reference insulin (NPH insulin) in a lifetime study. Similarly treated control and vehicle-control animals received isotonic sodium chloride (NaCl) solution or the vehicle solution, respectively. In mice, the mortality rate was comparable between all groups. In rats, the mortality rate compared with the NaCl control was significantly increased in the following groups: males treated with the vehicle control, all insulin glargine and NPH insulin groups, and in females in the high-dose insulin glargine and NPH insulin groups. There was no difference in the incidence of mammary tumors reported in both mice and rats when comparing the insulin glargine groups with the NaCl, vehicle-control, or the NPH insulin groups. In rats and mice, the distribution of subcutaneous malignant fibrous histiocytomas found at the injection site were not dose-dependent. These lesions are a rodent-specific event and were related to chronic tissue irritation and inflammation. In rats, neuronal necrosis of the cerebrum was attributed to persistent repeated episodes of hypoglycemia induced by high doses of insulin. In these studies, there were no neoplastic findings to indicate that insulin glargine had a systemic carcinogenic potential in mice or rats.

Does diabetes therapy influence the risk of cancer?

“…The daily doses tested were 12.5, 50 and 200 U/kg, and malignant tumours developed in 0, 11% and 23% of the rats, respectively. Insulin glargine, by contrast, was tested at the lower daily doses of 2, 5 and 12.5 U/kg [39], the last of which is said to correspond to human daily doses of approximately 100 U (rats) or 50 U (mice). It is worthy of note that insulin B10Asp would have passed the carcinogenicity testing to which insulin glargine was subjected and would now be in clinical use.…”

“…Interpretation of the insulin glargine studies was further complicated by a very high early mortality rate, which was probably due to hypoglycaemia at the higher insulin doses. This led the US Food and Drug Administration (FDA) to comment that 'the findings in female mice were not conclusive due to excessive mortality in all dose groups' [40], a caution which, curiously, finds no echo in the published report of the study [39]. Mammary tumours did indeed develop in 10-20% of the female rats, but were no more common in rats treated with insulin glargine than in those treated with neutral protamine Hagedorn (NPH) insulin or control solutions.…”

Insulin analogues display IGF‐I‐like mitogenic and anti‐apoptotic activities in cultured cancer cells

“…Accordingly, insulin analogues are divided into two subgroups known as long-acting and short-acting analogues. Although the clinical pharmacology of the insulin analogues in terms of glycemic control have been amply published [3], the long-term effects of most of these analogues have not yet been systematically evaluated [4,5].…”

Systematic Literature Review of Basal Bolus Insulin Analogue Therapy during Pregnancy

“…Hence, the concern for glargine interfering with fetal development [62]. However, studies in rats and mice failed to show an increase in tumor formation with prolonged glargine exposure [49,63]. Furthermore, Pollex et al [62] carried out an in vitro transplacental transfer study and demonstrated undetectable transfer of glargine at therapeutic concentrations of 150 pmol/L [64].…”