Evaluation of the Reproductive Toxicity and Embryotoxicity of Insulin Glargine (LANTUS) in Rats and Rabbits

Abstract

Insulin glargine (LANTUS) is a new insulin analog that has a prolonged duration of action with no pronounced peak of activity, rendering it an ideal basal insulin for the treatment of diabetes. The aim of these studies was to assess the reproductive and embryotoxicity of insulin glargine. Reproductive toxicity was assessed in 25 male and 25 female Wistar rats per group treated with a daily subcutaneous injection of control; 1 IU/kg, 3 IU/kg, and 10 IU/kg insulin glargine; or 3 IU/kg NPH insulin in the premating and mating periods, and throughout pregnancy and lactation in the females. Embryotoxicity was assessed in 20 female rats per group injected with daily subcutaneous doses of control; 2 IU/kg, 6.3 IU/kg, and 20 IU/kg insulin glargine; or 6.3 IU/kg NPH insulin from the 7th to 18th day of pregnancy. Embryotoxicity was also assessed in 20 female rabbits per group treated with 0 IU/kg, 0.5 IU/kg, 1 IU/kg, and 2 IU/kg insulin glargine, or 1 IU/kg NPH insulin from the 6th to 18th day of pregnancy. The data demonstrated that, with the exception of toxicologic effects induced by hypoglycemia in response to high doses of insulin glargine and NPH insulin (including the premature dropout of female rats in the reproductive toxicity study, and increased incidence of abortions, early intrauterine deaths, and single anomalies in the rabbit embryotoxicity study), insulin glargine had no effects on reproduction, embryofetal development, and postnatal development in rats. Maternal and embryofetal toxicity in rabbits treated with middle and high doses of insulin glargine was related to the hypoglycemic effect of insulin.

Toxicity studies of drugs and chemicals in animals: an overview

“…On the 21 st day of the study a caesarean section is performed and felaser with haemorrhagic bullae, limb malformations, exencephally, cleft palates, open eyelids, detail deformities, mortality and the number of live and dead animals are noted. Embryo toxicity assays such as embryonic stems cell test, micromass embryotoxicity assay and whole rat embryotoxicity assays can be done (Kimm-Brinson & Ramsdell, 2001;Hofmann et al, 2002;Booth et al, 2010). During generation reproduction toxicity study, genetic toxicity testing can be carried out to identify gene mutations, chromosomal changes and alterations on the DNA sequency.…”

Management of gestational diabetes mellitus

“…90 No data are available as yet on the capacity of these insulin analogues to cross the placenta. In a case-control pilot study involving 22 GDM cases treated with insulin glargine, Price et al could find no differences in maternal and fetal outcomes.…”

Type 2 diabetes in pregnancy: importance of optimized care before, during and after pregnancy

“…In animal studies, no embryotoxic effects have been demonstrated. 57 It does have theoretical risks in pregnancy because of its known activation of insulin-like growth factor 1 (IGF-1) receptors and mitogenic potency, however, small cohort studies have not demonstrated any concerns. 58 For women well-controlled on glargine prior to pregnancy it may be difficult to return to intermediate-acting insulins.…”