Antidiabetic Agent
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
The human data presented by the manufacturer and other sources indicate that the effects of insulin detemir on the embryo and/or the fetus are similar to human insulin. The animal data suggest risk, but the embryotoxicity and teratogenicity was thought to be secondary to maternal hypoglycemia. Moreover, there was no difference in developmental toxicity between insulin detemir and human insulin (1). Older forms of insulin, whether of human or of porcine origin, are considered compatible with pregnancy. As with all insulins, the primary concern is severe maternal hypoglycemia.
FETAL RISK SUMMARY
Insulin detemir is a long-acting basal insulin analog that differs from regular human insulin by the omission of the amino acid threonine in position B30 and the attachment of a C14 fatty-acid chain to amino acid B29. It is produced by recombinant DNA technology. Insulin detemir is indicated for once- or twice-daily SC administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
The mechanism of action of insulin detemir is similar to human insulin in that it binds to receptors in muscle and fat cells to facilitate the cellular uptake of glucose and, at the same time, inhibits glucose release from the liver. The duration of action ranges from 5.7 hours at the lowest dose to 23.2 hours at the highest dose. The long duration results from the slow systemic absorption of insulin detemir from the injection site caused by the strong self-association of the insulin molecules and the high binding to albumin in the blood. In contrast to human insulin, more than 98% of insulin detemir in the blood is bound to albumin (1).
Reproduction studies have been conducted in rats and rabbits. When female rats were given daily doses about 1.5 and 3 times the recommended human dose based on AUC (RHD) before and during mating and throughout pregnancy, an increased number of fetuses with visceral anomalies were observed at both doses. No effect on fertility was observed. In pregnant rabbits, a dose that was 135 times the RHD was associated with gall bladder abnormalities described as small, bilobed, bifurcated, and missing. When human insulin was used in control groups, the effects of insulin detemir and human insulin were similar in terms of embryotoxicity and teratogenicity. Carcinogenicity studies have not been conducted with insulin detemir, but no mutagenic or clastogenic effects were observed in tests (1).
It is not known if insulin detemir crosses the human placenta. Human insulin does not cross the placenta in clinically significant amounts (2). Because of the close similarity between insulin detemir and human insulin, and its high molecular weight (about 5917), insulin detemir probably does not cross either. However, there may be endogenous carrier proteins that allow passage of insulin, including insulin detemir, to the embryo early in gestation. After that period, the fetus produces its own insulin as insulin-secreting cells in the fetal pancreas become differentiated near the end of the 1st trimester (3).
The manufacturer reported an open-label, clinical study in 310 pregnant women with type 1 diabetes (1). The women, between 8 and 12 weeks’ gestation, were divided into two groups, insulin detemir N = 152 and NPH N = 158. The pregnancy outcomes in the two groups were similar (1).
Several reports have described the use of insulin detemir in human pregnancy (4–8). These reports concluded that the insulin analog had maternal efficacy and safety similar to other insulins. No embryo–fetal adverse effects related to the drug were observed (4–8).
BREASTFEEDING SUMMARY
No reports describing the use of insulin detemir during human lactation have been located. Insulin is a natural component of the blood and is excreted into breast milk. Insulin detemir probably also is present in milk.
References
1.Product information. Levemir. Novo Nordisk, 2012.
2.Schardein JL. Insulin and oral hypoglycemic agents. In: Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker, 2000:458.
3.Buchanan TA, Kjos SL. Diabetes in women. Early detection, prevention, and management. Clin Updates Women’s Health Care. 2002;1(4/Fall):47.
4.Todorova-Ananieva K, Genova M. Pregnancy outcomes in women with type 2 diabetes treated with long-acting insulin analogues. A case control study. Diabetologia 2008;51(Suppl 1):S456 (abstract 1120).
5.Lapolla A, Di Cianni G, Bruttomesso D, Dalfra MG, Fresa R, Mello G, Napoli A, Romanelli T, Sciacca L, Stefanelli G, Torlone E, Mannino G. Use of insulin detemir in pregnancy: a report on 10 type 1 diabetic women. Diabet Med 2009;26:1179–80.
6.Sciacca L, Marotta V, Insalaco F, Tumminia A, Squatrito S, Vigneri R, Ettore G. Use of insulin detemir during pregnancy. Nutr Metab Cardiovasc Dis 2010 May; 20(4):e15-6. doi:10.1016/j.numecd.2009.12.010.
7.Callesen NF, Damm J, Mathiesen JM, Ringholm L, Damm P, Mathiesen ER. Treatment with the long-acting insulin analogues detemir or glargine during pregnancy in women with type 1 diabetes: comparison of glycaemic control and pregnancy outcome. J Matern Fetal Neonatal Med 2013;26:588–92.
8.Lambert K, Holt RIG. The use of insulin analogues in pregnancy. Diabetes Obes Metab 2013;15:888–900.