Antidiabetic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
There are no reasons to believe that insulin aspart would pose a risk to the embryo or fetus different from that of other insulins. Older forms of insulin, whether of human or of porcine origin, are considered compatible with pregnancy. Insulin aspart can be classified similarly. As with all insulins, the primary concern is severe maternal hypoglycemia.
FETAL RISK SUMMARY
Insulin aspart is a rapid-acting human insulin analog that differs from regular human insulin by a single substitution of the amino acid praline by aspartic acid at position B28. It is produced by recombinant DNA technology. Insulin aspart is indicated for the treatment of patients with diabetes mellitus, for the control of hyperglycemia. It may be given by SC injection, as an SC infusion by an external insulin pump, or IV. The mechanism of action of insulin aspart 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. Because the substitution at position B28 reduces the tendency to form hexamers, as observed with regular human insulin, insulin aspart is absorbed more rapidly after SC injection and has a shorter duration of action. Similar to regular insulin, plasma protein binding of insulin aspart is low (0%–9%) (1).
The median times to maximum serum concentrations for insulin aspart and regular insulin after SC administration are 40–50 minutes and 80–120 minutes, respectively. The elimination half-life of insulin aspart also is shorter than regular insulin, 81 vs. 141 minutes, respectively (1).
Reproduction studies of SC insulin aspart have been conducted in rats and rabbits. In female rats, insulin aspart was given before and during mating, and throughout gestation. The embryo–fetal effects observed with insulin aspart did not differ from human insulin. These effects were pre- and postimplantation losses and visceral/skeletal malformations at a daily dose about 32 times the human dose based on BSA (HD). Similar results were obtained in rabbits given daily doses that were about three times the HD during organogenesis. The effects in both species probably were due to maternal hypoglycemia. No significant effects were observed in rats and rabbits at doses that were about eight times and equal to the HD, respectively (1).
In rats, insulin aspart given over a 52-week period resulted in an increased incidence of mammary gland tumors in females at the highest SC dose tested (about 32 times the HD). Similar effects have been observed with human regular insulin. Insulin aspart was not genotoxic in multiple tests, nor did it have any effect on fertility or reproductive performance in male and female rats, at SC doses up to 32 times the HD (1).
It is not known if insulin aspart crosses the human placenta. Human insulin does not cross the placenta in clinically significant amounts (2). Because of the very close similarity between insulin aspart and human insulin, and its high molecular weight (about 5826), insulin aspart probably does not cross either. However, there may be endogenous carrier proteins that allow passage of insulin, including insulin aspart, 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).
A 2003 report compared the effects of single doses of insulin aspart and human regular insulin on alternate days in 15 women with gestational diabetes (4). Pregnancy outcomes were not discussed.
In 2007, the FDA approved a change in the risk factor for insulin aspart from C to B (Novo Nordisk, press release, January 30, 2007). Insulin aspart was compared with human regular insulin in a randomized controlled trial at 63 sites in 18 countries involving 322 pregnant women with type 1 diabetes. The rates of maternal hypoglycemia and changes in hemoglobin A1c(HbA1c) were comparable between the two groups. However, insulin aspart showed improved, though not statistically significant outcomes in terms of fewer preterm deliveries (p <0.053), reduced risk of neonatal hypoglycemia requiring treatment, and consistently low rates of major hypoglycemia. The study was too small to evaluate the risk of congenital malformations (Novo Nordisk, data on file, January 30, 2007).
A 2008 study compared insulin aspart with human insulin, both combined with NPH insulin, in a randomized study involving 322 pregnant women (5). There was no difference between the groups with respect to fetal loss, perinatal mortality, congenital anomalies, and neonatal short-term complications,
One review concluded that rapid-acting insulin analogs (aspart and lispro) could be considered the insulin of choice in pregnancy (6).
BREASTFEEDING SUMMARY
Insulin is a naturally occurring constituent of the blood and is excreted into breast milk. In a 2012 study, milk samples were obtained from breastfeeding mothers, five without diabetes, four with type 1 diabetes, and five with type 2 diabetes (7). Samples were analyzed for total and endogenous insulin and for c-peptide. The type 1 diabetics were treated with artificial insulin (aspart plus lantis), whereas the type 2 diabetics received a diabetic diet either with (N = 3) or without (N = 2) metformin. Insulin was present in all of the samples at comparable concentration to serum, but only artificial insulin was detected in the milk of type 1 diabetics. The results showed that insulin, both endogenous and exogenous, is actively transported from the blood into milk and is protected from degradation and, presumably, has a functional or developmental role in the infant. If so, the authors suggested, it might be beneficial for formula-fed infants if insulin was added to formula milk (7).
References
1.Product information. Novolog. Novo Nordisk, 2007.
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.Pettitt DJ, Ospina P, Kolaczynski JW, Jovanovic L. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care 2003;26:183–6.
5.Hod M, Damm P, Kaaja R, Visser GHA, Dunne F, Demidova I, Hansen ASP, Mersebach H, for the Insulin Aspart Pregnancy Study group. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol 2008;198:186.e1–7.
6.Gonzalez C, Santoro S, Salzberg S, Di Girolamo G, Alvarinas J. Insulin analogue therapy in pregnancies complicated by diabetes mellitus. Expert Opin Pharmacother 2005;6:735–42.
7.Whitmore TJ, Trengove NJ, Graham DF, Hartmann PE. Analysis of insulin in human breast milk in mothers with type 1 and type 2 diabetes mellitus. Int J Endocrinol 2012;2012:296368. doi:10.1155/2012/296368. Epub 2012 Mar 5.