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Insulin Analogs and Pregnancy

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Insulin Analogs and Pregnancy In Brief Diabetes during pregnancy is a major risk factor for poor fetal, neonatal, and maternal outcomes; however, the risk can be greatly reduced by early institution of medical nutritional therapy and insulin treatment. Maintaining maternal glycemia as near to normal as possible reduces the risk of congenital anomalies, macrosomia, neonatal hypoglycemia, and large-for-gestational-age infants. Achieving normoglycemia has usually been accomplished with human insulin. However, the newer rapid-acting insulin analogs lispro and aspart, when com- pared to regular human insulin, demonstrate both efficacy and safety for the treatment of diabetes during pregnancy. NPH insulin is the only basal insulin that has been studied in pregnancy. There are not yet any published controlled studies evaluating the long-acting insulin analogs for use in pregnancy. Insulin Analogs and Pregnancy Pregnancy complicated by diabetes nancy can also decrease the preva- occurs in ~ 4% of pregnancies in the lence of neonatal hypoglycemia, United States.1 With appropriate insti- macrosomia, intrauterine death, and Angelina L. Trujillo, MD, FACE tution of intensive diabetes therapy and cesarean delivery.5–7 Achieving near- maintenance of glucose levels to normal glycemia means normalizing achieve a lowering of hemoglobin A1c not only fasting glucose, but also (A1C) levels before and during preg- postprandial hyperglycemia to reduce nancy complicated by diabetes, the rate the risk of an adverse pregnancy out- of fetal and maternal complications come.8–10 The infant mortality rate is can be reduced to the rate observed nearly zero when blood glucose con- among nondiabetic pregnancies.2 centration is maintained at near-nor- Whether the pregnancy is classified as moglycemia.11 In both type 1 and type pregestational diabetes (occurring in 2 diabetes, controlling pre- and post- women who have been diagnosed with prandial hyperglycemia can best be type 1 or type 2 diabetes before preg- accomplished during pregnancy by nancy) or as gestational diabetes melli- administering insulin via continuous tus (GDM, occurring when a nondia- subcutaneous insulin infusion from an betic woman develops diabetes only insulin pump or by self-administration during pregnancy), the goal of treat- of multiple daily injections of an inter- ment is to maintain maternal glucose mediate-acting basal human insulin levels as near to normal as possible (neutral protamine Hagedorn [NPH] throughout the pregnancy. insulin) combined with a short-acting Pregestational diabetes is a major or rapid-acting insulin. In GDM, risk factor for spontaneous abortions achieving normoglycemia can initially and congenital malformations, but the be attempted with medical nutrition risk can be significantly reduced when therapy and lifestyle modifications, hyperglycemia is controlled before but frequently, NPH insulin combined conception and during the early first with a short-acting or rapid-acting trimester when fetal organogenesis insulin must be added to attain opti- occurs.3,4 In both pregestational dia- mal glucose levels. betes and GDM, achieving near-nor- Throughout pregnancy, the placenta mal glycemic levels throughout preg- not only produces hormones that alter 94 Diabetes Spectrum Volume 20, Number 2, 2007 linemia can also produce neonatal Fr hypoglycemia after the infant is deliv- to Practiceom Research / Diabetes and Pregnancy ered and is no longer exposed to maternal hyperglycemia. Treatment of diabetic pregnant women with insulin to maintain maternal glucose levels near normal will prevent the develop- ment of fetal hyperinsulinemia in utero and decrease the risk of adverse fetal or neonatal outcomes associated with excess fetal growth. The insulin requirement necessary to achieve near-normal maternal glycemia is based on the patient’s weight and the number of weeks of gestation (Table 1).18 In recent years, molecularly engi- neered insulin analogs (the “new” insulins) have been developed and become available for the treatment Figure 1. Development of fetal hyperinsulinemia. Adapted from Ref. 15. of patients with hyperglycemia and diabetes. The currently available rapid-act- ing insulin analogs are lispro, aspart, Table 1. Calculation of Insulin Dosing and glulisine; the long-acting insulin analogs are glargine and detemir. Lispro, aspart, and glulisine are simi- • Woman’s weight in pounds ÷ 2.2 = woman’s weight in kilograms lar rapid-acting formulations used pri- • Weight in kilograms × k = total insulin requirement marily for mealtime insulin require- ments, whereas glargine and detemir → k = 0.7, 0.8, and 0.9 for first, second, and third trimesters, respectively are long-acting basal formulations.19–21 • 50% of total insulin requirement = daily basal insulin dosage provided by Also available are two biphasic for- mulations: biphasic aspart, which is a long-acting insulin mixture of 30% aspart with 70% pro- → A M Administered before breakfast (8:00 . .), before supper taminated aspart, and biphasic lispro (4:00 P.M.), and at midnight either consisting of 25% lispro and • 50% of total insulin requirement = daily bolus insulin dosage provided by 75% protaminated lispro or 50% rapid-acting insulin lispro and 50% protaminated lispro. The insulin analogs are produced → Administered before breakfast (8:00 A.M.), before lunch (noon), by recombinant DNA methods. and before supper (4:00 P.M.) Lispro, prepared by E. coli, differs Adapted from Ref. 18. from human insulin by two amino acid substitutions on the insulin β- chain; a lysine is substituted at posi- maternal carbohydrate and lipid Because of the facilitated diffusion tion 28 and a proline at position 29, metabolism, but it also controls the of glucose across the placenta, the both of which are the reverse of transplacental passage of glucose, fat, maternal glucose level determines the human insulin. Aspart uses saccha- and protein to provide fuel energy and glucose level of the fetus. When the romyces cerevisiae (yeast) to replace nutrients to the developing fetus. maternal glucose level is high, the the proline at position 28 with an Maternal insulin is not transferred fetus becomes hyperglycemic, result- aspartic acid. Glulisine also has a dou- across the placenta unless the insulin is ing in stimulation of the fetal pancreas ble substitution, replacing asparagine 12,13 bound to IgG antibodies. A study by to produce high levels of insulin with lysine at position 3 and lysine 14 15 Balsells et al. evaluated 50 women (Figure 1). with glutamic acid at position 29. with GDM before and after treatment Because insulin is a growth factor, These modifications of the insulin β- with human insulin, which is immuno- the high fetal insulin level increases chain inhibit the self-aggregation of genic, and found that 44% developed intrauterine fetal growth, producing a insulin to form dimers and hexamers, insulin antibodies. They also found newborn that is large for gestational resulting in monomers that are rapidly that cord blood titers at delivery age (LGA; weight > 90th percentile) or absorbed when administered subcuta- 16 reflected the maternal antibody levels, has macrosomia (weight > 4,000 g). neously and thus allowing a faster indicating transplacental passage of Both conditions are frequently associ- onset of action. human insulin when bound with ated with birth trauma, especially Glargine was the first long-acting maternal antibodies. In the same study, shoulder dystocia, which occurs in analog to become commercially avail- the status of the maternal insulin anti- 0.6–1.4% of fetuses weighing able. It has a glycine substituted for body did not appear to have an impact 2,500–4,000 g and in 5–9% of fetuses asparagine at position 21 on the 17 on fetal outcome. weighing > 4,000 g. Fetal hyperinsu- insulin α-chain and two arginines 95 Diabetes Spectrum Volume 20, Number 2, 2007 within 10–15 minutes, reaches peak Table 2. Insulin and Insulin Analogs concentration within 30–60 minutes and has a duration of action up to 3–4 hours.20 Aspart is similar to lispro Insulin Onset of action Time to peak Maximum but may have a slightly longer time to (minutes) concentration duration of peak concentration (40–50 minutes) (minutes) action (hours) as well as a slightly longer duration of 22 Regular insulin 30–60 90–120 5–12 action (3–5 hours). Glulisine also has a similar onset and duration of action, Insulin lispro 10–15 30–60 3–4 but has a slightly longer time to reach (Humalog) peak concentration (55 minutes).23 Overall, when administered subcuta- Insulin aspart 10–15 40–50 3–5 neously, the rapid-acting insulin Insulin glulisine 10–15 55 3–5 analogs appear to have very similar pharmacodynamic and pharmacoki- NPH insulin 60–120 240–480 10–20 netic profiles.24–26 Compared with regu- lar human insulin, which has an onset Insulin glargine 60–120 None 24 of action of 30–45 minutes and a rela- Insulin detemir 60–120 None 20 tively prolonged effect of 2–3 hours, the rapid-acting insulin analogs have Adapted from Refs. 19 and 20. each demonstrated faster onset of action, earlier peak concentration, and briefer duration of action to Table 3. Current Categories for Drug Use in Pregnancy achieve a more physiological dosing as Assigned by the U.S. Food and Drug Administration of insulin for lowering of prandial hyperglycemia while avoiding late- 27 Category Description onset hypoglycemia. A No increased risk of fetal abnormalities have been demonstrated in Long-Acting Insulin Analogs adequate, well-controlled studies in pregnant women. Glargine has a longer time to onset of action (1.5 hours) compared to NPH B There are no adequate and well-controlled studies in pregnant women; (0.8 hour) and ultralente insulin (1 however, animal studies have not revealed evidence of harm to the fetus. hour), whereas the duration of action C There are no adequate and well-controlled studies in pregnant women; of glargine is longer (20.5 hours) than however, an adverse effect has been shown in animal studies. that of NPH (13.2 hours) and is simi- -or- lar to that of ultralente (19 hours) 28 Adequate and well-controlled studies in pregnant women have failed to (Table 2).
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