Current Management of Gestational Diabetes Mellitus

Guido Menato; Simona Bo; Anna Signorile; Marie-Laure Gallo; Ilenia Cotrino; Chiara Botto Poala; Marco Massobrio

Disclosures

Expert Rev of Obstet Gynecol. 2008;3(1):73-91. 

In This Article

Insulin Therapy

Regular insulin, which is often used in pregnancy for the treatment of diabetes, has some drawbacks: it starts its action from 30 to 60 min after subcutaneous injection and it peaks too late (2-3 h after injection) to be very effective in postprandial control; in addition, it lasts too long (duration of 8-10 h), with an increased risk of postprandial hypoglycemia.[48] Insulin molecules clump in hexamers that must be broken up to dimers and monomers before absorption, so delaying their effectiveness.

Therefore, in the last few years, insulin analogues started to be used to optimize glucose control during pregnancy.

Insulin Lispro. The first rapidly acting analogue developed was approved for clinical use in 1996. It is obtained by inverting of the lysine at position 28 and the proline at position 29 on the ß-chain of the insulin molecule: it confers a conformational change that results in a quick dissociation of hexamers into monomers in subcutaneous tissue. Insulin lispro has a very rapid action, with a peak 1 h after subcutaneous injection, and a duration of 2-4 h.[49]

There are various safety issues to consider: immunogenicity, teratogenicity and embryotoxicity, and retinopathy.

  • Immunogenicity: placental passage of insulin occurs when it complexes with immunoglobulins and forms an antigen-antibody complex. The studies on the immunologic response to insulin lispro are reported in Table 2 . A successive in vitro perfusion study confirms the result of Boskovic.[50]

  • Teratogenicity and embryotoxicity: studies on experimental animals have not shown any embryotoxic or teratogenetic effects of insulin lispro. The studies made in pregnant women are shown in Table 3 .

  • Retinopathy: the studies carried out concluded that insulin lispro therapy has no adverse impact on progression of retinopathy in pregnant women with Type 1 or Type 2 diabetes ( Table 4 ).

With regard to effectiveness, all clinical studies show no differences in rate of caesarean sections, frequencies of preterm delivery, pre-eclampsia or other neonatal morbidities between the treatment with lispro and regular insulin, with a lower frequency of hypoglycemic episodes at birth.[49] The studies reported to date suggest that insulin lispro may be considered a treatment option in patients with GDM.[14] The studies of effectiveness of insulin lispro in pregnancy are reported in Table 5 .

Insulin aspart was the second rapidly acting analogue introduced, approved for clinical use in Europe in 1999 and by the FDA in 2000 for patients with Type 1 or Type 2 diabetes. It is obtained by replacing the proline at position 28 on the ß-chain of the insulin molecule with negatively charged aspartic acid: similarly to lyspro insulin, this change results in a fast dissociation of hexamers into monomers in subcutaneous tissue. Insulin aspart has a very rapid onset of action, with a peak from 31 to 70 min after subcutaneous injection, and a duration of 2-4 h.[49]

  • Teratogenicity and embryotoxicity: Studies on experimental animals did not show any embryotoxic or teratogenetic effects of insulin aspart.

  • Effectiveness and safety: No studies about the possible placental transfer of insulin aspart are available in the literature. A randomized controlled trial of 322 subjects with Type 1 diabetes found similar safety in the use of aspart insulin compared with regular human insulin.[51] Therefore, aspart insulin is now approved for use in pregnancy and offers a valuable treatment option.[52] The studies on effectiveness and safety of insulin aspart in pregnancy are reported in Table 6 .

Insulin glulisine is a rapidly acting analogue with a pharmacokinetic profile that is similar to those of insulin lispro and insulin aspart.[48] It is created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin.

Insulin glulisine mimics the pharmacokinetic and pharmacodynamic profiles of physiological human insulin, has a rapid onset, peak effect at 1 h, and a shorter duration of action (~4 h). Its rapid-action properties are maintained across subject types.

Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or regular insulin, respectively. Formal clinical evaluations show that it can be administered safety and effectively pre- and post-meal. At present no reports on glulisine use in pregnancy are available.[53]

Insulin Glargine. The first long-acting insulin analogue was approved for clinical use in patients with Type 1 and Type 2 diabetes in 2000 and it was introduced in 2001 in the USA. Insulin glargine is produced by recombinant DNA technology: it results from substitution of glycine for asparagine at position A21 of the insulin molecule and by the addition of two arginine molecules to the C terminus of the B chain, which shifts the isoelectric point from a pH of 5.4 to 6.7. It results in an insulin molecule less soluble at the injection site, that precipitates in the subcutaneous tissue forming a depot from which insulin is slowly released.

Its action begins approximately 90 min after subcutaneous injection and lasts approximately 24 h; it's considered 'peakless'.[48,54]

  • Teratogenicity and embryotoxicity: Studies on experimental animals did not show any embryotoxic or teratogenetic effects of insulin glargine. In a case-control study in rats and rabbits treated with different doses of insulin glargine and isophane insulin (NPH), Hofmann et al. found no effects on reproduction, embryofetal development and postnatal development.[55] Some toxic maternal and embryofetal effects (miscarriages, early intrauterine death, single anomalies) were related to the hypoglycemia induced by the high doses injected of both insulins.

  • Effectiveness and safety: Insulin glargine has not been studied systematically in pregnancy so far; however, several case reports and one case-control study on its use during pregnancy are available ( Table 7 ).

At present the use of insulin glargine in pregnancy is not approved: well-planned investigations and controlled trials are needed to achieve a final risk assessment in order to use it in pregnancy.

Thus, human NPH as part of a multiple injection regimen should be used for intermediate-acting insulin effect in GDM.[14]

Insulin detemir is a long-acting analogue produced by covalent acylation of the amino group of lysine in B, the 29 position, which confers a neutral pH to the insulin molecule. Detemir is slowly absorbed from the injection site and, once in the bloodstream, it binds to albumin through a fatty-acid chain attached to the lysine at residue B29: there is a reduction in its free level and a slow distribution to peripheral target tissues.[48,56]

When compared with NPH insulin, detemir appears to have less variability in absorption and less association with risk of hypoglycemia. It has a shorter time-action profile than glargine insulin: so - Type 1 patients are therefore indicated twice-daily injections.[57,58]

At present there are no data on the use of detemir in pregnancy.

The starting insulin dose can be calculated on the basis of the patient's weight[59]: for nonobese patients used doses are 0.8 U/kg and 0.9-1.0 U/kg in overweight and obese women, respectively. In a pregnant diabetic patient the rationale for insulin therapy is based on mimicking the physiology of insulin secretion. The basal insulin is supplied by the administration of NPH-lente-ultralente insulin at bedtime or both before breakfast and at bedtime. The meal-related (glucose excursion) insulin includes the use of insulin lispro or aspart before meals (0-15 min) or regular insulin before meals (30-45 min).[60] This algorithm characterized the intensified therapy (multiple injections daily) versus conventional therapy (one or two injection daily). If after 3-7 days the GDM patient does not achieve the desired level of glycemic control, the total insulin dose should increase from 10 to 20% and thereafter adjusted when needed.[1]

Conventionally, there are two methods for administering insulin: subcutaneous multiple daily injections (MDI) and continuous subcutaneous insulin infusion pump (CSII).

Randomized controlled trials have compared CSII with MDI for pregnant women with diabetes. There is not a strong evidence to support the use of a particular form of insulin administration over another for pregnant women with diabetes. The data are limited because of the small number of trials appropriate for meta-analysis, the small study sample size and the questionable generalizability of the trial. In conclusion, the current data available are incomplete and therefore a wide randomized trial is needed, adequately powered to assess the efficacy of CSII versus MDI in terms of appropriate outcomes for women with diabetes.[61,62]

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