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

Oral Antidiabetic Agents

Traditionally, insulin therapy has been considered the gold standard for management because of its efficacy in achieving tight glucose control and the fact that it does not cross the placenta. Insulin is, however, an expensive and invasive treatment. Insulin therapy involves daily injections, and patient compliance is often suboptimal. Women would prefer tablets rather then multiple injections.[63]

A less invasive, more acceptable alternative that could enhance patient compliance while achieving similar perinatal outcome, would be a welcome replacement. Since GDM and Type 2 diabetes are characterized by insulin resistance and relatively decreased insulin secretion, a treatment with oral hypoglycemic agents could be of potential interest. The use of oral agents is a pragmatic alternative to insulin therapy in pregnancy because of easy administration and patient's satisfaction due to a noninvasive treatment. However, even taking into account these considerations, the introduction of a new drug is unjustified if improvements in pregnancy outcomes and cost-effectiveness are not definitively demonstrated. Different oral hypoglycemic and anti-hyperglycemic agents act upon diverse mechanisms of action. These drug characteristics provide an enhanced physiological approach to the treatment of Type 2 diabetes and GDM in comparison to insulin.

In Europe and in South Africa, glyburide and metformin have been used for years without reported adverse side-effects to the fetus. The main restraint to their use in pregnancy is the risk of developing congenital anomalies, fetal compromise and fetal hypoglycemia through direct stimulation of the fetal pancreas. Therefore, the ACOG and the ADA do not currently recommend oral hypoglycemic agents. The recommendation does not take into account the fact that congenital anomalies cannot be the result of pharmacological agents after the first trimester.[2]

Few data exist regarding the use of acarbose (oral α-glucosidase inhibitor) in pregnancy. In a prospectively randomized controlled trial on GDM patients' adverse reactions or fetal anomalies have not been demonstrated in the acarbose group, but 6% required insulin therapy due to inability to tolerate dosage increases. Initial acarbose dosing was 25 mg orally three- times daily, increased to a maximum of 100 mg orally three-times daily.[64] Both in this trial and in a perspective preliminary study, efficacy in reducing post-prandial glucose excursions in GDM has been shown, but with the expected high frequency of abdominal cramping.[65] A small proportion of this drug may be absorbed systematically, and safety and potential transplacental passage have not been fully evaluated.

Use of thiazolidinediones, glinides and glucagon-like peptide 1 agonists during pregnancy are considered experimental. There are no controlled data available in pregnancy and one study reported that rosiglitazone crossed the human placenta at 10-12 weeks' gestation, with fetal tissue levels measured at approximately half of maternal serum levels. Ex vivo human placental perfusion studies of glucagon-like peptide 1 agonist detected minimal levels on the fetal side.[14]

Most data regarding oral antidiabetic drug safety in pregnancy are regarding glyburide. To date, 1261 women treated with glyburide have been described in the iterature. Sulfonylureas are currently the only drugs to be studied in GDM women in randomized controlled trials. In vitro studies on nondiabetic and diabetic placentas showed that glyburide does not cross the placenta in a significant amount (4% ex vivo). In mothers treated with therapeutic doses of glyburide, the drug was undetectable in the cord blood of their neonates.[66] Since glyburide has been demonstrated to have minimal transfer across the human placenta, it cannot determine neonatal hypoglycemia or fetal anomalies. In addition, most GDM patients are identified between 24 and 28 weeks' gestation and the fetus could be exposed to the drug during organogenesis. Glyburide is not present in the milk of lactating mothers when measured in vivo and in vitro.[67]

Glyburide increases insulin secretion, and it decreases insulin resistance by reducing glucose toxicity. Its onset of action is approximately 4 h, and its duration of action is approximately 10 h. The starting dose is 2.5 mg orally in the morning. If the targeted level of glycemia is not reached, 2.5 mg could be added to the morning dose. If indicated (after 3-7 days), a further 5 mg could be added in the evening. Thereafter, the dose could be increased by 5 mg to a total of 20 mg/day. If patients fail to achieve glycemic objectives, long-acting insulin can be added to the regimen.[66]

The efficacy of glyburide in achieving glycemic control was confirmed by several studies. For all glycemic ranges glyburide-treated and insulin-treated subjects had a similar success rate in achieving targeted glucose levels and favorable pregnancy outcomes.[68] Adequate glycemic control was obtained in the glyburide group with significantly fewer hypoglycemic episodes than in the insulin group.[66] Using a CGM system recording data every 5 min for 72 h continuously, with 288 measurements a day, asymptomatic hypoglycemic events (> 30 consecutive minutes with glucose values < 50 mg/dl) occurred in 63% of subjects receiving insulin compared with 28% of subjects receiving glyburide.[69] The insulin-treated patients and the glyburide-treated patients obtained comparable results for many outcomes: cord serum insulin concentrations, incidence of macrosomia, increased Ponderal Index, percentage of large for gestational age infants, and prevalence of neonatal metabolic complications, respiratory complications, pre-eclampsia and cesarean delivery. The perinatal outcomes in the glyburide and the intensified-treated subjects were comparable.[66] Among women achieving targeted goals, there was overall satisfaction about the mode of therapy.[63] A recent report from a large managed care organization on more than 500 patients found that glyburide was at least as effective as insulin in achieving glycemic control and adequate birth weights in offspring of women who failed with diet. The authors, however, reported an increased risk of pre-eclampsia and a higher need for phototherapy in the glyburide group.[70] This is the first and only report of adverse pregnancy outcomes with glyburide.[71] There is some evidence that glyburide may be less successful in obese patients or those with marked hyperglycemia earlier in pregnancy.[72]

It was observed that glyburide is considerably less expensive than insulin (average saving per patient: US$166-200 based on rates in 2000).[73] Glyburide is a cost-effective, acceptable, potentially adherence-enhancing therapy that leads to perinatal outcomes similar to those of insulin therapy.

Metformin is currently approved by the US FDA to be used in the treatment of Type 2 diabetes. Its off-label use in the treatment of infertility caused by polycystic ovary syndrome (PCOS) has increased over the past decade. Therefore, despite the discontinuation of metformin by experts, as soon as a diagnosis of pregnancy is confirmed, it is not unusual for PCOS women to be exposed to metformin during part or the entire period of embryogenesis.[74] The drug efficacy in reversing known defects responsible for insulin resistance, and its safety with respect to hypoglycemia, suggest that it may represent an ideal drug for a primary prevention study in GDM.

Metformin is classified as a category B drug, which implies that there is no evidence of animal or fetal toxicity or teratogenicity. Reproduction studies in rats and rabbits demonstrated no teratogenicity at doses up to 600 mg/kg per day, approximately twice the maximum recommended human dose.[2] A partial placental barrier to metformin was observed on comparison of fetal and maternal drug concentrations. On the basis of many studies, in Type 2 diabetes the prevalence of malformations in the metformin group is 1.7%, which is well within the baseline rate for malformation in the general population.[75] A recent meta-analysis shows that, on the basis of eight small and nonblinded studies available from 1966 and 2006, metformin does not appear to be unsafe to be used during pregnancy with respect to major malformations.[74] The concentration of metformin in breast milk is generally low and mean infant exposure to the drug is clearly below the 10% level. Therefore, use of metformin by breast-feeding mothers is safe.[76,77]

Metformin lowers glucose levels by decreasing peripheral insulin resistance, hepatic production and intestinal absorption of glucose and by decreasing increasing peripheral uptake and utilization of glucose. Furthermore, metformin does not stimulate insulin secretion and does not cause hypoglycemia. Metformin does not stimulate the fetal pancreas to oversecrete insulin.[2] The incidence of lactic acidosis with metformin is approximately 0.03 cases per 1000 patients annually. The risk of developing lactic acidosis in a healthy young cohort is less than theoretical and this should not be used in the decision-making process for drug selection in pregnancy. In fact, in several studies the drug has been used through pregnancy without reported maternal acidosis.[63]

Metformin peak levels occur within 4 h. Its absorption is reduced in the presence of food, although it should be administered with meals to minimize gastrointestinal intolerance. The elimination half-life is approximately 6 h. It is recommended that metformin is introduced gradually in 500- or 850-mg increments to a maximum of 2000 mg daily. Intermittent diarrhea or gastritis are common in the first 3 weeks of metformin therapy but, generally, they resolve spontaneously. In Australasia, a prospective, randomized, open-label, multicenter trial comparing metformin with insulin treatment in women with GDM (The Metformin in Gestational Diabetes trials), is in progress. Metformin is prescribed at a starting dose of 500 mg for the first day and increased up to 2500 mg as tolerated, depending on maternal glucose level. If inadequate diabetes control is achieved, insulin is started and metformin continued.[2] According to the few studies found in the literature, 30% of women treated with metformin required insulin to obtain adequate glycemia control.[78]

In PCOS, use of metformin is associated with a tenfold reduction in gestational diabetes (from 31 to 3%)[79] and it is safely associated with spontaneous abortion reduction (from 73 to 10%).[80] In a subset of women with prior history of miscarriage, early pregnancy loss rate was 11.1% in the metformin group versus 58.3% in the controls (p = 0.002).[81] In PCOS, metformin use does not adversely affect birth length and weight, growth or motor-social development in the first 18 months of life.[82] There is no evidence of congenital defects, intrauterine growth retardation and neonatal hypoglycemia requiring intervention.[79,80] Placental weight, Apgar scores and pH of the umbilical vein do not differ.[83] These findings in nondiabetic women are supported by the extensive clinical experience in women with diabetes.[84,85,86] There is, however, one published study that reports an increased perinatal loss rate in a cohort of women with GDM and Type 2 diabetes mellitus treated with metformin between 1966 and 1991 (n = 50), when compared with reference group treated with insulin.[87] The study was retrospective and poorly controlled, with outcomes unrelated to the treatment. One of the four fetal losses occurred in a women to whom metformin was administrated for a week, another occurred in a women who had severe fetal growth restriction prior to starting metformin and the remaining two women were noncompliant patients with poor glycemic control.[78] In the same study, the author reported that treatment with metformin during pregnancy was associated with an increased prevalence of pre-eclampsia and higher perinatal mortality.[87] These data have not been confirmed either in a cohort of women with PCOS[88] or in a recent study that reviewed pregnancy outcome in 93 women with Type 2 diabetes mellitus treated with metformin. In this study, no differences in the rate of pre-eclampsia, perinatal loss or neonatal morbidity (including rate of prematurity, neonatal unit admission, respiratory distress and treatment with intravenous dextrose), were found between the metformin and control group.[86]

At the moment, considering all the studies published until now, the Committee of the Fifth International Workshop Conference on Gestational Diabetes Mellitus has concluded that there is no evidence to recommend metformin treatment for GDM except in clinical trial which should include long-term follow- up of infants.[14]

In summary, most current studies demonstrate that oral hypoglycemic agents, such as glyburide and metformin, are safe to use in pregnancy with maternal and perinatal outcomes similar to insulin treatment, but there is a need for a randomized controlled trial in women with Type 2 diabetes and GDM in pregnancy with long-term follow up of both mothers and children.[72]

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