Clinical Review

Gestational diabetes and oral hypoglycemic agents: A fresh look at the safety profile

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Although insulin has been the treatment of choice when dietary measures fail, oral hypoglycemic drugs are increasingly recognized as safe and effective.


 

References

KEY POINTS
  • Well-designed studies have found no association between oral hypoglycemic agents and congenital malformations. Data suggest that glyburide and possibly metformin are safe and effective for gestational diabetes.
  • Reserve medical therapy with oral agents for patients whose fasting plasma glucose levels remain above 95 mg/dL (or postprandial levels above 120 mg/dL) despite diet therapy, and for those who are not appropriate candidates for diet therapy alone.
  • Substitute combination or insulin therapy for oral therapy if desired levels of glucose control are not achieved.

Although use of oral hypoglycemic and antihyperglycemic agents in pregnancy has long been thought to increase the risk of fetal anomalies, 2 trials within the past decade indicate otherwise. In those trials, blood glucose levels—rather than the drugs themselves—were responsible for the greater rate of anomalies.1,2

As a result, oral hypoglycemic agents are gaining recognition as a safe and effective alternative to insulin when diet alone fails to optimize the glycemic profile in gestational diabetes. Sulfonylureas are the only oral agents that have been studied in randomized, controlled trials in women with gestational diabetes,3 but other drugs may have an even greater therapeutic effect. Indeed, use of these other agents for type 2 diabetes has become the standard of care for the nongravid patient.4,5 Only recently has their use in pregnancy become arguable in US scientific forums.

Ninety percent of gravidas with diabetes—the most common medical complication of pregnancy—have gestational diabetes, and a significant number (20% to 50%) develop type 2 diabetes within 10 years.6 Both gestational and type 2 diabetes are characterized by peripheral insulin resistance, decreased insulin secretion (declining betacell function), and impaired regulation of hepatic glucose, each of which represents a different point in the continuum of deteriorating glucose tolerance.

Intensified therapy can maximize pregnancy outcome by decreasing the rates of macrosomia, metabolic and respiratory complications, shoulder dystocia, neonatal intensive care admission, and other complications to rates found in the general population. This treatment approach requires self-monitoring of blood glucose several times daily using a memory reflectance meter, adherence to proper criteria when initiating glyburide or insulin therapy (ie, fasting plasma glucose <90 mg/dL), and achievement of targeted glycemic control.7

Here, a specific treatment plan is offered along with a review of the evidence on use of oral agents in pregnancy. In addition, earlier interpretations that may have distorted the overall picture are discussed.

Studies of oral hypoglycemics and fetal anomalies

Early case reports and small-scale studies suggested an association between oral hypoglycemic agents and congenital anomalies. This anecdotal evidence was even translated into guidelines by the American College of Obstetricians and Gynecologists and the American Diabetes Association, among others. Unfortunately, these guidelines were based largely on a retrospective study involving 20 women with type 2 diabetes—all with glycosylated hemoglobin A1c concentrations exceeding 8%—in whom there was an increased rate of anomalies.8 However, the fact that maternal hyperglycemia existed prior to conception makes it impossible to determine whether the increased rate of anomalies was the result of medication or elevated glucose levels.

Other drawbacks of studies from this time: Few of the agents investigated are in common use today; most studies reported perinatal mortality and congenital anomalies, but failed to address neonatal morbidity; and many subjects had type 2 diabetes.9-15

In the past decade, 2 studies have suggested there is no association between oral hypoglycemic agents and congenital malformations. For example, no significant adverse effects associated with oral therapy were found in a study of 332 women with type 2 diabetes treated with diet therapy, exogenous insulin, or sulfonylurea compounds during the first 8 weeks of gestation.1 However, the level of glycemia and maternal age contributed significantly to the rate of anomalies.

Do oral hypoglycemic agents cross the placenta?

Among the factors that determine the placental transfer capability of a drug are molecular weight, pKa, lipid solubility, placental blood flow, blood protein binding, and elimination half-life.

In the early 1990s, my colleagues and I evaluated the potential of first-generation and second-generation sulfonylureas to cross the placenta, and found no significant transport of glyburide in the maternal-to-fetal and fetal-to-maternal directions.1 Even increasing the glyburide concentration to 100 times the therapeutic level did not alter transport noticeably. Glyburide remained undetected when cord blood was analyzed using high-performance lipid chromatography with appropriate gradient concentration between the maternal and fetal sites.2 Moreover, at least 99.8% of the glyburide was bound to protein. Thus, glyburide was neither metabolized nor appropriated by the placenta.

In a second series of studies, we found that second-generation oral hypoglycemic agents—especially glyburide—did not significantly cross diabetic and nondiabetic placentae.3,4 Fetal concentrations reached no more than 1% to 2% of maternal concentrations. Glipizide crossed the placenta in small amounts that were significantly higher than glyburide. Tolbutamide diffused across the placenta most freely.

REFERENCES

1. Elliot B, Langer O, Schenker S, Jonhson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol. 1991;165:807-812.

2. Langer O. Oral hypoglycemic agents and the pregnant diabetic: “from bench to bedside.” Semin Perinatol. 2002;26:215-224.

3. Elliot B, Schenker S, Langer O, Johnson R, Prihoda T. Comparative placental transport of oral hypoglycemic agents. A model of human placental drug transfer. Am J Obstet Gynecol. 1994;171:653-660.

4. Elliot B, Langer O, Schussling F. A model of human placental drug transfer. Am J Obstet Gynecol. 1997;176:527-530.

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