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Oral Antihyperglycemic Agents and Diabetes in Pregnancy

It is well recognized that the complications and adverse perinatal outcomes associated with gestational diabetes and type 2 diabetes in pregnancy are glucose dependent. The main question in medical management, therefore, is how to maximize glycemic control.

The choice of medication should be determined by the ability of the drug to achieve the targeted level of glycemic control. For some patients, oral antihyperglycemic agents will be the drug of choice while in others combination therapy and/or insulin should be used.

For years, pharmacologic therapy for diabetes in pregnancy was limited to insulin. Obstetricians feared that oral antihyperglycemic agents, as an alternative to insulin therapy, could cause adverse pregnancy outcomes, particularly congenital anomalies and metabolic complications. Because of these concerns, sulfonylurea drugs were contraindicated in pregnancy.

These recommendations were founded, however, on anecdotal reports and poorly designed retrospective studies that were performed prior to the availability of second-generation sulfonylureas such as glyburide.

Today, there is clear evidence from in vivo and in vitro studies that glyburide does not cross the placenta in any appreciable quantity while metformin, another oral glucose-lowering agent, crosses the placenta freely.

Several randomized studies (five glyburide and two metformin studies), as well as other well-designed studies published over the last decade, also have demonstrated that glyburide is as effective and safe as insulin therapy for glycemic control during pregnancy.

Research has shown, moreover, that it's the blood glucose levels—not the drugs themselves—that cause adverse outcomes.

This is good news, because the use of oral antihyperglycemic agents enhances drug compliance for the patient.

Taking a tablet once in the morning and once in the evening is easier, more convenient, and less expensive than giving oneself insulin injections several times a day. Given the choice of insulin injections versus tablets, almost all women will opt for the latter.

Offering glyburide as a safe and effective alternative to insulin has been recommended by several editorials and professional organizations. Indeed, the use of glyburide has become the standard of care in the management of gestational diabetes mellitus (GDM) in many centers and private practices throughout the United States.

It is important to appreciate, however, that in general, as disease severity increases, there is diminishing success in achieving the desired levels of glycemic control.

Although the majority of women with gestational diabetes will benefit from the use of these drugs (approximately 80%), fewer women with type 2 diabetes will be able to achieve optimal glycemic control.

The emphasis overall in diabetes management must therefore be on the level of glycemic control achieved by the patient, with the failure of a drug signaling the need to change the drug algorithm.

Safety, Efficacy of Glyburide

Oral antihyperglycemic drugs—most commonly glyburide and metformin—are the first-line drugs for treating nonpregnant women with type 2 diabetes. These patients are typically older and suffer from greater disease severity (higher fasting and postprandial blood glucose levels and a decreased pancreatic reserve of 50%-80%). They therefore are not comparable to patients with gestational diabetes who are relatively younger and have greater pancreatic reserve.

This begs the following question: If the oral antihyperglycemic drugs are in fact safe for the fetus and can potentially optimize glycemic control—enabling patients to reach targeted levels of glucose control in pregnancy with the same efficacy as insulin—why should GDM patients who represent the milder form of intolerance on the glucose continuum not be treated with these drugs?

In the early 1990s, my colleagues and I evaluated the potential of first-generation and second-generation sulfonylureas to cross the placenta. Using the single-cotyledon placental model—a model that is widely used to characterize the transport and metabolism of drugs and nutrients—we found only minimal transport of glyburide in either the maternal-fetal or the fetal-maternal direction (Am. J. Obstet. Gynecol. 1991;165:807-12).

The transfer of glyburide remained negligible even when we varied the albumin concentration and increased maternal glyburide levels to 100 times the therapeutic level. In no case was there any appreciable metabolism of the agent. First-generation sulfonylureas, on the other hand, crossed the placenta in this model. Metformin did as well, almost freely.

Thereafter, several studies from different centers confirmed that glyburide does not cross the placenta significantly. The studies demonstrated, for instance, that 99.8% of the glyburide is bound to albumin, that the agent has a short elimination half-life, and that effluxes are affected from the fetal-maternal direction. Research also confirmed that metformin does cross the placenta.

In a later prospective, randomized trial comparing glyburide and insulin in 404 women with GDM, my colleagues and I found no significant differences in either the degree of glycemic control or perinatal outcomes (N. Engl. J. Med. 2000;343:1134-8). Target levels of glycemic control were achieved in 82% of the patients receiving glyburide and 88% of those receiving insulin.


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