We also must caution that the effectiveness of dietary change may be significantly less in many populations than it was in Dr. Landon’s study because his study focused on a subset of women who had only mild glucose intolerance. In our patient population, for example, we can achieve good glucose control with diet alone in about 60%-70% of cases.
The Science on Glyburide
Pharmacologic therapy for patients in whom dietary measures fail is no longer limited to insulin. Insulin is certainly still an option as a first-line therapy, and is necessary as an adjunct therapy in patients who are not achieving glucose targets with another agent. It has proven efficacy and well-studied pharmacokinetics. It does not cross the placenta, and research has shown that it may be beneficial by "resting" pancreatic islet cells. Moreover, several forms of insulin – short acting, intermediate, and long-acting – are available, so therapy can be fairly customizable.
Insulin is not an optimal therapy for GDM for several reasons, however. Many patients find it cumbersome to use, and most offices are not equipped for, or used to, teaching women how to give themselves the insulin injections. Insulin itself is also unfamiliar to many patients and can even be scary; some of the families we care for see insulin as a stigma, believing that a person who takes insulin has diabetes while a person who takes a pill does not truly have the condition.
In our practice, we have found that women who take oral hypoglycemics are more likely to have better glycemic control, probably because their drug compliance is better. With insulin, our patients tend to be suboptimally compliant.
Glyburide, one of the oral anti-hyperglycemic drugs that we have been able to transfer from use in the nonpregnant diabetic population to use during pregnancy, has been well-used and studied by this point in time.
When Dr. Oded Langer and his colleagues led the first and only randomized trial comparing glyburide and insulin more than a decade ago, women with GDM were rarely treated with a sulfonylurea drug largely because of reports of prolonged severe hypoglycemia in neonates born to mothers who were receiving the drug at the time of delivery. There were also questions about whether glyburide, a second-generation sulfonylurea, could effectively control postprandial peaks in blood glucose while avoiding periods of hypoglycemia in the mother.
In the nonpregnant population, glyburide has been used for decades as a twice-daily oral medication. After months of use, patients develop active metabolites that prolong the drug’s half life and enable it to last for 12 hours, at least.
Glyburide use in pregnancy is a slightly different story, however. Patients take the medication for a relatively short time and consequently may not build up the active metabolites that nonpregnant patients acquire. The metabolic changes in pregnancy also make women vulnerable to hypoglycemia at certain times of the day, typically in the late morning, the late afternoon, and between 3 a.m. and 4 a.m.
Dr. Langer’s trial, which randomized 404 women with GDM to receive glyburide or insulin, demonstrated similar outcomes in the insulin and glyburide groups. There were no differences in mean birth weight, the percentage of large for gestational age newborns, macrosomia, fetal anomalies, or newborn hypoglycemia. The rate of maternal hypoglycemia, however, was much higher in the insulin-treated group; 20% of the women receiving insulin experienced symptomatic hypoglycemia, compared with only 2% of the women taking glyburide.
In short, glyburide was just as effective as insulin in achieving desired levels of glycemic control (a fasting blood glucose less than 90 mg/dL and 2-hour postprandial glucose of 120 mg/dL) and controlling fetal obesity, while being significantly less likely to cause hypoglycemia in the mothers. (N. Engl. J. Med. 2000;343:1134-8).
Glyburide dosing in Dr. Langer’s trial was increased weekly, as needed, to a maximum of 20 mg per day; women took the drug twice a day. Insulin was administered per a standard intensified schedule of regular NPH (intermediate-acting, lasting 6-12 hours) and regular TID (lasting 2-4 hours).
Despite the impressive findings from the trial, some have contended that the results of one randomized trial are insufficient for adopting glyburide as a first-line therapy. However, numerous retrospective or case-controlled studies also have since shown glyburide to be a clinically effective alternative to insulin therapy, with no adverse neonatal or fetal effects. These studies have shown, moreover, that it can be easier to avoid hypoglycemia and achieve optimal glycemic control with glyburide than with insulin.
One of the best large retrospective studies looked at 584 women at Kaiser Permanente Northern California and found that glyburide was at least as effective as insulin in achieving glycemic control and resulted in similar birth weights in women with GDM who had failed diet therapy alone (Am. J. Obstet. Gynecol. 2005;193:118-24).