Glyburide as effective as insulin for gestational diabetes [Classics Series]

Classics Series, Landmark Trials in Medicine

1. Among women with gestational diabetes requiring treatment, those randomized to glyburide achieved similar glycemic control to women in the insulin control group.

Original Date of Publication: October 2000

Study Rundown: The adverse pregnancy outcomes associated with diabetes have been well documented. Following diagnosis, women with gestational diabetes mellitus are initially managed with dietary therapy, termed modified nutritional therapy (MNT). If glycemic control is not achieved with MNT, the next step in treatment is the initiation of insulin therapy. Insulin is well-studied in pregnancy and known to be highly effective and safe. Yet, insulin is an expensive and onerous treatment that can be cumbersome to learn, inconvenient and difficult to adhere to, and painful for patients. Oral agents are a well-established treatment for insulin-dependent diabetes outside of pregnancy. They have been infrequently used in pregnancy, however, due to demonstrated risks of neonatal hypoglycemia associated with early-generation sulfonylurea drugs and metformin, both of which cross the placenta. Sulfonylurea drugs improve glycemic control by increasing insulin secretion, which decreases hepatic glucose production and thereby indirectly improves insulin sensitivity. Subsequent to these investigations, however, newer oral hypoglycemic agents were developed, including glyburide. Study authors of the present work investigated the pharmacologic profile of glyburide in pregnant women and found that glyburide does not cross the human placenta in any meaningful concentration. Given this low likelihood that glyburide crosses the placenta and the mild degree of hyperglycemia affecting most women with gestational diabetes, authors postulated that treatment with glyburide might achieve glycemic control similar to that of insulin therapy while also offering a more convenient and cost-effective option.

This landmark study demonstrated that women with gestational diabetes randomized to glyburide achieved similar glycemic control and no increased incidence of adverse neonatal or maternal complications compared to women in the insulin control group. Strengths included randomized design. Single-center design, lack of blinding and lack of long-term follow-up limited applicability of findings but should not impact internal validity. Because adverse maternal and fetal outcomes associated with sulfonylurea treatment in pregnancy may have gone undetected in the present work, further investigation employing multi-center design, long-term follow-up data and most notably a large sample size (powered to minimize Type II error) is merited before glyburide can be routinely recommended as an acceptably safe alternative to insulin.

Click to study in NEJM

Dr. Alan Peaceman, MD, talks to 2 Minute Medicine: Northwestern University School of Medicine; Chief, Division of Obstetrics and Gynecology-Maternal Fetal Medicine.

“This landmark trial was the first to demonstrate that that glyburide is an effective alternative to insulin for treatment of gestational diabetes. Findings suggest that this oral agent is an efficacious treatment, though multi-center investigation with longer-term follow-up data is merited.”

In-Depth [randomized trial]: A total of 404 women with ongoing singleton pregnancy between 11 and 33 weeks gestational age with gestational diabetes requiring medical treatment were randomized to the oral agent glyburide (n=201) or standard therapy with insulin (n=203). Primary outcomes included achievement of glycemic control, defined as the mean blood glucose concentration between 90 and 105mg/dL. Secondary outcomes assessed included neonatal and maternal complications. All were assessed by intention to treat analysis.

Among women with gestational diabetes requiring medical treatment, there was no difference in glycemic control as measured by mean blood glucose concentration between those randomized to glyburide and those in the insulin control groups (105 vs. 105mg/dL, P=0.99). There were no differences between groups in the incidences of fetal macrosomia, large for gestational age infants, fetal hypoglycemia or fetal anomalies. Glyburide was not detected in the cord blood of any infant in the glyburide treatment group.

Image: PD

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