What's the Best First-Line Tx for Gestational Diabetes?

Glyburide versus subcutaneous insulin did not result in a greater frequency of perinatal complications

Study findings did not support noninferiority of an oral second-generation sulfonylurea for prevention of perinatal complications of gestational diabetes, researchers reported.

Glyburide failed to show noninferiority for the prevention of perinatal complications -- defined as a composite of macrosomia, neonatal hypoglycemic, and hyperbilirubinemia -- versus subcutaneous insulin among women diagnosed with gestational diabetes between 24 and 34 weeks of gestation (27.6% glyburide versus 23.4% insulin, 1-sided 97.5% CI −∞ to 10.5%, P=0.19), reported Marie-Victoire Sénat, MD, PhD, of Hôpital Bicêtre in France, and colleagues.

The findings of the multicenter, randomized Insulin Daonil (INDAO) trial did not meet the prespecified noninferiority margin of 7%, they wrote in the Journal of the American Medical Association.

The authors concluded that glyburide treatment failed to show it doesn't result in more complications compared with subcutaneous insulin, which is recommended by the American Diabetes Association as first-line treatment in these patients.

The American Association of Clinical Endocrinologists (AACE) highlight that women should be aware that glyburide treatment is not currently FDA approved for use during pregnancy, but "exhibits minimal transfer across the placenta" according to the various formulations. The AACE noted that "several studies have found no harmful effects from glyburide in either early or late pregnancy and have reported effective glycemic control with favorable neonatal outcomes including reduced rates of macrosomia, neonatal intensive care unit admissions, and neonatal hypoglycemia."

Sénat's group conducted this study because of the fact that glyburide is "more convenient for patients, with greater ease of administration and reduced costs" compared with other treatments such as insulin with self-monitoring of blood glucose. However, they stressed "these findings do not justify the use of glyburide as a first-line treatment," adding how "the higher rate of the primary outcome in the glyburide group was mainly due to an increased rate of neonatal hypoglycemia."

The trial included pregnant women from 13 tertiary care enters in France diagnosed who required pharmacologic intervention following 10 days of dietary intervention. Of these women, 460 were assigned to glyburide and 454 to subcutaneous insulin.

Women assigned to receive glyburide started at a once-daily oral dose of 2.5 mg that increased by 2.5 mg, 4 days after initiation. Following an initial increase, patients could be increased by 5 mg every 4 days to a maximum daily dose of 20 mg/day. Women on subcutaneous insulin started at a dose between 4 IU and 20 IU administered one to four times daily and could later be increased as needed.

In regards to the composite primary endpoint outcomes, macrosomia was defined as a birth weight over 4,000 g (8.82 lbs) or over the 90th percentile for gestational age. Hyperbilirubinemia was considered as requirement for phototherapy without having another cause of jaundice, while neonatal hypoglycemia was considered a blood glucose value <36 mg/dL after the first 2 hours of life.

In an adjusted model for gestational age at treatment and including multiparity, the frequency of complications was still similar between the groups (difference 4.4%, 1-sided 97.5% −∞ to 10.5%, P=0.20).

"Although the data do not allow a conclusion that glyburide is not inferior to insulin in the prevention of perinatal complications, the results suggest that the increase in complications may be no more than 10.5% compared with insulin," the authors wrote, recommending that this finding "should be balanced with the ease of use and better satisfaction with glyburide."

"In clinical situations in which an oral agent may be necessary, mothers, informed by their physicians, would be appropriate decision makers based on their own weighing of benefits and risks," they suggested.

In an accompanying editorial, Donald R. Coustan, MD, of Warren Alpert Medical School of Brown University in Providence, Rhode Island, and Linda Barbour, MD, MSPH, of University of Colorado School of Medicine in Aurora, agreed on weighing the individual benefits with potential risk. However, they also pointed out that "failure to demonstrate noninferiority does not mean that glyburide is inferior to insulin."

Coustan and Barbour also highlighted there was no information provided on the exact timing of glyburide administration, noting that titration and mealtime administration may affect the outcomes. They also suggested future studies should specifically look at long-term outcomes of in utero glyburide treatment on offspring, as well as if glyburide levels are high enough to possibly stimulate fetal insulin or may have the ability to exposure the fetal pancreas to an insulin secretagogue during critical stages of development.



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