Seventy-nine percent of patients with gestational diabetes maintained glycemic control using metformin and glyburide, but this strategy failed to demonstrate noninferiority to insulin in preventing large-for-gestational-age infants, according to a recent study.

A randomized clinical trial assessed whether a sequential oral glucose-lowering strategy starting with metformin and adding glyburide, if needed, was noninferior to insulin for preventing large-for-gestational-age (LGA) infants in gestational diabetes. Published in JAMA, the study, part of the SUGAR-DIP trial, was performed at 25 Dutch centers from 2016 to 2022 and included 820 patients with singleton pregnancies diagnosed with gestational diabetes who had insufficient glycemic control after two weeks of dietary modifications.

Patients were randomized to receive either metformin (n=409), titrated up to 1000 mg twice daily, or insulin (n=411). If glycemic targets were not met in the metformin group, glyburide was added at doses of 2.5 to 15 mg daily, with insulin initiated as a final step. The primary outcome was the proportion of infants born LGA, defined as a birth weight exceeding the 90th percentile for gestational age and sex. Secondary outcomes included maternal hypoglycemia, cesarean delivery, preeclampsia, neonatal hypoglycemia, and neonatal intensive care unit admission.

The incidence of large-for-gestational-age (LGA) infants was 23.9% (97/406) in the oral glucose-lowering group and 19.9% (79/398) in the insulin group (absolute risk difference, 4.0%; 95% CI, −1.7% to 9.8%; P=0.09 for noninferiority). Noninferiority was not established, as the upper confidence limit exceeded the prespecified margin of 8%. Maternal hypoglycemia occurred more frequently in the oral agent group (20.9%) compared with the insulin group (10.9%; absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). Other secondary outcomes, including cesarean delivery, neonatal hypoglycemia, and NICU admission, did not differ significantly between the groups. Additionally, 79% of participants in the oral glucose-lowering group maintained glycemic control without requiring insulin.

Additional Findings

Adverse Effects:
Adverse effects were more common among participants receiving oral agents compared to those receiving insulin. Nausea (39% vs. 13%), diarrhea (39% vs. 5%), and vomiting (15% vs. 1.7%) were reported significantly more often in the oral agent group.

Exploratory Outcomes:
Intravenous glucose therapy was required more frequently in the oral agent group compared to the insulin group (6.4% vs. 3.2%), although no significant differences were observed in other exploratory neonatal outcomes.

Patient Satisfaction:
Patients receiving oral glucose-lowering agents reported higher satisfaction with their treatment. They were more likely to recommend the therapy to others and expressed greater satisfaction with continuing their current regimen.

Subgroup Analysis:
No significant differences were observed across key subgroups, including by ethnicity, age, and body mass index (BMI). This reinforces the broad applicability of the findings across diverse populations.

The findings indicate that an oral glucose-lowering strategy reduced insulin dependency, with 79% of patients maintaining glycemic control without insulin. However, higher rates of maternal hypoglycemia and the inability to demonstrate noninferiority emphasize the importance of evaluating treatment options on an individual basis. These results provide comparative data on the efficacy and safety of oral agents versus insulin in gestational diabetes management.

Full disclosures can be found in the published study.