ESPE Yearbook of Paediatric Endocrinology

JAMA. 2025;333(6):470–478. doi: 10.1001/jama.2024.23410

Brief Summary: This randomized noninferiority trial evaluated whether a sequential oral glucose-lowering strategy (metformin, followed by glyburide if needed) is noninferior to insulin in preventing large-for-gestational-age (LGA) infants in gestational diabetes.

Conducted at 25 Dutch centers with 820 participants between 16–34 weeks of gestation, all had inadequate glycemic control on dietary management. Participants were randomized to oral agents (n = 409) or insulin (n = 411). Metformin was initiated and up-titrated, with glyburide added if targets were not met. Primary outcome was infants born LGA (>90th percentile). LGA occurred in 23.9% of infants in the oral agent group vs 19.9% in the insulin group (absolute risk difference, 4.0%; 95% CI: −1.7% to 9.8%); the upper confidence interval exceeds the predefined noninferiority margin, 8%. Notably, 79% of women in the oral agents arm maintained glycemic control without requiring insulin. However, maternal hypoglycemia occurred more often with oral agents (20.9% vs 10.9%). No significant differences were found for other secondary outcomes, including caesarean delivery, preterm birth, or neonatal complications.

This study suggests that while most women managed gestational diabetes successfully with oral agents, the strategy did not meet statistical criteria for noninferiority to insulin in preventing LGA births. Findings support continued prioritization of insulin therapy for optimal perinatal outcomes.