• Doortje Rademaker, Leon de Wit, Ruben G Duijnhoven, Daphne N Voormolen, Ben Willem Mol, Arie Franx, J Hans DeVries, Rebecca C Painter, Bas B van Rijn, SUGAR-DIP Study Group, Sarah E Siegelaar, AkerboomBettina M CBMCDepartment of Obstetrics and Gynecology, Albert Schweitzer Hospital, Dordrecht, the Netherlands., Rosalie M Kiewiet-Kemper, Marion A L Verwij-Didden, Fahima Assouiki, Simone M Kuppens, Mirjam M Oosterwerff, Eva Stekkinger, Mattheus J M Diekman, Tatjana E Vogelvang, Gerdien Belle-van Meerkerk, Sander Galjaard, Koen Verdonk, Annemiek Lub, Tamira K Klooker, Ineke Krabbendam, Jeroen P H van Wijk, HuisjesAnjoke J MAJMDepartment of Obstetrics and Gynecology, Gelre Hospitals, Apeldoorn, the Netherlands., Thomas van Bemmel, Remco G W Nijman, Annewieke W van den Beld, Wietske Hermes, Solrun Johannsson-Vidarsdottir, Anneke G Vlug, Remke C Dullemond, Henrique J Jansen, Marieke Sueters, Eelco J P de Koning, van LaarJudith O E HJOEHDepartment of Obstetrics and Gynecology, Máxima Medical Center, Veldhoven, the Netherlands., Pleun Wouters-van Poppel, Inge M Evers, Marina E Sanson-van Praag, Eline S van den Akker, Catherine B Brouwer, Brenda B Hermsen, Ralph Scholten, Rick I Meijer, Marsha van Leeuwen, Johanna A M Wijbenga, WijnbergerLia D ELDEDepartment of Obstetrics and Gynecology, Rijnstate Hospital, Arnhem, the Netherlands., Arianne C van Bon, Flip W van der Made, Silvia A Eskes, Mirjam Zandstra, William H van Houtum, Braams-LismanBabette A MBAMDepartment of Obstetrics and Gynecology, Tergooi MC, Location Hilversum, Hilversum, the Netherlands., Catharina R G M Daemen-Gubbels, Janna W Nijkamp, Harold W de Valk, WoutersMaurice G A JMGAJDepartment of Obstetrics and Gynecology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Richard G IJzerman, Irwin Reiss, van der PostJoris A MJAMDepartment of Obstetrics and Gynecology, Amsterdam University Medical Center Location AMC, Amsterdam, the Netherlands.Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands., and Judith E Bosmans.
• Department of Obstetrics and Gynecology, Amsterdam University Medical Center Location AMC, Amsterdam, the Netherlands.
• JAMA. 2025 Jan 6.

ImportanceMetformin and glyburide monotherapy are used as alternatives to insulin in managing gestational diabetes. Whether a sequential strategy of these oral agents results in noninferior perinatal outcomes compared with insulin alone is unknown.ObjectiveTo test whether a treatment strategy of oral glucose-lowering agents is noninferior to insulin for prevention of large-for-gestational-age infants.Design, Setting, And ParticipantsRandomized, open-label noninferiority trial conducted at 25 Dutch centers from June 2016 to November 2022 with follow-up completed in May 2023. The study enrolled 820 individuals with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation who had insufficient glycemic control after 2 weeks of dietary changes (defined as fasting glucose >95 mg/dL [>5.3 mmol/L], 1-hour postprandial glucose >140 mg/dL [>7.8 mmol/L], or 2-hour postprandial glucose >120 mg/dL [>6.7 mmol/L], measured by capillary glucose self-testing).InterventionsParticipants were randomly assigned to receive metformin (initiated at a dose of 500 mg once daily and increased every 3 days to 1000 mg twice daily or highest level tolerated; n = 409) or insulin (prescribed according to local practice; n = 411). Glyburide was added to metformin, and then insulin substituted for glyburide, if needed, to achieve glucose targets.Main Outcomes And MeasuresThe primary outcome was the between-group difference in the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex). Secondary outcomes included maternal hypoglycemia, cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission.ResultsAmong 820 participants, the mean age was 33.2 (SD, 4.7) years). In participants randomized to oral agents, 79% (n = 320) maintained glycemic control without insulin. With oral agents, 23.9% of infants (n = 97) were large for gestational age vs 19.9% (n = 79) with insulin (absolute risk difference, 4.0%; 95% CI, -1.7% to 9.8%; P = .09 for noninferiority), with the confidence interval of the risk difference exceeding the absolute noninferiority margin of 8%. Maternal hypoglycemia was reported in 20.9% with oral glucose-lowering agents and 10.9% with insulin (absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). All other secondary outcomes did not differ between groups.Conclusions And RelevanceTreatment of gestational diabetes with metformin and additional glyburide, if needed, did not meet criteria for noninferiority compared with insulin with respect to the proportion of infants born large for gestational age.Trial RegistrationNetherlands Trial Registry Identifier: NTR6134.

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