TY - JOUR
T1 - Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes
T2 - A Randomized Clinical Trial
AU - Rademaker, Doortje
AU - De Wit, Leon
AU - Duijnhoven, Ruben G.
AU - Voormolen, Daphne N.
AU - Mol, Ben Willem
AU - Franx, Arie
AU - Devries, J. Hans
AU - Painter, Rebecca C.
AU - Van Rijn, Bas B.
AU - Siegelaar, Sarah E.
AU - Akerboom, Bettina M.C.
AU - Kiewiet-Kemper, Rosalie M.
AU - Verwij-Didden, Marion A.L.
AU - Assouiki, Fahima
AU - Kuppens, Simone M.
AU - Oosterwerff, Mirjam M.
AU - Stekkinger, Eva
AU - Diekman, Mattheus J.M.
AU - Vogelvang, Tatjana E.
AU - Belle-Van Meerkerk, Gerdien
AU - Galjaard, Sander
AU - Verdonk, Koen
AU - Lub, Annemiek
AU - Klooker, Tamira K.
AU - Krabbendam, Ineke
AU - Van Wijk, Jeroen P.H.
AU - Huisjes, Anjoke J.M.
AU - Van Bemmel, Thomas
AU - Nijman, Remco G.W.
AU - Van Den Beld, Annewieke W.
AU - Hermes, Wietske
AU - Johannsson-Vidarsdottir, Solrun
AU - Vlug, Anneke G.
AU - Dullemond, Remke C.
AU - Jansen, Henrique J.
AU - Sueters, Marieke
AU - De Koning, Eelco J.P.
AU - Van Laar, Judith O.E.H.
AU - Wouters-Van Poppel, Pleun
AU - Evers, Inge M.
AU - Sanson-Van Praag, Marina E.
AU - Van Den Akker, Eline S.
AU - Brouwer, Catherine B.
AU - Hermsen, Brenda B.
AU - Scholten, Ralph
AU - Meijer, Rick I.
AU - Van Leeuwen, Marsha
AU - Wijbenga, Johanna A.M.
AU - Wijnberger, Lia D.E.
AU - Van Bon, Arianne C.
AU - Van Der Made, Flip W.
AU - Eskes, Silvia A.
AU - Zandstra, Mirjam
AU - Van Houtum, William H.
AU - Braams-Lisman, Babette A.M.
AU - Daemen-Gubbels, Catharina R.G.M.
AU - Nijkamp, Janna W.
AU - De Valk, Harold W.
AU - Wouters, Maurice G.A.J.
AU - Ijzerman, Richard G.
AU - Reiss, Irwin
AU - Van Der Post, Joris A.M.
AU - Bosmans, Judith E.
N1 - Publisher Copyright:
Copyright © 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
PY - 2025/1/6
Y1 - 2025/1/6
N2 - Importance: Metformin 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. Objective: To 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 Participants: Randomized, 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). Interventions: Participants 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 Measures: The 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. Results: Among 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 Relevance: Treatment 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.
AB - Importance: Metformin 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. Objective: To 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 Participants: Randomized, 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). Interventions: Participants 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 Measures: The 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. Results: Among 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 Relevance: Treatment 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.
UR - http://www.scopus.com/inward/record.url?scp=85215827552&partnerID=8YFLogxK
U2 - 10.1001/jama.2024.23410
DO - 10.1001/jama.2024.23410
M3 - Article
C2 - 39761054
AN - SCOPUS:85215827552
SN - 0098-7484
VL - 333
SP - 470
EP - 478
JO - JAMA
JF - JAMA
IS - 6
ER -
