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Comparative Study
. 2025 Feb 11;333(6):470-478.
doi: 10.1001/jama.2024.23410.

Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial

Doortje Rademaker  1   2 , Leon de Wit  3 , Ruben G Duijnhoven  1   4 , Daphne N Voormolen  3 , Ben Willem Mol  5   6 , Arie Franx  7 , J Hans DeVries  8 , Rebecca C Painter  2   9 , Bas B van Rijn  10   11 ; SUGAR-DIP Study Group; Sarah E Siegelaar  8   12 , Bettina M C Akerboom  13 , Rosalie M Kiewiet-Kemper  14 , Marion A L Verwij-Didden  15 , Fahima Assouiki  16 , Simone M Kuppens  17 , Mirjam M Oosterwerff  18 , Eva Stekkinger  19 , Mattheus J M Diekman  20 , Tatjana E Vogelvang  21 , Gerdien Belle-van Meerkerk  22 , Sander Galjaard  23 , Koen Verdonk  24 , Annemiek Lub  25 , Tamira K Klooker  26 , Ineke Krabbendam  27 , Jeroen P H van Wijk  28 , Anjoke J M Huisjes  29 , Thomas van Bemmel  30 , Remco G W Nijman  31 , Annewieke W van den Beld  32 , Wietske Hermes  33 , Solrun Johannsson-Vidarsdottir  34 , Anneke G Vlug  35 , Remke C Dullemond  36 , Henrique J Jansen  37 , Marieke Sueters  38 , Eelco J P de Koning  39 , Judith O E H van Laar  10 , Pleun Wouters-van Poppel  40 , Inge M Evers  41 , Marina E Sanson-van Praag  42 , Eline S van den Akker  43 , Catherine B Brouwer  44 , Brenda B Hermsen  43 , Ralph Scholten  45 , Rick I Meijer  46 , Marsha van Leeuwen  47 , Johanna A M Wijbenga  48 , Lia D E Wijnberger  49 , Arianne C van Bon  50 , Flip W van der Made  51 , Silvia A Eskes  52 , Mirjam Zandstra  53 , William H van Houtum  54 , Babette A M Braams-Lisman  55 , Catharina R G M Daemen-Gubbels  56 , Janna W Nijkamp  3 , Harold W de Valk  57 , Maurice G A J Wouters  9 , Richard G IJzerman  8   12 , Irwin Reiss  58 , Joris A M van der Post  1   2 , Judith E Bosmans  59
Affiliations
Comparative Study

Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial

Doortje Rademaker et al. JAMA. .

Abstract

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.

Trial registration: Netherlands Trial Registry Identifier: NTR6134.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mol reported receipt of grants, personal fees, and nonfinancial support from Merck; personal fees from Organon; and nonfinancial support from Norgine. Dr Painter reported grants from ZonMW outside the submitted work and grants from Leading the Change. Dr Belle–van Meerkerk reported receipt of personal fees from Lilly and organizing a conference sponsored by Lilly, Novo Nordisk, Boehringer Ingelheim, and Sanofi. Dr Meijer reported receipt of grants from the Dutch Diabetes Research Foundation. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Participants in the SUGAR-DIP Trial
aScreening logs were not kept.
Figure 2.
Figure 2.. Subgroup Analyses of Incidence of Large-for-Gestational-Age Infants
aCalculated as weight in kilograms divided by height in meters squared.
See this image and copyright information in PMC

Comment on

References

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