口服降糖药与胰岛素治疗妊娠期糖尿病的随机临床试验

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

作者信息

Rademaker Doortje, de Wit Leon, Duijnhoven Ruben G, Voormolen Daphne N, Mol Ben Willem, Franx Arie, DeVries J Hans, Painter Rebecca C, van Rijn Bas B, Siegelaar Sarah E, Akerboom Bettina M C, Kiewiet-Kemper Rosalie M, Verwij-Didden Marion A L, Assouiki Fahima, Kuppens Simone M, Oosterwerff Mirjam M, Stekkinger Eva, Diekman Mattheus J M, Vogelvang Tatjana E, Belle-van Meerkerk Gerdien, Galjaard Sander, Verdonk Koen, Lub Annemiek, Klooker Tamira K, Krabbendam Ineke, van Wijk Jeroen P H, Huisjes Anjoke J M, van Bemmel Thomas, Nijman Remco G W, van den Beld Annewieke W, Hermes Wietske, Johannsson-Vidarsdottir Solrun, Vlug Anneke G, Dullemond Remke C, Jansen Henrique J, Sueters Marieke, de Koning Eelco J P, van Laar Judith O E H, Wouters-van Poppel Pleun, Evers Inge M, Sanson-van Praag Marina E, van den Akker Eline S, Brouwer Catherine B, Hermsen Brenda B, Scholten Ralph, Meijer Rick I, van Leeuwen Marsha, Wijbenga Johanna A M, Wijnberger Lia D E, van Bon Arianne C, van der Made Flip W, Eskes Silvia A, Zandstra Mirjam, van Houtum William H, Braams-Lisman Babette A M, Daemen-Gubbels Catharina R G M, Nijkamp Janna W, de Valk Harold W, Wouters Maurice G A J, IJzerman Richard G, Reiss Irwin, van der Post Joris A M, Bosmans Judith E

机构信息

Department of Obstetrics and Gynecology, Amsterdam University Medical Center Location AMC, Amsterdam, the Netherlands.

Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands.

出版信息

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

DOI:10.1001/jama.2024.23410

PMID:39761054

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11815519/

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.

摘要

重要性

二甲双胍和格列本脲单药治疗在妊娠期糖尿病管理中用作胰岛素的替代方案。与单独使用胰岛素相比，这些口服药物的序贯治疗策略是否能带来非劣效的围产期结局尚不清楚。

目的

检验口服降糖药治疗策略在预防大于胎龄儿方面是否不劣于胰岛素。

设计、设置和参与者：2016年6月至2022年11月在荷兰25个中心进行的随机、开放标签非劣效性试验，随访于2023年5月完成。该研究纳入了820例妊娠期糖尿病且为单胎妊娠的个体，孕周在16至34周之间，在进行2周饮食调整后血糖控制不佳（定义为空腹血糖>95mg/dL[>5.3mmol/L]、餐后1小时血糖>140mg/dL[>7.8mmol/L]或餐后2小时血糖>120mg/dL[>6.7mmol/L]，通过毛细血管血糖自我检测）。

干预措施

参与者被随机分配接受二甲双胍（起始剂量为每日500mg，每3天增加至每日1000mg，分两次服用或达到最高耐受水平；n = 409）或胰岛素（根据当地实践处方；n = 411）。必要时，在二甲双胍基础上加用格列本脲，然后用胰岛素替代格列本脲，以实现血糖目标。

主要结局和测量指标

主要结局是两组间大于胎龄儿（出生体重基于孕周和性别处于第90百分位数以上）出生百分比的组间差异。次要结局包括母体低血糖、剖宫产、妊娠高血压、先兆子痫、母体体重增加、早产、产伤、新生儿低血糖、新生儿高胆红素血症以及新生儿重症监护病房入院情况。

结果

在820名参与者中，平均年龄为33.2（标准差，4.7）岁。在随机分配接受口服药物的参与者中，79%（n = 320）在未使用胰岛素的情况下维持了血糖控制。使用口服药物时，23.9%的婴儿（n = 97）为大于胎龄儿，而使用胰岛素时这一比例为19.9%（n = 79）（绝对风险差异，4.0%；95%置信区间，-1.7%至9.8%；非劣效性检验P = 0.09），风险差异的置信区间超过了8%的绝对非劣效界值。口服降糖药组报告的母体低血糖发生率为20.9%，胰岛素组为10.9%（绝对风险差异，10.0%；95%置信区间，3.7% - 21.2%）。所有其他次要结局在两组间无差异。