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

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 &gt;95 mg/dL [&gt;5.3 mmol/L], 1-hour postprandial glucose &gt;140 mg/dL [&gt;7.8 mmol/L], or 2-hour postprandial glucose &gt;120 mg/dL [&gt;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 &gt;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.</p

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

INTRODUCTION: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. METHODS: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6134; Pre-results

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Screening for gestational diabetes mellitus

Gestational diabetes mellitus is associated with increased risk of complications for mother and child. Along with the growing epidemic of obesity and type 2 diabetes, the prevalence of gestational diabetes is expected to rise. With adequate and timely treatment, the risk of complications is reduced. Detection of gestational diabetes however is complicated, since often there are no symptoms. Currently no uniform strategy for detection of gestational diabetes exists. This thesis aims to evaluate costs and effects of various screening strategies in order to obtain a uniform (cost-)effective strategy for detection of gestational diabetes

Accuracy of the random glucose test as screening test for gestational diabetes mellitus: a systematic review

AbstractObjectiveAlthough not formally supported by guidelines, random glucose testing (RGT) is frequently used to screen for gestational diabetes mellitus (GDM). Results on test accuracy are inconclusive. The aim of this study was to systematically review the literature and calculate summary estimates of accuracy measures of RGT as screening test for GDM.Study designSystematic review to identify studies comparing RGT to oral glucose tolerance testing before 32 weeks of pregnancy. A systematic search without language restrictions was performed in MEDLINE (1950 till April 2008) and EMBASE (1980 to April 2008). Study selection and data extraction were performed by two independent reviewers. Outcome measures were summary estimates of test accuracy of RGT.ResultsSix studies were included, reporting on 3537 women. Due to the small number of studies and heterogeneity, no summary estimates of test accuracy were calculated. Reported sensitivities and specificities of individual studies varied. For 100% sensitivity, specificity was around 40%. For sensitivity of 60% specificity was at most 80%. When specificity approached 100%, sensitivity dropped to 20–30%.ConclusionAvailable evidence on the accuracy of RGT to test for GDM is limited. Based on studies in our systematic review, we consider single random glucose measurement inadequate to screen for GDM

Comparison of accuracy measures of two screening tests for gestational diabetes mellitus

OBJECTIVE: To compare the accuracy measures of the random glucose test and the 50-g glucose challenge test as screening tests for gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: In this prospective cohort study, pregnant women without preexisting diabetes in two perinatal centers in the Netherlands underwent a random glucose test and a 50-g glucose challenge test between 24 and 28 weeks of gestation. If one of the screening tests exceeded predefined threshold values, the 75-g oral glucose tolerance test (OGTT) was performed within 1 week. Furthermore, the OGTT was performed in a random sample of women in whom both screening tests were normal. GDM was considered present when the OGTT (reference test) exceeded predefined threshold values. Receiver operating characteristic (ROC) analysis was used to evaluate the performance of the two screening tests. The results were corrected for verification bias. RESULTS: We included 1,301 women. The OGTT was performed in 322 women. After correction for verification bias, the random glucose test showed an area under the ROC curve of 0.69 (95% CI 0.61-0.78), whereas the glucose challenge test had an area under the curve of 0.88 (0.83-0.93). There was a significant difference in area under the curve of the two tests of 0.19 (0.11-0.27) in favor of the 50-g glucose challenge test. CONCLUSIONS: In screening for GDM, the 50-g glucose challenge test is more useful than the random glucose tes

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

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

SUGAR-DIP trial:Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals