Glyburide and Metformin for the Treatment of Gestational Diabetes Mellitus. Systematic Review

Study Overview
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Brief Summary
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Since the publication in the New England Journal of Medicine (NEJM) in 2000 of the Langer's trial comparing glyburide vs insulin in the treatment of gestational diabetes mellitus (GDM), additional studies of oral agents for the treatment of GDM have been published (observational, randomized controlled trials (RCT), and trials using other drugs like metformin). Some meta-analysis to summarize the evidence have been published: Nicholson 2009 (including 4 RCT addressing different drugs), Dhulkotia 2010 (including 6 RCT addressing different drugs, the meta-analysis combining all drugs altogether), Gui 2013 (including 5 RCT addressing metformin vs insulin). Oral agents are increasingly used for the treatment of GDM. Investigators aim to update the evidence on RCTs comparing glyburide and metformin vs insulin or between them and summarize this evidence using meta-analysis tools. Specifically, investigators aim at producing distinct meta-analyses for each one of the three drug comparisons. This information is not available in the literature since the most recent systematic reviews specifically dealing on oral agents for the treatment of GDM have addressed a single drug comparison (Gui 2013) or have combined different drug comparisons into a single meta-analysis (Dhulkotia 2010)

Detailed Description
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This project involves the systematic review of RCT addressing the use of glyburide or metformin for the treatment of GDM. The review will include RCT comparing these drugs versus insulin or making direct comparisons between the two oral agents in pregnant women with GDM. Investigators have pre-specified a series of maternal and fetal outcomes of interest. A comprehensive electronic search strategy will be complemented with a search of bibliographies from relevant studies and the contact of authors from the eligible studies regarding issues on study design or information on primary outcomes. The risk of bias of included studies will be analyzed and this information used to perform sensitivity analyses. If possible, data from original studies will be pooled into relative risks for dichotomous outcomes and mean differences for continuous outcomes. Heterogeneity will be explored for all the analyses. Analyses will be undertaken using a fixed effects model that will be repeated using a random effects model in case of substantial heterogeneity. Results of the systematic review will be published following PRISMA guidance.

Official Title
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Glyburide and Metformin for the Treatment of Gestational Diabetes Mellitus. A Systematic Review and Meta-analysis of Randomized Controlled Trials Comparing These Drugs Either vs Insulin or vs Each Other.

Conditions
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Gestational Diabetes Mellitus

Intervention / Treatment
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* Drug: Glyburide vs Insulin trials
* Drug: Metformin vs Insulin trials
* Drug: Metformin vs Glyburide trials


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RCT GDM comparing Glyburide vs Insulin, Metformin vs Insulin or Metformin vs Glyburide data on fetal and/or maternal outcomes full text available Exclusion Criteria: significant overlap with other articles of the same group
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Glyburide (Glyburide vs Insulin)<br>Glyburide vs Insulin trials | Drug: Glyburide vs Insulin trials<br>* Affecting groups 1 and 2<br>|
| Insulin (Glyburide vs Insulin)<br>Glyburide vs Insulin trials | Drug: Glyburide vs Insulin trials<br>* Affecting groups 1 and 2<br>|
| Metformin (Metformin vs Insulin)<br>Metformin vs Insulin trials | Drug: Metformin vs Insulin trials<br>* Affecting groups 3 and 4<br>|
| Insulin (Metformin vs Insulin)<br>Metformin vs Insulin trials | Drug: Metformin vs Insulin trials<br>* Affecting groups 3 and 4<br>|
| Metformin (Metformin vs Glyburide)<br>Metformin vs Glyburide trials | Drug: Metformin vs Glyburide trials<br>* Affecting groups 5 and 6<br>|
| Glyburide (Metformin vs Glyburide)<br>Metformin vs Glyburide trials | Drug: Metformin vs Glyburide trials<br>* Affecting groups 5 and 6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3rd trimester glycated hemoglobin | mean difference of 3rd trimester glycated hemoglobin | 3rd trimester of pregnancy | 
| total maternal weight gain | mean difference of total maternal weight gain (as defined by the authors) | during pregnancy | 
| severe maternal hypoglycemia | relative risk of severe maternal hypoglycemia (as defined by the authors) | from enrollment to delivery | 
| preeclampsia | relative risk of preeclampsia (as defined by the authors) | during pregnancy or puerperium | 
| cesarean section | relative risk of cesarean section (as defined by the authors) | at the end of pregnancy | 
| gestational age at birth | mean difference of gestational age at birth (as defined by the authors) | at birth | 
| preterm birth | relative risk of preterm birth (as defined by the authors) | at birth | 
| birthweight | mean difference of birthweight (as defined by the authors) | at birth | 
| macrosomia | relative risk of macrosomia (defined as birthweight >=4000 g) | at birth | 
| large-for-gestational age newborn | relative risk of large-for-gestational age newborn (as defined by the authors) | at birth | 
| small-for-gestational age newborn | relative risk of small-for-gestational age newborn (as defined by the authors) | at birth | 
| neonatal hypoglycemia | relative risk of neonatal hypoglycemia (as provided by the authors) | in the neonatal period | 
| perinatal mortality | relative risk of perinatal mortality (as defined by the authors) | in the perinatal period | 
| insulin treatment | relative risk of insulin treatment (for trials comparing metformin vs glyburide) | from enrollment to delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fasting blood glucose | mean difference of fasting blood glucose (as defined by the authors) | in the period from enrollment to delivery | 
| postprandial blood glucose | mean difference of postprandial blood glucose (as defined by the authors) | in the period from enrollment to delivery | 
| maternal weight gain since enrollment | mean difference of maternal weight gain since enrollment (as defined by the authors) | in the period from enrollment to delivery | 
| pregnancy-induced hypertension | relative risk of pregnancy-induced hypertension (as defined by the authors) | during pregnancy | 
| induction of labour | relative risk of induction of labour (as described by the authors) | at the end of pregnancy | 
| cord C peptide | mean difference of cord C peptide (as defined by the authors) | at birth | 
| cord insulin | mean difference of cord insulin (as defined by the authors) | at birth | 
| abnormal 1 min Apgar | relative risk of abnormal 1 min Apgar (defined as lower than 7) | at birth | 
| abnormal 5 min Apgar | relative risk of abnormal 5 min Apgar (defined as lower than 7) | at birth | 
| obstetric trauma | relative risk of obstetric trauma (as defined by the authors) | at birth | 
| severe neonatal hypoglycemia | relative risk of severe neonatal hypoglycemia (as defined by the authors) | in the neonatal period | 
| neonatal jaundice | relative risk of neonatal jaundice (as defined by the authors) | in the neonatal period | 
| significant respiratory distress | relative risk of significant respiratory distress (described as respiratory distress syndrome or requiring respiratory support) | in the neonatal period | 
| stillbirth | relative risk of stillbirth (as defined by the authors) | in the antenatal period | 
| neonatal mortality | relative risk of neonatal mortality (as defined by the authors) | in the neonatal period | 
| Neonatal Intensive Care Unit (NICU) admittance | relative risk of NICU admittance (as defined by the authors) | in the neonatal period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gestational diabetes mellitus, glyburide, metformin, oral agents, insulin, outcomes