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

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.

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)

Study Overview

• Status: Completed
• Conditions: Gestational Diabetes Mellitus
• Intervention / Treatment: Drug: Glyburide vs Insulin trials; Drug: Metformin vs Insulin trials; Drug: Metformin vs Glyburide trials

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 2509

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

pregnant women with gestational diabetes mellitus requiring drug treatment

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Glyburide (Glyburide vs Insulin); Glyburide vs Insulin trials	Drug: Glyburide vs Insulin trials; Affecting groups 1 and 2
Insulin (Glyburide vs Insulin); Glyburide vs Insulin trials	Drug: Glyburide vs Insulin trials; Affecting groups 1 and 2
Metformin (Metformin vs Insulin); Metformin vs Insulin trials	Drug: Metformin vs Insulin trials; Affecting groups 3 and 4
Insulin (Metformin vs Insulin); Metformin vs Insulin trials	Drug: Metformin vs Insulin trials; Affecting groups 3 and 4
Metformin (Metformin vs Glyburide); Metformin vs Glyburide trials	Drug: Metformin vs Glyburide trials; Affecting groups 5 and 6
Glyburide (Metformin vs Glyburide); Metformin vs Glyburide trials	Drug: Metformin vs Glyburide trials; Affecting groups 5 and 6

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Publications and helpful links

General Publications

• Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003-15. doi: 10.1056/NEJMoa0707193. Erratum In: N Engl J Med. 2008 Jul 3;359(1):106.
• Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000 Oct 19;343(16):1134-8. doi: 10.1056/NEJM200010193431601.
• Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis. Am J Obstet Gynecol. 2010 Nov;203(5):457.e1-9. doi: 10.1016/j.ajog.2010.06.044. Epub 2010 Aug 24.
• Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review. Obstet Gynecol. 2009 Jan;113(1):193-205. doi: 10.1097/AOG.0b013e318190a459.
• Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: a meta-analysis. PLoS One. 2013 May 27;8(5):e64585. doi: 10.1371/journal.pone.0064585. Print 2013.
• Silva JC, Fachin DR, Coral ML, Bertini AM. Perinatal impact of the use of metformin and glyburide for the treatment of gestational diabetes mellitus. J Perinat Med. 2012 Jan 10;40(3):225-8. doi: 10.1515/jpm-2011-0175.
• Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ. 2015 Jan 21;350:h102. doi: 10.1136/bmj.h102.

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: November 8, 2013
• First Submitted That Met QC Criteria: November 25, 2013
• First Posted (Estimate): November 28, 2013

Study Record Updates

• Last Update Posted (Estimate): March 24, 2015
• Last Update Submitted That Met QC Criteria: March 23, 2015
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: outcomes; insulin; metformin; gestational diabetes mellitus; oral agents; glyburide
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes, Gestational; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Metformin; Glyburide
• Other Study ID Numbers: IIBSP-ADO-2013-153