Evidence-Based Medicine Online First, published on April 23, 2015 as 10.1136/ebmed-2015-110186

Therapeutics

Systematic review with meta analysis

In women with gestational diabetes requiring drug treatment, glibenclamide may be inferior to insulin and metformin: metformin ( plus insulin when required) performs better than insulin 10.1136/ebmed-2015-110186

associated with significantly higher birth weights (mean difference 109 g, 95% CI 35.9 to 181), macrosomia (RR=2.62, 95% CI 1.35 to 5.08) and neonatal hypoglycaemia (RR=2.04, 95% CI 1.30 to 3.20). The average failure rate with glibenclamide was 6.37%. When metformin was compared with insulin, metformin was associated with significantly less maternal weight gain (mean difference −1.14 kg, 95% CI −2.22 to −0.06), lower gestational age at delivery (mean difference 0.16 weeks, 95% CI −0.30 to −0.02) and more preterm births (RR=1.50, 95% CI 1.04 to 2.16). The average failure rate with metformin was 33.8%. When metformin was compared with glibenclamide, metformin was associated with significantly less maternal weight gain (mean difference −2.06 kg, 95% CI −3.98 to −0.14), lower birth weight (mean difference −209 g, 95% CI −314 to −104), less macrosomia (RR=0.33, 95% CI 0.13 to 0.81) and fewer large for gestational age newborns (RR=0.44, 95% CI 0.21 to 0.92). The average failure rate was 26.8% with metformin compared with 23.5% with glibenclamide.

Dana Carroll, Kristi W Kelley Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Auburn, Alabama, USA Correspondence to: Professor Dana Carroll, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, 850 5th Ave East, Auburn, AL 35401, USA; [email protected]

Commentary on: Balsells M, Garia-Patterson A, Solà I, et al. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015;350:h102.

Context Insulin therapy is recommended as a first-line approach after failure of diet therapy to manage gestational diabetes (GDM).1 2 Not all women are suitable candidates or decline to use insulin to manage their blood glucose levels and alternative options are needed. Metformin and glibenclamide are mentioned as alternatives to insulin for management of gestational diabetes mellitus (GDM) in several guidelines,1 2 while National Institute for Health and Care Excellence guidelines recommend metformin as a firstline.3 This systematic review and meta-analysis examines the short-term maternal and neonatal outcomes in women with GDM receiving glibenclamide, metformin or insulin in randomised controlled trials (RCTs).

Methods This was a review of RCTs comparing glibenclamide or metformin versus insulin or each other for the management of GDM requiring drug treatment. The primary maternal outcomes assessed were glycated haemoglobin (3rd trimester), severe maternal hypoglycaemia, pre-eclampsia, total weight gain during pregnancy, caesarean section and treatment failure. The primary fetal outcomes were gestational age at delivery, preterm birth, birth weight, macrosomia, large for gestational age newborns, small for gestational age newborns, any neonatal hypoglycaemia and perinatal mortality. The review clearly stated the question being addressed, the search strategy, study selection, assessment of study quality, data extraction and synthesis. It adhered to recognised protocols for systematic reviews and meta-analyses from the Cochrane Collaboration and PRISMA. The results were reported as relative risk (RR) estimates and CI.

Findings Fifteen RCTs met the inclusion criteria, reporting on 2509 participants. When glibenclamide was compared with insulin, glibenclamide was

Commentary This meta-analysis is unique in that it only included RCTs utilising glibenclamide versus insulin, metformin versus insulin and glibenclamide versus metformin and it assessed maternal and fetal short-term outcomes. The prespecified maternal and fetal outcomes are appropriate and more numerous than previously published meta-analyses. The variation in definitions or lack of definitions for maternal and fetal outcomes in GDM trials could be significant confounders in this and other meta-analyses assessing GDM. Other potential confounders in this meta-analysis are lack of published treatment protocols (glibenclamide vs insulin trials) and the open label trial design (all trials). As per the authors’ own admission, one of the greatest limitations of their meta-analysis is use of aggregate patient data rather than individual patient data. Finally, the largest clinical trial (n=10 682) published to date, a retrospective cohort assessing glibenclamide in the management of GDM, is not included in this meta-analysis based on its design (inclusion criteria).4 While there is a limitation in the trial’s retrospective design, the large sample size should be considered as it is 10 times larger than the sample (glibenclamide vs insulin) in this meta-analysis.4

Implication for practice This meta-analysis does not provide convincing evidence for a change in practice but does highlight the need for larger, well-designed studies assessing short-term and long-term outcomes to mother and fetus managed with pharmacotherapy for GDM. Insulin remains the medication of choice in the management of GDM. Metformin and glibenclamide can be considered as alternatives. Based on the evidence, glibenclamide should be reserved for the treatment of women with GDM if insulin or metformin is unavailable, poorly tolerated or contraindicated. Competing interests None declared. Provenance and peer review Commissioned; internally peer reviewed. References 1. Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol 2013;122(2 Pt 1):406–16. 2. Pregnancy and Diabetes. International Diabetes Federation. http://www.idf.org/ webdata/docs/Pregnancy_EN_RTP.pdf (accessed 9 Mar 2015). 3. Diabetes in Pregnancy. National Institute for Health and Clinical Excellence. http:// www.nice.org.uk/guidance/ng3/chapter/1-recommendations (accessed 10 Mar 2015). 4. Cheng YW, Chung JH, Block-Kurbisch I, et al. Treatment of gestational diabetes mellitus: glyburide compared with subcutaneous insulin therapy and associated perinatal outcomes. J Matern Fetal Neonatal Med 2012;25:379–84.

Evid Based Med Month 2015 | volume 0 | number 0 |

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In women with gestational diabetes requiring drug treatment, glibenclamide may be inferior to insulin and metformin: metformin (plus insulin when required) performs better than insulin.

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