Glibenclamide, Metformin, and Insulin for the Treatment of Gestational Diabetes: A Systematic Review and Meta-analysis

Gestational diabetes is a common complication in pregnancy that is typically treated with insulin. However, this complication is on the rise, and oral medications, such as glibenclamide (glyburide) and metformin, are being considered as an alternative to insulin. In recent years, oral agents have been more frequently used in pregnant women with gestational diabetes mellitus (GDM), but there have been no randomized controlled trials (RCTs) that comprehensively evaluate the effect of oral drug treatments on maternal and fetal outcomes. The goal of this study was to compare short-term outcomes of glibenclamide or metformin to insulin and glibenclamide versus metformin in a systematic review of RCTs. Using electronic searches in MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE, studies meeting 5 points of criteria were included for review. Studies that met the following criteria: (1) RCTs; (2) subjects were women with GDM requiring drug treatment; (3) compared glibenclamide or metformin with insulin, or metformin versus glibenclamide; (4) provided information about maternal or fetal outcome; and (5) a published full article. Data were reviewed by prespecified primary and secondary outcomes with 6 maternal and 8 fetal primary outcomes, and 5 maternal and 11 fetal secondary outcomes. Meta-analysis was used in comparing baseline characteristics; bodymass index was the only significant baseline characteristic in comparing metformin and insulin. Fifteen studies were eligible for analysis and included subjects in the United States, Brazil, and India. Among the primary outcomes of glibenclamide versus insulin, there were significant differences with glibenclamide associated with higher birth weight (pooled mean difference 109 g; 95% confidence interval [CI], 35.9-181 g), macrosomia (risk ratio, 2.62; 95% CI, 1.35-5.08), and neonatal hypoglycemia (risk ratio, 2.04; 95% CI, 1.30-3.20). In the glibenclamide group, there was also an average treatment failure of 6.37% and additional adverse effects reported in 6.3% of women. However, there were no significant differences in secondary outcomes. In primary outcomes of metformin versus insulin, metformin was found to be associated with less maternal weight gain (mean difference, -1.14 kg; 95% CI, -2.22 to -0.06 kg), lower gestational age at delivery (mean difference, -0.16 weeks; 95% CI, -0.03 to -0.02 weeks), and higher rates of preterm birth (risk ratio, 1.50; 95% CI, 1.04-2.16). The average treatment failure of the metformin group was 33.8%. Secondary outcomes revealed that metformin was associated with lower postprandial blood glucose (mean difference, -1.23 kg; 95% CI, -1.72 to -0.73 kg), less pregnancy-induced hypertension (risk ratio, 0.53; 95% CI, 0.31-0.90), and less severe neonatal hypoglycemia (risk ratio, 0.62; 95% CI, 0.42-0.94). In the 2 trials analyzed that compared metformin and glibenclamide, metformin was associated with less maternal weight gain (mean difference, -2.06 kg; 95% CI, -3.98 to -0.14 kg), lower birth weight (mean difference, -209 g; 95% CI, -314 to -104), and less macrosomia (risk ratio, 0.33; 95% CI, 0.13-0.81). Treatment failure was 26.8% in themetformin group versus 23.5% in the glibenclamide group. According to this meta-analyses, metformin is the preferable treatment in the short-term outcome versus glibenclamide in GDM that requires oral medication treatment. However, metformin has higher treatment failure, is associated with a higher rate of preterm birth, and poses questions regarding long-term safety. Given that its outcomes are better than glibenclamide and that it has a lower preterm birth rate than metformin, insulin should likely remain the vanguard of diabetes treatment in pregnancy.