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Metformin in Gestational Diabetes

Should metformin or glyburide, or a combination of both drugs, be the first-line treatment for gestational diabetes?

Uncontrolled hyperglycemia during pregnancy is known to affect fetal development and increase the prevalence of gestational diabetes mellitus (GDM) that complicates 5-7% of pregnancies. Studies show that routine care including healthy diet, physical activity, and glucose monitoring may not be adequate to achieve glucose control in those pregnant women. Although, previously US Food and Drug Administration (FDA) had approved insulin as the only treatment for GDM, ongoing studies have shown promising results with oral hypoglycemic drugs: Glyburide and Metformin are cost effective, therapeutically efficacious, easy to administer, and safe pharmacological treatment options for GDM.

In a prospective, open-labeled, randomized, parallel study, women at 13–33 weeks of gestation diagnosed with GDM, between the ages of 18–45 years were recruited to compare the efficacy and safety of glyburide versus metformin in the treatment of GDM. Also, the improvement in glycemic control after their replacement due to adverse effects or after adding the second drug due to failure of the first were also evaluated. Pharmacotherapy was initiated in subjects with either fasting blood glucose (BG) >95 mg/dL, a 1.5-h postprandial of >130 mg/dL, or a daily average >100 mg/dL after at least a week of dietary treatment. Subjects underwent a sonographic dating of the pregnancy earlier than 24 weeks and signed a consent form.

The study hypothesized that GDM is one of the chief conditions that contributes to obstetrical complications and prenatal morbidity and that they can be improved with glycemic control by improving patient compliance and satisfaction. The purpose of the study was to compare the efficacy and safety of glyburide versus metformin and their combination for the treatment of GDM. The primary outcomes were the rate of treatment failure and glycemic control after the first-line medication according to mean daily glucose charts. The secondary outcomes were the rate of second-line treatment required due to poor glycemic control or adverse events. Statistically, a two-sided α of 5% and power of 90% was used to detect a 10 mg/dL difference in mean daily BG between the two groups with an SD of 15 mg/dL difference. The student t-test and x2 test was used for continuous and categorical variables, respectively, to compare the group baseline characteristics and outcomes. The fasting and postprandial average daily BG values were compared with the use of a locally weighted scatterplot smoother (LOESS) nonparametric regression model.

Glyburide and metformin were initiated in 53 and 51 patients, respectively. The glyburide study arm showed failure in 18 patients: due to hypoglycemia in 6 patients (11%) and lack of glycemic control in 12 patients (23%). The metformin group showed failure in 15 patients: due to gastrointestinal events in 1 patient (2%) and lack of glycemic control in 14 patients (28%). Higher success after adding a second-line therapy was seen in the metformin subjects (87%) versus in the glyburide group (50%) with a P = 0.03. Eventually, 9 patients were treated with insulin in glyburide group compared to two patients in the metformin group (P = 0.03). The combination therapy reduced insulin need from 32% to 11% (P = 0.0002). Moreover, daily average BG and other obstetrical and neonatal outcomes were comparable between groups consisting of electrolyte imbalance, macrosomia, and neonatal hypoglycemia.

The patients initiated with metformin showed lower probability of requiring insulin due to a lower rate of adverse events and its mechanism of action where it increases insulin sensitivity and may have potentiated the glyburide effect. Other studies have highlighted the benefits of metformin with lower maternal weight gain, gestational hypertension, and postprandial BG. In this study, both treatments were similar in their efficacy and safety and it is too soon to declare superiority of one oral hypoglycemic drug over the other because only two RCTs had compared the glycemic control between glyburide and metformin in the treatment of GDM. Although, no significant difference was found in the primary outcome of glycemic control, the treatment failure was ~25%, which led to insulin use. The hypothesis was proven correct where the two medications yield success in glycemic control if one medication fails to produce therapeutic effect, thus raising the treatment success from 69% to 89% and only 11% patients needing insulin.

In conclusion, glyburide and metformin are comparable oral treatments for GDM regarding glucose control and treatment failure. Combination therapy allowed a higher efficacy rate and reduced the need for insulin that should be reserved for patients with no response or have experienced adverse effects with both oral drugs. Overall, the results support the benefit of using an additional oral hypoglycemic agent in the case of a treatment failure before switching to insulin.

Practice Pearls:

  • Metformin and glyburide combination therapy demonstrates a high efficacy rate with a significantly reduced need for insulin.
  • Glyburide and metformin are comparable oral treatments for GDM regarding glucose control and adverse effects.
  • Metformin had a possible advantage over glyburide as first-line therapy due to reduced adverse effects and increasing insulin sensitivity of glyburide before its initiation.


Castillo WC, Boggess K, Sturmer T, Brookhart A, Benjamin DK, and Funk MJ. Association of Adverse Pregnancy Outcomes With Glyburide vs Insulin in Women With Gestational Diabetes. JAMA Pediatr. May 2015;169(5):452-458. Doi:10.1001/jamapediatrics.2015.74

“Metformin May Be a Better First-Line Treatment for Gestational Diabetes.” BLOCK. Diabetes Care. 25 Jan, 2017. http://www.practiceupdate.com/content/metformin-may-be-better-first-line-treatment-for-gestational-diabetes/48752#commentarea. Accessed 21 Feb. 2017.

Nachum Z, Zafran N, Salim R, Hissin N, Hasanein J, Letova YGZ, et al. Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study. Diabetes Care. March 2017;40:332-337/dc16-2307.