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Metformin for Gestational Diabetes Mellitus: Progeny, Perspective, and a Personalized Approach

Given the rapidly growing population of women diagnosed with gestational diabetes mellitus (GDM), approximating 1 in 7 pregnancies globally (1), in conjunction with the rising cost of insulins and lack of affordability (2), the popularity of using an oral agent such as metformin is expanding enormously. In fact, a number of organizations have supported its use as an alternative to insulin (3–6). However, recent long-term studies on offspring have provided conflicting results, with two of three studies recently published on the 4- to 9-year-old children of mothers with GDM or polycystic ovarian syndrome (PCOS) suggesting some long-term metabolic programming effects on the offspring (7–9). This has given some clinical investigators and organizations (10,11) pause in embracing metformin as equivalent to insulin (12–17).

In the short term, there is an abundance of evidence that metformin has a safe track record and may have some benefits compared with insulin or glyburide when used for the treatment of GDM (18). Metformin is not teratogenic, with reassuring data for use in the first trimester (19–21), and in several meta-analyses, women with GDM randomized to metformin (often used with insulin) had less gestational weight gain, less gestational hypertension, and fewer infants who were large-for-gestational age (LGA) or with macrosomia (birth weight >4,000 g), and their infants had less neonatal hypoglycemia, than those randomized to insulin or glibenclamide (glyburide) therapy (22–24). However, metformin has a high failure rate, and 46% of women randomized to metformin needed to add insulin in the Metformin in Gestational Diabetes (MiG) randomized controlled trial (RCT) (25). In comparison, in a large multisite RCT in which insulin was compared with glyburide for GDM, the failure rate of glyburide was 18% (26). Important in interpreting RCT data is that glyburide …