Gestational diabetes mellitus - Emerging treatments

General considerations

Although pharmacologic therapy for GDM has traditionally been restricted to insulin, more recent evidence suggests widespread use of oral antihyperglycemic agents in contemporary obstetric practice.[99] The use of oral agents remains controversial due to lack of data on long term offspring outcomes in pregnancies treated with these agents. Several studies suggest that these drugs (e.g., metformin, glyburide), when used at therapeutic doses, can be used as an alternative therapy to insulin when diet fails to control blood sugar.[100][101][102] The American Diabetes Association emphasizes that insulin is the treatment of choice during pregnancy.[1] However, it recognizes that there are some women with GDM requiring medical therapy who may not be able to use insulin safely or effectively in pregnancy, advising that oral agents may be an alternative in these women after a discussion of the known risks and the need for more long-term safety data in offspring.[1] Other guidelines support consideration of the use of metformin in women with GDM.[19][103]

Metformin

Metformin is increasingly used for treatment of GDM, and was endorsed in 2018 by the Society for Maternal-Fetal Medicine as a first-line alternative to insulin in patients requiring intensified treatment after initial medical nutrition therapy.[103] Metformin freely crosses the placenta to achieve measurable concentrations in cord blood.[104] Despite this, limited follow-up data have suggested no adverse developmental effects and no early childhood differences in overall body composition in offspring.[105][106] However, follow-up data in 7- to 9-year-olds exposed to metformin in utero suggested that metformin-exposed offspring were larger at 9 years, but not at 7 years; they were otherwise similar.[107] One randomized controlled trial found that using insulin plus metformin to treat preexisting type 2 or GDM diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome compared with insulin plus placebo. Metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46 to 0.86]) when compared with the placebo group.[108] Further data are needed to fully understand the impact of metformin exposure on long-term offspring metabolic outcomes. While some studies reported that metformin during pregnancy was associated with increased preeclampsia and perinatal mortality, several others have reported that treatment with insulin versus metformin resulted in similar outcomes.[104][109][110][111] A large, register-based cohort study from Finland found no increased long-term risk to off-spring associated with pregnancy exposure to metformin compared with insulin.[112] The efficacy of metformin alone is unclear; in one large randomized controlled trial, 50% of women in the metformin group required supplemental insulin for maintenance of glycemic control, particularly those with fasting hyperglycemia, and nearly all women required the maximum metformin dose.[113] Two systematic reviews comparing outcomes of GDM treated with oral antihyperglycemic agents versus insulin found that metformin and insulin therapy yielded similar outcomes.[114][115] There are limited data comparing metformin with glyburide. [ ] The American Association of Clinical Endocrinology indicates that metformin is a potential option for patients with GDM due to cumulative evidence of its safety in pregnancy, but advises that the prescriber needs to discuss the potential risks and benefits of oral agent therapy during pregnancy with the patient.[42] In the UK, the National Institute for Health and Care Excellence (NICE) recommends metformin as a safe option under certain circumstances.[19] Check your local protocol for further information. Due to the potential for growth restriction or acidosis in the setting of placental insufficiency, metformin should not be used in women with hypertension, preeclampsia, or who are at risk for intrauterine growth restriction.[1][97]

Glyburide

Glyburide was compared with insulin therapy in a randomized study of pregnancies complicated by GDM; this study of 404 patients showed comparable outcomes with both treatments.[116] One systematic review comparing outcomes of GDM treated with oral antihyperglycemic agents versus insulin found that glyburide and insulin therapy yielded similar outcomes.[114] However, another systematic review found that, compared with insulin, glyburide was associated with a nonstatistically significant 93 g higher birth weight.[82] A randomized trial comparing the perinatal impacts of glyburide and metformin in the treatment of pregnant women with GDM who required adjunctive therapy to diet and physical activity found that neonatal blood glucose levels were lower with glyburide, while newborn weight and the ponderal index (birth weight/height³ × 100) were lower with metformin.[117] A retrospective analysis using insurance claims data suggested the possibility of harm associated with glyburide, with an increased risk of adverse outcomes, including neonatal intensive care unit admission, respiratory distress, hypoglycemia, large for gestational age, and birth injury in women treated with glyburide compared with those treated with insulin.[118] A randomized non-inferiority trial of glyburide compared with insulin demonstrated increased rates of perinatal complications (27.6% for the glyburide group vs. 23.4% in the insulin group) and therefore did not find glyburide to be noninferior.[119] While early data suggested minimal placental transfer, the amount of fetal exposure to glyburide remains unclear.[116][120] There are no studies that assess the long-term impact of glyburide exposure on offspring outcomes.