WASHINGTON – The American College of Obstetricians and Gynecologists’ conclusion that insulin should be considered the first-line pharmacologic treatment for gestational diabetes came under fire at a recent meeting on diabetes in pregnancy, indicating the extent to which controversy persists over the use of oral antidiabetic medications in pregnancy.
“Like many others, I’m perplexed by the strong endorsement,” Mark Landon, MD, professor and chair of the department of obstetrics and gynecology at Ohio State University, Columbus, said during an open discussion of oral hypoglycemic agents held at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.
Dr. Landon and several other researchers and experts in diabetes in pregnancy expressed discontent with any firm prioritization of the drugs most commonly used for gestational diabetes, saying that there are not yet enough data to do so.
Dr. Mark Landon
The endorsement of insulin as the first-line option when pharmacologic treatment is needed is a level A conclusion/recommendation in ACOG’s updated practice bulletin on gestational diabetes mellitus, released in July 2017 (Obstet Gynecol. 2017;130[1]:e17-37). In accompanying level B recommendations, ACOG stated that in women who decline insulin therapy or who are believed to be “unable to safely administer insulin,” metformin is a “reasonable second-line choice.” Glyburide “should not be recommended as a first-line pharmacologic treatment because, in most studies, it does not yield equivalent outcomes to insulin.”
Level A recommendations are defined as “based on good and consistent scientific evidence,” while the evidence for level B recommendations is “limited or inconsistent.”
Asked to comment on the concerns voiced at the meeting, an ACOG spokeswoman said that the recommendations were developed after a thorough literature review, but that the evidence was being reexamined with the option of updating the practice bulletin.
Current recommendations
In its practice bulletin, ACOG noted that oral antidiabetic medications, such as glyburide and metformin, are increasingly used among women with GDM, despite not being approved by the Food and Drug Administration for this indication and even though insulin continues to be the recommended as first-line therapy by the American Diabetes Association (ADA).
The ADA, in a summary of its 2017 guideline on the management of diabetes in pregnancy, stated that insulin is the “preferred medication for treating hyperglycemia in gestational diabetes mellitus, as it does not cross the placenta to a measurable extent.” Metformin and glyburide are options, “but both cross the placenta to the fetus, with metformin likely crossing to a greater extent than glyburide” (Diabetes Care. 2017 Jan;40[Suppl 1]:S114- 9).Regarding metformin, the ACOG bulletin cited two trials that randomized women to metformin or insulin – one in which both groups experienced similar rates of a composite outcome of perinatal morbidity, and another in which women receiving metformin had lower mean glucose levels, less gestational weight gain, and neonates with lower rates of hypoglycemia.
ACOG also cited a meta-analysis, that found “minimal differences” between neonates of women randomized to metformin versus insulin, but also noted that “interestingly, women randomized to metformin experienced a higher rate of preterm birth” and a lower rate of gestational hypertension (BMJ. 2015;350:h102).
With respect to glyburide, the ACOG bulletin said that two recent meta-analyses had demonstrated worse neonatal outcomes with glyburide, compared with insulin, and that observational studies have shown higher rates of preeclampsia, hyperbilirubinemia, and stillbirth with the use of glyburide, compared with insulin. However, many other outcomes have not been statistically significantly different, according to the practice bulletin.
Additionally, at least 4%-16% of women eventually require the addition of insulin when glyburide is used as initial treatment, as do 26%-46% of women who take metformin, according to ACOG.
Regarding placental transfer, ACOG’s bulletin said that while one study that analyzed umbilical cord blood revealed no detectable glyburide in exposed pregnancies, another study demonstrated that glyburide does cross the placenta. Metformin has also been found to cross the placenta, with the fetus exposed to concentrations similar to maternal levels, the bulletin noted.
“Although current data demonstrate no adverse short-term effects on maternal or neonatal health from oral diabetic therapy during pregnancy, long-term outcomes are not yet available,” ACOG wrote in the practice bulletin.