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Evidence Shows Possible Benefit of Metformin and Glyburide Use in Pregnancy

A review of recent studies suggests that some oral hypoglycemic agents may be safe and effective in pregnant patients….

Insulin is traditionally the treatment of choice in pregnant patients requiring medication to manage their blood glucose levels, as it is a hormone the body already produces naturally and should therefore theoretically pose less risk to a developing fetus. New evidence, however, suggests that certain oral hypoglycemic agents may be suitable alternatives for these patients. These oral agents would help to simplify medication regimens in many of these patients, as insulin administration is known to be demanding, unpleasant, and inconvenient.

A literature search was performed using Pubmed and other electronic databases to identify articles pertaining to this topic. In particular, the keywords pregnancy, diabetes, and the names of different oral hypoglycemic agents were used to find this information. Manufacturers of different oral agents were also contacted for further information.

Studies found metformin to be safe for use throughout pregnancy, and to be associated with several additional benefits. These include: reduced pregnancy loss, less maternal weight gain, and less neonatal hypoglycemia. Also, several studies found an up to 10-fold reduction in incident gestational diabetes in women treated with metformin. A trial is currently being conducted to examine whether it is beneficial to begin metformin therapy in pregnant type 2 diabetics treated with insulin, as previous studies focus on type 1. Randomized controlled trials in patients with gestational diabetes found no difference in a composite of neonatal complications between patients taking metformin and patients using insulin. Metformin was also found to have a higher treatment satisfaction rate.

Glyburide was found to be an effective alternative to insulin in this patient population as well, though there is some doubt remaining as to its safety. The biggest safety concerns with glyburide are possible increased rates of neonatal jaundice and hypoglycemia. This is thought to be due to the ability of sulfonylureas to cross the placenta and stimulate fetal insulin secretion. When compared to metformin use, pregnant women using glyburide had more maternal weight gain, and the average birthweight was 200g greater for babies whose mothers took glyburide while pregnant. Women treated with insulin were more likely to experience hypoglycemia than those treated with glyburide, though a smaller percentage of those treated with glyburide were able to achieve the target glycemic control. Other studies found glycemic control to be better with glyburide.

Studies also looked at other classes or oral hypoglycemic agents. Thiazolidinediones are not recommended in pregnancy because they can readily cross the placenta, and have been associated with fetal death and growth retardation due to placental dysfunction. Alpha-glucosidase inhibitors have not been show to have harmful effects in animals, but are not recommended because of the lack of safety data in human pregnancy. Incretin-based therapies should not be used in pregnancy because reports have shown evidence of growth retardation and animal studies demonstrate delayed ossification and other skeletal effects. SGLT-2 inhibitors are also not recommended in pregnancy because animal studies have shown them to cause toxicity in the developing kidney during the 2nd and 3rd trimesters, and higher doses may cause low birth weight.

Though evidence suggests that metformin and glyburide may be good alternatives to insulin in pregnant patients, current guidelines do not recommend their use, and say these drugs should only be used in pregnancy if the patient is participating in a controlled clinical trial. For patients already taking either of these medications before becoming pregnant, they should continue to use these agents until insulin can be initiated, as risk of hyperglycemia is considered more dangerous than the effects of either of these drugs. In the UK, experts recommend the use of either of these agents to treat gestational diabetes, and say that metformin can be used in the pre-conception period and during pregnancy as an adjunct treatment or alternative treatment to insulin. Their argument is that the improved glycemic control that will occur as a result of using these medications will outweigh any risks associated with them.

Practice Pearls:
  • Metformin and glyburide may be safe and effective alternatives to insulin therapy in the treatment of diabetes during pregnancy, though further research is needed. The guidelines only recommend their use in pregnancy in patients that are part of a controlled clinical trial.
  • Metformin is favored over glyburide due to less maternal weight gain, lower birth weight, and treatment satisfaction. Glyburide is thought to possibly have more harmful effects on the fetus as well.
  • All other hypoglycemic drugs are not recommended due to a known risk in pregnancy or a lack of safety data.

Holt RIG, Lambert KD. “The use of oral hypoglycemic agents in pregnancy” Diabetic Medicine. 2014:31(3): 282-291.