Several recent reviews of glyburide studies, such as one that looked at nine glyburide studies covering 745 patients taking glyburide and 645 patients taking insulin, also have been published (Ann. Pharmacother. 2008;42:483-90). In 2007, moreover, the 5th International Workshop-Conference on GDM concluded that glyburide is a legitimate alternative to insulin for GDM (Diabetes Care 2007;30:S251-60).
We also now know that unlike other, first-generation sulfonylureas that tend to cross the placenta freely, glyburide is 99.8% protein-bound and thus crosses the placenta only minimally.
Theoretically, there is one potential problem with glyburide. Because the drug acts by stimulating maternal pancreatic insulin production, it could potentially promote "pancreatic burnout," thus shortening the time to development of overt diabetes in women whose pancreas is struggling to begin with. Women who are obese and have significant insulin resistance at the start of their pregnancies thus might be susceptible to pancreatic burnout. Although this potential effect has not been demonstrated in any trials, it must be kept in mind.
It would be informative to conduct long-term follow-up studies that track the children of mothers who used glyburide during their pregnancies, but at this point it is unclear if such studies will be designed and carried out. The likelihood of additional randomized trials being conducted is practically nil, given the extent to which women already are choosing the oral hypoglycemics over insulin.
Glyburide in Practice
As clinicians, we must appreciate that the pharmacodynamics of glyburide are quite different in pregnant women, with important dosing implications for our patients. Indeed, for pregnant women, glyburide is not the 12-hour medication that it is in nonpregnant women.
During pregnancy, glyburide action peaks about 2.5 hours after it’s taken, and the increased renal clearance and metabolism of pregnancy (in addition to the short duration of therapy in this patient population) leave the drug with a "useful" life of only about 6-8 hours.
Because blood glucose peaks 60-90 minutes after a meal, we instruct our patients to take a glyburide dose a full hour before a planned meal. Otherwise, postprandial glucose peaks will not be controlled. Usually, a dose taken an hour before breakfast will help control postprandial peaks after breakfast and lunch but will not last for dinner. Another dose 1 hour before an evening meal can be given.
To effectively control fasting blood glucose, we instruct patients to take a glyburide dose between 10 p.m. and midnight so that the drug will still be active in the early morning when it is needed. If the dose is taken too early at night – at 8-9 p.m., for instance – it will peak between 10 p.m. and midnight, and will not be working at 6 a.m.
As it is with insulin, careful glucose monitoring is critical for determining optimal administration of glyburide and for balancing glyburide action with meals and snacks. Individual glycemic profiles should be analyzed each week, with the goal of keeping fasting blood glucose below 90 mg/dL, and postprandial levels below 130 mg/dL, while preventing maternal hypoglycemia.
Attention must be paid not only to times of consistent elevation in blood glucose levels, but also to the potential for dosage overlap – for instance, a prelunch dosage administered to correct consistently high postprandial glucose levels after the mid-day meal could lead to low blood glucose levels at about 4-5 p.m. as its action overlaps with the end duration of a morning dose.
Patients should always be prepared for vulnerable times and have a glucose tablet, juice box, or food with them to correct any periods of hypoglycemia.
Insulin should be added if more than 30% of blood glucose readings are above target with administration of 15-20 mg/day of glyburide.
Metformin as an Option
As ob.gyns, our experience with metformin, the other oral anti-hyperglycemic agent now available for treating GDM, came originally from its use as an infertility treatment in women with polycystic ovary syndrome (PCOS).
Metformin is frequently prescribed for women with PCOS to improve ovulation. These women have significant insulin resistance and are at high risk for developing GDM during their pregnancies. The main concern in this population, however, has been infertility, and studies have shown that metformin induces ovulation in women with PCOS.
Although metformin crosses the placenta, numerous studies have shown no increase in birth anomalies in women who conceive while taking the agent.
A study published a decade ago in women who chose whether or not to continue metformin treatment throughout their pregnancies showed that of those who discontinued metformin, 31% developed GDM, compared with only 3% of those who continued their metformin treatment (Fertil. Steril. 2002;77:520-5). These results helped fuel the idea that the agent may be a logical treatment for women with GDM.