Antidiabetic Agent
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The evidence suggests that glyburide may be an acceptable alternative to insulin in gestational diabetes, but the risk factors for failure need to be considered in the decision to use the oral agent. Glyburide also may be beneficial for decreasing the incidence of fetal and newborn morbidity and mortality in developing countries and in some populations where the proper use of insulin is problematic. Moreover, either the agent does not cross the placenta in detectable amounts or is actively transported back to the mother. In either case, neonatal hypoglycemia secondary to glyburide appears to be a low risk. Insulin is the treatment of choice for diabetic types 1 and 2. For non-insulin-dependent diabetics (type 2), close control of the mother’s blood glucose with insulin, preferably starting before conception, will help to prevent the fetal and neonatal complications that occur with this disease. High maternal glucose levels, as may occur in diabetes mellitus, are associated with a number of maternal and fetal adverse effects, including fetal structural anomalies if the hyperglycemia occurs early in gestation. To prevent this toxicity, the American College of Obstetricians and Gynecologists recommends that insulin be used for types 1 and 2 diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (1,2).
FETAL RISK SUMMARY
Glyburide is a second-generation, oral sulfonylurea agent, structurally similar to acetohexamide and glipizide that is used for the treatment of adult-onset diabetes mellitus. It is not the treatment of choice for the pregnant diabetic patient. Glyburide is metabolized to inactive metabolites. The decrease in glyburide serum levels is biphasic with a terminal half-life of about 10 hours (3).
No fetotoxicity or teratogenicity was observed in pregnant mice, rats, and rabbits fed large doses of the agent (4). In pregnant rats, glyburide crossed the placenta to the fetus (fetal:maternal ratio 0.541) in amounts similar to diazepam (fetal:maternal ratio 0.641) (5).
In studies using in vitro techniques with human placentas, only relatively small amounts of glyburide were observed to transfer from the maternal to the fetal circulation (6–11), and the use of placentas from diabetic patients (7) or with high glucose concentrations (8) did not change the amounts transferred. Concentrations used on the maternal side of the perfused placenta model were approximately 800 ng/mL, much higher than the average peak serum level of 140–350 ng/mL obtained after a single 5-mg oral dose (9). Transport of the drug to the fetal side of the placenta was 0.62% at 2 hours.
The in vitro placental transfer, using a single cotyledon human placenta, of four oral hypoglycemic agents has been described (10). As expected, molecular weight was the most significant factor for drug transfer, with the dissociation constant (pKa) and lipid solubility providing a significant additive effect. The cumulative percentage placental transfer at 3 hours of the four agents and their approximate molecular weights (shown in parentheses) were tolbutamide (270) 21.5%, chlorpropamide (277) 11.0%, glipizide (446) 6.6%, and glyburide (494) 3.9% (10). In a study using similar in vitro techniques with human placentas, glyburide did not increase glucose transfer to the fetus or affect the placental uptake of glucose (11).
A commentary in 2001 considered several factors (pKa, molecular weight, lipid solubility, elimination half-life, and protein binding) that could limit glyburide from crossing the placenta (12). The short elimination half-life (4 hours) and extensive protein binding (99.8%) were thought to be the major determinants limiting transplacental transfer (12).
A 2006 study using an in vitro perfused human placental cotyledon reported evidence of active glyburide transport from the fetal to the maternal side (13). The transfer was against a concentration gradient, as the initial fetal:maternal concentration ratio was 0.92 and then decreased over 3 hours to 0.31. The investigators concluded that this was the first direct evidence of active transport from the fetus to the mother of any medicinal drug used during pregnancy (13).
A 1991 report described the outcomes of pregnancies in 21 non-insulin-dependent diabetic women who were treated with oral hypoglycemic agents (17 sulfonylureas, 3 biguanides, and 1 unknown type) during the 1st trimester (14). The duration of exposure was 3–28 weeks, but all patients were changed to insulin therapy at the first prenatal visit. Forty non-insulin-dependent diabetic matched women served as a control group. Eleven (52%) of the exposed infants had major or minor congenital malformations compared with 6 (15%) of the controls. Moreover, ear defects, a malformation that is observed, but uncommonly, in diabetic embryopathy, occurred in six of the exposed infants and in none of the controls. Two of the infants with defects (anencephaly; ventricular septal defect) were exposed in utero to glyburide during the first 10 and 23 weeks of gestation, respectively, but these and the other malformations observed, with the possible exception of the ear defects, were thought to be related to poor blood glucose control during organogenesis. The cluster of ear defects, however, suggested a drug effect or synergism between the drug and lack of metabolic control in the mother. Sixteen live births occurred in the exposed group compared with 36 in the control group. The groups did not differ in the incidence of hypoglycemia at birth (53% vs. 53%), but 3 of the exposed newborns (not exposed to glyburide) had severe hypoglycemia lasting 2, 4, and 7 days, even though the mothers had not used oral hypoglycemics close to delivery. This was attributed to irreversible β-cell hyperplasia that may have been increased by exposure to oral hypoglycemics. Hyperbilirubinemia was noted in 10 (67%) of 15 exposed newborns compared to 13 (36%) of controls (p <0.04), and polycythemia and hyperviscosity requiring partial exchange transfusions were observed in 4 (27%) of 15 exposed vs. 1 (3.0%) control (p <0.03) (1 exposed infant was not included in these data because of delivery after completion of study) (14).
The use of glyburide in all phases of human gestation has been reported in other studies (15–19). In these studies, glyburide (glibenclamide) was either used alone or combined with the oral antihyperglycemic agent, metformin (see Metformin). Neonatal hypoglycemia (blood glucose <25 mg/dL) was present in 4 of 15 (27%) newborns who were exposed to glyburide during gestation (16,17). This adverse effect was 3.5 times that observed in a group of newborns whose mothers were treated with insulin. Moreover, in one newborn, the hypoglycemia persisted for more than 48 hours (16).
A study published in 1995 assessed the risk of congenital malformations in infants of mothers with non-insulin-dependent diabetes (NIDDM) over a 6-year period (20). Women were included in the study if, during the first 8 weeks of pregnancy, they had not participated in a preconception care program and then had been treated either with diet alone (group 1), diet and oral hypoglycemic agents (predominantly chlorpropamide, glyburide, or glipizide) (group 2), or diet and exogenous insulin (group 3). The 302 women eligible for analysis gave birth to 332 infants (5 sets of twins and 16 with two or three separate singleton pregnancies during the study period). A total of 56 (16.9%) of the infants had one or more congenital malformations, 39 (11.7%) of which were classified as major anomalies (defined as those that were either lethal, caused significant morbidity, or required surgical repair). The major anomalies were divided among those involving the central nervous system, face, heart and great vessels, gastrointestinal, genitourinary, and skeletal (includes caudal regression syndrome) systems. Minor anomalies included all of these, except those of the central nervous system, and a miscellaneous group composed of sacral skin tags, cutis aplasia of the scalp, and hydroceles. The number of infants in each group and the number of major and minor anomalies observed were group 1—125 infants, 18 (14.4%) major, 6 (4.8%) minor; group 2—147 infants, 14 (9.5%) major, 9 (6.1%) minor; and group 3—60 infants, 7 (11.7%) major, 2 (3.3%) minor. There were no statistical differences among the groups. Six (4.1%) of the infants exposed in utero to oral hypoglycemic agents and four other infants in the other two groups had ear anomalies (included among those with face defects). Another important finding of this study was the independent association between the risk of major anomalies and poor glycemic control in early pregnancy. The study did not find an association between the use of oral hypoglycemics during organogenesis and congenital malformations because the observed anomalies appeared to be related to poor maternal glycemic control (20).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 37 newborns had been exposed to glyburide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (2.7%) major birth defect was observed (two expected), which was a cardiovascular defect (0.4 expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
A study published in 2000 compared the pregnancy outcomes in gestational diabetic women with singleton pregnancies who were randomly assigned to treatment with glyburide or insulin (21). A majority of the women (83%) were Hispanic, mostly Mexican American. The study was not blinded. The goals of treatment were the achievement of a mean glucose concentration of 90–105 mg% and fasting, preprandial, and postprandial glucose levels of 60–90, 80–95, and <120 mg%, respectively. A total of 404 women were enrolled, 201 in the glyburide group and 203 in the insulin group. The mean pretreatment glucose concentrations, fasting, preprandial, and postprandial concentrations, and the glycosylated hemoglobin’s in the glyburide and insulin groups were 114 vs. 116 mg%, 104 vs. 108 mg%, 104 vs. 107 mg%, 130 vs. 129 mg%, and 5.7% vs. 5.6%, respectively. These results are indicative of mild hyperglycemia. There were no significant differences between the groups in terms of any characteristic, including the gestational age at start of therapy and at delivery. The mean doses of glyburide and insulin were 9 mg/day and 85 units/day, respectively. Eight (4%) of the women randomized to glyburide failed to achieve good glycemic control and were changed to insulin. During treatment, the mean blood glucose concentrations and the mean fasting, preprandial, and postprandial values did not differ significantly between the glyburide and insulin groups. Nor was there a difference in the mean glycosylated hemoglobin values, 5.5% vs. 5.4%, respectively, measured late in the 3rd trimester. In 12 randomly selected women a mean 8 hours after the last dose, the glyburide maternal serum concentrations ranged from 50 to 150 ng/mL, whereas glyburide was undetectable in cord serum. No significant differences were measured between the groups in terms of neonatal features, metabolic outcomes, or perinatal mortality (21). An accompanying editorial explored the strengths and limitations of the study (22).
Several reports and an editorial have studied (23–27) or discussed (28) the use of glyburide for the treatment of gestational diabetes not controlled by diet. The studies reported favorable control of glucose levels with relatively few patients requiring a change to insulin therapy. However, in one study, glyburide-treated women had an increased risk of preeclampsia and their infants were more likely to require phototherapy for hyperbilirubinemia (25). Several risk factors have been identified that were predictors of glyburide failure: higher mean glucose values on glucose challenge test and more likely to have a test value ≥200 mg/dL (26); and diagnoses of diabetes earlier in gestation (23 vs. 28 weeks’) of older age (34 vs. 29 years) and multiparity, and with higher fasting glucoses (>110 mg/dL) (27).
BREASTFEEDING SUMMARY
Nondetectable levels of glyburide in breast milk were reported in a 2005 study involving 11 lactating women, 3 of whom were nursing infants (29). The analysis of glyburide in milk was conducted at two different laboratories. Of eight nonbreastfeeding subjects, six received a single 5- mg dose and two received a single 10-mg dose. Glyburide was not detected in the milk of these cases (detection limit 0.005 mcg/mL). Three breastfeeding women on a steady-state dose of glyburide (5 mg every morning for 4–7 days) also had nondetectable peak (4 hours post-dose) and trough glyburide levels in their milk (detection limit 0.080 mcg/mL). Blood glucose levels were normal in two of the breastfed infants (not determined in the third infant because supplements were being given) (29).
References
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