Diabetes Use Research Articles

243: Neonatal metabolic complications of gestational diabetes: comparison of glyburide, insulin & diet therapy

The use of glyburide for the treatment of gestational diabetes (GD) uncontrolled by diet alone has increased. While maternal glucose control with glyburide has been reported to be effective for treating GD,concern regarding the incidence of neonatal side effects remains. We compared the incidence of neonatal metabolic complications of infants born to women with GD treated with diet, glyburide, and insulin.

Glycemic control and hypoglycemia in Veterans Health Administration patients converted from glyburide to glipizide.

In 2009, the Veterans Health Administration (VHA) released a national bulletin regarding the risk of hypoglycemia associated with the use of glyburide in elderly patients with renal dysfunction. Providers were encouraged to avoid glyburide and use glipizide in patients with a calculated creatinine clearance (CrCl) of less than 50 mL per minute. Since this initiative, many veterans were converted by their providers from glyburide to glipizide regardless of renal impairment. To (a) identify whether hemoglobin A1c remained equivalent in patients converted from glyburide to glipizide, (b) evaluate the prevalence of hypoglycemia during treatment with glyburide or glipizide, (c) compare change in glycemic control for renally impaired versus nonimpaired patients, and (d) analyze dosage conversion ratios selected by providers and measures of patient follow-up after conversion including time until A1c measurement and number of glipizide dose titrations. This was a single-center, retrospective analysis of veterans converted from glyburide to glipizide from January 1, 2008, through May 31, 2010, who had documented A1c values concurrent with glyburide and glipizide use. A 2-sided equivalence analysis was used for the primary outcome. Equivalence was defined as a change in mean A1c of ± 0.2. Hypoglycemia was defined as blood glucose of less than 70 mg per dL, symptoms of hypoglycemia, or hypoglycemia that led to a fall, loss of consciousness, emergency room visit, hospitalization, or death. The pre- to post-conversion change in rates of hypoglycemia was tested for significance using a McNemar's test. In the 141 (99.3% male, 53.9% CrCl less than 50 mL per minute, mean age = 74.0 years) patients meeting inclusion criteria between 2008-2010, the average change in A1c (+ 0.34) was nonequivalent after conversion from glyburide to glipizide (7.08% vs. 7.42%, respectively). Hypoglycemia occurred more frequently during treatment with glyburide than glipizide (31.2% vs. 12.8%, respectively, P less than 0.001). Mean dose conversion ratios were consistent with VHA recommendations (1 mg per day glyburide = 1.26- 1.55 mg per day glipizide). Conversion from glyburide to glipizide was associated with an increase in A1c, but the incidence of hypoglycemia was reduced. Results of this study are consistent with the recommendation of the American Diabetes Association and European Association for the Study of Diabetes to use second-generation sulfonylureas other than glyburide. Patients converted to glipizide should be monitored closely to adjust therapy as appropriate to maintain glycemic control.

Impact of renal impairment on the risk of severe hypoglycaemia associated with the use of insulin and glyburide

Impact of renal impairment on the risk of severe hypoglycaemia associated with the use of insulin and glyburide

Intervention to Decrease Glyburide Use in Elderly Patients With Renal Insufficiency

Objectives The objectives of this study were to describe changes in glyburide prescribing in cohorts that were and were not targeted by a risk reduction project, assess factors associated with glyburide discontinuation, and evaluate changes in glycated hemoglobin (ie, HbA 1c) levels and rates of serious hypoglycemia. Methods This historical cohort study included a targeted cohort of 4368 outpatient veterans aged ≥65 years with active prescriptions for glyburide between April 1, 2007 and June 30, 2007 and serum creatinine (SCr) ≥2 mg/dL and a nontargeted cohort of 1886 outpatients meeting these same criteria between July 1, 2007 and September 3, 2007. The intervention in the risk reduction project took place on September 4, 2007 and entailed giving regional pharmacy leaders information about the increased risk of hypoglycemia with glyburide and the list of targeted patients for follow up with providers. For each patient, the study period was the time between the date they first met the eligibility criteria and March 31, 2008. All data were obtained from Veterans Affairs (VA) administrative databases. The primary outcome was the discontinuation of glyburide. Secondary outcomes were the change in HbA 1c after stopping glyburide and the rate of serious hypoglycemia after intervention. Results Incidence rate ratios (IRRs) for glyburide discontinuation in targeted versus nontargeted cohorts were statistically significantly elevated in September (IRR 2.1; 95% CI 1.7–2.5), October (IRR 1.3; 95% CI 1.1–1.6), and November 2007 (IRR 1.4; 95% CI 1.1–1.7). The intervention, black race, SCr, Charlson comorbidity score, new glyburide use, and VA region were independently associated with discontinuation. Among patients in the targeted cohort who discontinued glyburide, mean (SD) HbA 1c at baseline and after discontinuation were 7.17% (1.35%), and 7.22% (1.34%), respectively ( P = 0.36). The hypoglycemia rates/1000 person-days were 0.093 before the intervention and 0.070 afterwards ( P = 0.10). Conclusion A one-time intervention in a risk reduction project decreased glyburide use over a 3-month period in elderly outpatients with renal insufficiency without compromising glucose control.

Gestational diabetes mellitus: Non-insulin management.

Gestational diabetes mellitus (GDM) complicates a substantial number of pregnancies. There is consensus that in patients of GDM, excellent blood glucose control, with diet and, when necessary, oral hypoglycemics and insulin results in improved perinatal outcomes, and appreciably reduces the probability of serious neonatal morbidity compared with routine prenatal care. Goals of metabolic management of a pregnancy complicated with GDM have to balance the needs of a healthy pregnancy with the requirements to control glucose level. Medical nutrition therapy is the cornerstone of therapy for women with GDM. Surveillance with daily self-monitoring of blood glucose has been found to help guide management in a much better way than blood glucose checking in labs and clinics, which tends to be less frequent. Historically, insulin has been the therapeutic agent of choice for controlling hyperglycemia in pregnant women. However, difficulty in medication administration with multiple daily injections, potential for hypoglycemia, and increase in appetite and weight make this therapeutic option cumbersome for many pregnant patients. Use of oral hypogycemic agents (OHAs) in pregnancy has opened new vistas for GDM management. At present, there is a growing acceptance of glyburide (glibenclamide) use as the primary therapy for GDM. Glyburide and metformin have been found to be safe, effective and economical for the treatment of gestational diabetes. Insulin, however, still has an important role to play in GDM. GDM is a window of opportunity, which needs to be seized, for prevention of diabetes in future life. Goal of our educational programs should be not only to improve pregnancy outcomes but also to promote healthy lifestyle changes for the mother that will last long after delivery. Team effort on part of obstetricians and endocrinologists is required to make “the diabetes capital of the world” into “the diabetes care capital of the world”.

More Reasons to Say Goodbye to Glyburide

Sulfonylureas have been used to control hyperglycemia in type 2 diabetes longer than any class of agents except insulins. Their use early in the course of diabetes is supported by evidence of long-term medical benefit (1), and although available in generic form and thus not commercially promoted, they are widely prescribed (2). Given these facts, it is surprising that much remains unknown about these agents, notably how the various members of the class should be deployed in current treatment algorithms. An article by Zeller et al. in this issue of JCEM (3) sheds considerable light on this question. The authors report analyses of prospectively collected data from a French registry concerning experience of patients with type 2 diabetes who were hospitalized for myocardial infarction. The question posed was what association, if any, might exist between prior use of sulfonylureas and death and other in-hospital outcomes in these patients. Analyses included comparisons between the individual sulfonylureas used in this population: glyburide (called glibenclamide in Europe), glimepiride, and gliclazide (in most cases given as an extended-acting formulation). The rationale for the study came from the known adverse effect of glyburide on cardiac ischemic preconditioning, the clinical relevance of which has been uncertain. One key finding of the French study was that, among the 1310 acutely ill patients studied, unadjusted mortality rates were lower for those whose treatment on admission included a sulfonylurea (3.9%) than for those taking insulin (9.4%), those on no antihyperglycemic drugs (8.4%), and those on oral therapies other than sulfonylureas (6.4%). Another was that when patients taking glyburide were compared with those taking gliclazide or glimepiride, two sulfonylureas that appear to lack cardiac effects, early mortality was almost 3-fold higher (7.5 vs. 2.7%) with glyburide. It is well known that epidemiological analyses of “real-world” experiences with prescribed pharmacotherapy may be confounded by incomplete collection of information on actual drug usage, concomitant therapies, and medical outcomes, in addition to biases introduced by physicians’ tendencies to assign different treatments to different kinds of patients. Many of these problems were reduced or eliminated by the prospective design of this study, which included systematic recording of detailed clinical information on all patients in a narrow window of time by a structured team of investigators. The problem of allocation bias in assignment of treatments, however, remains in this study as in others. Hence, the authors used several statistical methods to adjust for this kind of confounding, including an extensive multivariable model, further adjustment using a propensity score for assignment to glyburide treatment, and analysis of findings with glyburide vs. the other sulfonylureas by subgroups. These statistical adjustments did not alter the associations of sulfonylurea use with lower mortality than other forms of therapy, and of glyburide use with higher mortality than seen with the other sulfonylureas. The excess of mortality with glyburide vs. other sulfonylureas showed no tendency toward heterogeneity between subgroups. Thus, several approaches to testing the validity of the observations were supportive, and the magnitude of the effects was substantial. After multivariable adjustment, the risk of death accompanyinguseofa sulfonylureawashalf thatwhena sulfonylurea was not used (odds ratio, 0.50; 95% confidence interval, 0.27–0.94; P 0.03). After similar adjustment for covariates, the risk of early mortality was 85% lower with glimepiride or gliclazide than with glyburide (odds ratio, 0.15; 95% confidence interval, 0.04–0.56; P 0.005), and with the propensity score included in the model, the risk was 87%lower(oddsratio,0.13;95%confidence interval,0.21–

Impaired renal function modifies the risk of severe hypoglycaemia among users of insulin but not glyburide: a population-based nested case–control study

Little evidence justifies the avoidance of glyburide in patients with impaired renal function. We aimed to determine if renal function modifies the risk of hypoglycaemia among patients using glyburide. We conducted a nested case-control study using administrative records and laboratory data from Ontario, Canada. We included outpatients 66years of age and older with diabetes mellitus and prescriptions for glyburide, insulin or metformin. We ascertained hypoglycaemic events using administrative records and estimated glomerular filtration rates (eGFR) using serum creatinine concentrations. From a cohort of 19,620 patients, we identified 204 cases whose eGFR was ≥ 60mL/min/1.73m(2) (normal renal function) and 354 cases whose eGFR was < 60mL/min/1.73m(2) (impaired renal function). Compared to metformin, glyburide is associated with a greater risk of hypoglycaemia in patients with both normal [adjusted odds ratio (OR) 9.0, 95% confidence interval (95% CI) 4.9-16.4] and impaired renal function (adjusted OR 6.0, 95% CI 3.8-9.5). We observed a similar relationship when comparing insulin to metformin; the risk was greater in patients with normal renal function (adjusted OR 18.7, 95% CI 10.5-33.5) compared to those with impaired renal function (adjusted OR 7.9, 95% CI 5.0-12.4). Tests of interaction showed that among glyburide users, renal function did not significantly modify the risk of hypoglycaemia, but among insulin users, impaired renal function is associated with a lower risk. In this population-based study, impaired renal function did not augment the risk of hypoglycaemia associated with glyburide use.

Contributions of human cytochrome P450 enzymes to glyburide metabolism

Glyburide (GLB) is a widely used oral sulfonylurea for the treatment of gestational diabetes. The therapeutic use of GLB is often complicated by a substantial inter-individual variability in the pharmacokinetics and pharmacodynamics of the drug in human populations, which might be caused by inter-individual variations in factors such as GLB metabolism. Therefore, there has been a continued interest in identifying human cytochrome P450 (CYP) isoforms that play a major role in the metabolism of GLB. However, contrasting data are available in the present literature in this regard. The present study systematically investigated the contributions of various human CYP isoforms (CYP3A4, CYP3A5, CYP2C8, CYP2C9 and CYP2C19) to in vitro metabolism of GLB. GLB depletion and metabolite formation in human liver microsomes were most significantly inhibited by the CYP3A inhibitor ketoconazole compared with the inhibitors of other CYP isoforms. Furthermore, multiple correlation analysis between GLB depletion and individual CYP activities was performed, demonstrating a significant correlation between GLB depletion and the CYP3A probe activity in 16 individual human liver microsomal preparations, but not between GLB depletion and the CYP2C19, CYP2C8 or CYP2C9 probe activity. By using recombinant supersomes overexpressing individual human CYP isoforms, it was found that GLB could be depleted by all the enzymes tested; however, the intrinsic clearance (V(max)/K(m)) of CYP3A4 for GLB depletion was 4-17 times greater than that of other CYP isoforms. These results confirm that human CYP3A4 is the major enzyme involved in the in vitro metabolism of GLB.

The glyburide report card

Over the past decade, several studies have been published describing the use of glyburide for the treatment of women with gestational diabetes (GDM). These studies include randomized prospective trials, prospective studies, and cohort studies. With a total of more than 1000 patients, they encompass a wide range of patient populations and treatment centers and demonstrate the effectiveness of oral treatment in achieving good glycemic control in women with GDM. Taken together, these studies have demonstrated that glyburide is as safe and as useful as insulin for the treament of women with GDM and will likely become universally accepted as the first line drug of choice for treatment of this condition.

Oral hypoglycemic therapy: Understanding the mechanisms of transplacental transfer

The current trend towards an increase in the rate of Type 2 diabetes in women of childbearing age will inevitably result in an increasing number of women requiring hypoglycemic therapy throughout pregnancy. For patients with Type 2 diabetes or gestational diabetes, oral hypoglycemic agents (OHAs) represent an attractive alternative to insulin therapy. However, there exists some apprehension regarding the use of OHAs during pregnancy. Although the current accepted understanding is that most drugs administered during pregnancy can permeate the placental barrier, there is sufficient evidence to suggest that the placenta is capable of limiting fetal exposure to drugs. In particular, large sets of data on the transplacental transfer and clinical use of glyburide in pregnancy have suggested that glyburide may be a safe alternative to insulin therapy. Glyburide's limited fetal transfer has been attributed to its high protein binding, rapid clearance rate and the role of placental efflux transporters such as the breast cancer resistance protein. However, there are a number of maternal, placental and fetal factors that may alter the transplacental passage of drugs used in pregnancy. Therefore, it is essential that OHAs are further investigated to determine their safety with confidence and provide better treatment options for diabetes in pregnancy.

Safety of Glyburide for Gestational Diabetes: A Meta-Analysis of Pregnancy Outcomes

Gestational diabetes mellitus affects approximately 4% of all pregnancies. As with other oral hypoglycemics, the use of glyburide in pregnancy has been limited by fears of neonatal hypoglycemia following fetal exposure. Recent experimental and clinical studies have suggested, however, that the drug is not detectable in umbilical blood. To determine the safety of glyburide use in pregnancy in the treatment of gestational diabetes compared with insulin therapy by analyzing all available human studies. We conducted a systematic review and meta-analysis of all randomized and cohort studies that reported on the perinatal complications among women with gestational diabetes who received glyburide versus insulin. MEDLINE, EMBASE, and biological abstracts using BIOSIS previews were searched from inception of these databases through October 2006. The following outcomes were included: macrosomia, birthweight, gestational age, neonatal hypoglycemia, and intensive care unit (ICU) admissions. Odds ratios were calculated by the random effects method using Cochrane's Review Manager version 4.3. Nine studies met the inclusion criteria, including a total of 745 glyburideexposed pregnancies and 637 insulin-exposed pregnancies, with each adverse perinatal outcome reported by 4-7 studies. The use of glyburide was not associated with risk of macrosomia (OR 1.07; 95% CI 0.78 to 1.47), differences in birth weight (weighted mean difference [WMD] OR 20.46 g; 95% CI -34.90 to 75.82), rate of large for gestational age (OR 1.04; 95% CI 0.75 to 1.43), differences in gestational age at birth (WMD 0.02 wk; 95% CI -0.23 to 0.26), ICU admission (OR 0.95; 95% CI 0.43 to 2.09), or increased risk of neonatal hypoglycemia (OR 1.24; 95% CI 0.91 to 1.69). The data shown here do not suggest increased perinatal risks with glyburide. The effectiveness and safety of glyburide require further evaluation, as most studies to date were not randomized.

Treating the mother – protecting the unborn: The safety of hypoglycemic drugs in pregnancy

The purpose of this review is to provide a brief overview of the safety of antidiabetics in pregnancy. Specifically, concerns over teratogenicity due to the possible placental transfer of antidiabetics as well as maternal and neonatal outcomes are addressed. Several new insulin analogs are currently available for the treatment of diabetes. Due to the improved glycemic control demonstrated in non pregnant patients, these analogs may also prove to be beneficial in pregnancy. Insulin lispro is the only insulin analog that has been systematically studied in pregnancy. Results of these studies show a lack of transfer across the placenta and no adverse fetal and neonatal outcomes. The use of oral hypoglycemic agents in pregnancy is also generating interest. To date, there has been only one randomized controlled trial investigating the use of glyburide which found it to be safe and effective in the management of gestational diabetes mellitus. The lack of randomized controlled trials for antidiabetics in pregnancy highlights the need for more comprehensive investigation regarding their safety and efficacy.

Interactions of K+ ATP channel blockers with Na+/K+-ATPase

Two K(+) (ATP) channel blockers, 5-hydroxydecanoate (5-HD) and glyburide, are often used to study cross-talk between Na(+)/K(+)-ATPase and these channels. The aim of this work was to characterize the effects of these blockers on purified Na(+)/K(+)-ATPase as an aid to appropriate use of these drugs in studies on this cross-talk. In contrast to known dual effects (activating and inhibitory) of other fatty acids on Na(+)/K(+)-ATPase, 5-HD only inhibited the enzyme at concentrations exceeding those that block mitochondrial K(+) (ATP) channels. 5-HD did not affect the ouabain sensitivity of Na(+)/K(+)-ATPase. Glyburide had both activating and inhibitory effects on Na(+)/K(+)-ATPase at concentrations used to block plasma membrane K(+) (ATP) channels. The findings justify the use of 5-HD as specific mitochondrial channel blocker in studies on the relation of this channel to Na(+)/K(+)-ATPase, but question the use of glyburide as a specific blocker of plasma membrane K(+) (ATP) channels, when the relation of this channel to Na(+)/K(+)-ATPase is being studied.

Pharmacological Management of Gestational Diabetes

To provide a review of the background literature regarding the pharmacological management of gestational diabetes. This is a literature review. Information is available regarding the use of some, but not all, oral antidiabetes agents in pregnancy. Available evidence supports the use of glyburide during pregnancy. Evidence is inadequate to support or refute the use of metformin, an agent that has been shown to cross the placenta and thus could be helpful or harmful to the developing fetus.

Identification of glyburide metabolites formed by hepatic and placental microsomes of humans and baboons

Glyburide (glibenclamide) is a second-generation sulfonylurea used for treatment of type-2 and gestational diabetes mellitus. To date, two glyburide metabolites have been identified in maternal urine: namely, 4- trans-hydroxycyclohexyl glyburide and 3- cis-hydroxycyclohexyl glyburide. The use of glyburide to treat gestational diabetes prompted us to investigate its metabolism by the placenta. The metabolism of glyburide by microsomal preparations from human and baboon placenta was compared with metabolism by their livers. The metabolites formed by the microsomes of the four tissues were identified by high-performance liquid chromatography–mass spectrometry using retention times, ion current (extracted at m/ z 510), and selected-ion monitoring. The data obtained revealed the formation of six distinct hydroxylated derivatives of glyburide by each of the four microsomal preparations. However, the amounts of the six metabolites formed by the placentas were a fraction of that formed by the livers. Moreover, the relative quantities of each metabolite formed differed between species as well as between the two tissues. Also, the structure of the unidentified metabolites was determined by comparison with synthesized standards. These metabolites were identified as the 4- cis-hydroxycyclohexyl glyburide, 3- trans-hydroxycyclohexyl glyburide, and 2- trans-hydroxycyclohexyl glyburide. Therefore, one glyburide metabolite remains to be identified, but the data we obtained allowed us to suggest its structure.

Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization

This study was undertaken to compare the use of glyburide with insulin for the treatment of gestational diabetes mellitus (GDM) unresponsive to diet therapy. A retrospective study was performed among women with singleton pregnancies who had GDM diagnosed, with fasting plasma glucose 140 mg/dL or less on glucose tolerance testing, between 12 and 34 weeks who failed diet therapy from 1999 to 2002. We identified 584 women and compared those treated with insulin between 1999 and 2000 with women treated with glyburide between 2001 and 2002. Maternal and neonatal outcomes and complications were assessed. Statistical methods included univariate analyses and multivariable logistic regression. In 1999 through 2000, 268 women had GDM diagnosed and were treated with insulin; in 2001 through 2002, 316 women had GDM diagnosed of which 236 (75%) received glyburide. The 2 groups were similar with regard to age, nulliparity, and historical GDM risk factors; however, women in the insulin group had a higher mean body mass index (31.9 vs 30.6 kg/m 2 , P=.04), a greater proportion identified themselves as white (43%, 28%, P<.001) and fewer as Asian (24%, 37%, P=.001), and they had a significantly higher mean fasting on glucose tolerance test (105.4 vs 102.4 mg/dL , P=.005) compared with the glyburide group. There were no significant differences in birth weight (3599+/-650 g vs 3661+/-629 g, P=.3), macrosomia (24%, 25%, P=.7), or cesarean delivery (35%, 39 %, P=.4). Women in the glyburide group had a higher incidence of preeclampsia (12%, 6%, P=.02), and neonates in the glyburide group were more likely to receive phototherapy (9%, 5%, P<.05), and less likely to be admitted to the neonatal intensive care unit (NICU) (15%, 24%, P=.008) though they had a longer NICU length of stay (4.3+/-9.6 vs 8.0+/-10.1, P=.002). Posttreatment glycemic control data were available for 122 women treated with insulin and 137 women treated with glyburide. More women in the glyburide group achieved mean fasting and postprandial goals (86%, 63%, P<.001). These findings remained significant in logistic regression analysis. In a large managed care organization, glyburide was at least as effective as insulin in achieving glycemic control and similar birth weights in women with GDM who failed diet therapy. The increased risk of preeclampsia and phototherapy in the glyburide group warrant further study.

Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization

Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization

Use of Glyburide for the Treatment of Gestational Diabetes: The San Antonio Experience

A recent randomized trial showed glyburide to be as effective as insulin for treating gestational diabetes mellitus (GDM). The present study evaluated glyburide in 75 women with GDM, diagnosed using the American DiabetesAssociation criteria. All women received nutritional therapy and were given a glucose meter with which to monitor blood sugar before and 2 hours after each meal and at bedtime. If good control (mean glucose of 105 mg/dL or less; fasting/premeal values of 95 mg/dL or lower; 2-hour postprandial values of 115 mg/dL or below) was not achieved within 2 weeks, women were offered glyburide as long as they were at 11 to 33 weeks gestational age and had a fasting blood glucose of less than 140 mg/dL during a 3-hour glucose tolerance test (GTT). The starting dose was 2.5 mg daily, usually given in the morning. The dose was adjusted as needed but only at intervals of 3 days or longer. Insulin was administered if glyburide treatment failed to produce adequate glycemic control. Glyburide provided good glycemic control in 63 of the 75 women (84%), whereas 12 received insulin before delivery. Patient characteristics and diabetes risk factors were similar in the 2 groups, but women who responded had significantly lower glucose levels on the GTT. The 2 groups did not differ in body mass index before pregnancy or at the time GDM was diagnosed. Women who required insulin had lower gestational ages at the time glyburide therapy began, and their overall mean blood glucose was higher (114 vs. 108 mg/dL). Only 2 of the 12 insulin-treated women had received maximum doses of glyburide. Eight of them did not achieve adequate blood sugar control by the time of delivery. Approximately three fourths of responsive women took 1 2.5- or 5-mg dose of glyburide once a day. Fetal macrosomia (birth weight exceeding 4000 g) was similarly frequent in the 2 groups, as were mean birth weights. A larger proportion of infants born to women who did not respond to glyburide required intravenous glucose infusions while in the nursery because of hypoglycemia (25% vs. 13%). Glyburide is effective in a substantial majority of women with GDM for whom nutritional therapy alone fails to adequately lower the blood glucose.

The transfer of glyburide into breast milk

Purpose To determine the extent of transfer of glyburide into breast milk in women with type 2 diabetes. Presently women are advised not to breastfeed while on oral hypoglycemics. Methods Six women were studied following a single 5 mg oral dose of glyburide. Glyburide concentrations in plasma and milk were measured by high performance liquid chromatography with fluorescence detection following liquid-liquid extraction with chloroform and derivatization with NBD-Chloride. Results The subjects had a mean age of 38 years (range 33-42 years) and a mean body weight of 91 kg (range 69–123 kg). When normalized to body weight, the median dose of glyburide was 0.06 mg•kg−1•day−1 (range 0.04-0.07 mg•kg−1•day−1). There was no detectable glyburide in any of the milk samples (limit of detection (LOD) 5ng/ml) over an 8 hour period. In contrast, plasma concentrations were within the normal range for patients taking 5 mg per day of the drug. Conclusions The concentrations of glyburide in breast milk are not detectable above the 5ng/ml LOD. Thus the maximum relative infant exposure is negligible for breastfeeding. We conclude that glyburide use by breastfeeding mothers is safe. Nevertheless, it is still prudent to follow the baby for potential signs of hypoglycemia. Clinical Pharmacology & Therapeutics (2004) 75, P24–P24; doi: 10.1016/j.clpt.2003.11.089

Use of glyburide for the treatment of gestational diabetes: the San Antonio experience

Objective: Equivalent efficacy of glyburide and insulin for treatment of gestational diabetes (GDM) was demonstrated in a recent randomized trial. We describe our experience with glyburide in practice, and suggest factors that predict failure of glyburide treatment.Methods: Women with GDM treated with glyburide were studied. They were divided into two groups: those who achieved adequate glycemic control with glyburide, and those who did not. The groups were compared in terms of baseline characteristics, including diabetes risk factors and glucose testing values. Receiver operating characteristics (ROC) curves were generated to identify thresholds for fasting plasma glucose and body mass index (BMI) that would predict glyburide failure.Results: Seventy-five women were analyzed: 63 (84%) were successfully treated with glyburide, and 12 (16%) were not. Baseline characteristics were similar between the groups, except that failures had higher 3-h glucose tolerance test (GTT) values at all time points. ROC curves for fasting plasma glucose, pre-pregnancy BMI and BMI at diagnosis revealed no cut-off points for predicting failure of glyburide therapy. However, when fasting plasma glucose value on the GTT was ≥110 mg/dl, 24% of women failed to respond to glyburide, compared to 12% at <110 mg/dl (p=0.15).Conclusion: In treatment of GDM, glyburide is successful in achieving good glycemic control in most women. Women with high fasting plasma glucose levels, however, may not respond adequately to glyburide therapy.