Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice

Abstract

Glyburide's pharmacokinetics (PK) and pharmacodynamics have not been studied in women with gestational diabetes mellitus (GDM). The objective of this study was to assess steady-state PK of glyburide, as well as insulin sensitivity, beta-cell responsivity, and overall disposition indices after a mixed-meal tolerance test (MMTT) in women with GDM (n = 40), nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 26), and healthy pregnant women (n = 40, MMTT only). At equivalent doses, glyburide plasma concentrations were approximately 50% lower in pregnant women than in nonpregnant subjects. The average umbilical cord/maternal plasma glyburide concentration ratio at the time of delivery was 0.7 +/- 0.4. Insulin sensitivity was approximately fivefold lower in women with GDM as compared with healthy pregnant women. Despite comparable beta-cell responsivity indices, the average beta-cell function corrected for insulin resistance was more than 3.5-fold lower in women with glyburide-treated GDM than in healthy pregnant women. Women with GDM in whom glyburide treatment has failed may benefit from alternative medication or dosage escalation; however, fetal safety should be kept in mind.

Figure 1

Dose-normalized, steady state, mean glyburide plasma concentration-time profiles in gestational diabetic subjects during pregnancy and non-pregnant type 2 diabetic control subjects. Error bars represent standard deviations.

Figure 2

Semi logarithmic plot of simulated steady-state glyburide plasma concentration-time curves in gestational diabetic subjects denoted by red lines (1.25 mg to 23.75 mg glyburide every 12 hours) and non-pregnant type 2 diabetic control subjects (1.25 mg to 10 mg of glyburide every 12 hours) with the 99% confidence interval bordered by the blue lines. The simulations are based on a hundred sets of parameters at each dosage, with dosage increased in increments of 1.25 mg within the dosage range for both groups.

Figure 3

Mean glucose (panel A), insulin (panel B) and C-peptide (panel C) concentration time profiles following mixed meal tolerance test in gestational diabetic subjects considered to be clinically controlled with glyburide (diamonds), gestational age-matched healthy pregnant subjects (triangles) and non-pregnant type 2 diabetic subjects (squares). Error bars represent standard deviations.

Figure 4

Hyperbolic relationship between beta-cell responsivity index and insulin sensitivity for normal healthy pregnant subjects (mean: dotted line, individual subjects: open triangles), gestational diabetic subjects (mean: solid line, individual subjects: open diamonds), type 2 diabetic subjects (mean: dashed line, individual subjects: open squares). Large solid circle on each line represents the mean for the population. The hyperbolas for each group have been calculated not by fitting curves to the points, but rather by plotting the mean disposition index for each group (GDM: 193.1 min-2 per μU/mL; Healthy pregnant: 698.8 min-2 per μU/mL; T2DM: 165.6 min-2 per μU/mL). Therefore, the plot lines describe all the possible pairs of insulin sensitivity index and beta-cell responsivity index for a typical gestational diabetic, healthy pregnant and type-2 diabetic subject.