Are We Optimizing Gestational Diabetes Treatment With Glyburide? The Pharmacologic Basis for Better Clinical Practice

Abstract

Glyburide's PK and PD have not been studied in women with gestational diabetes mellitus (GDM). The objective was to assess steady-state PK of glyburide as well as insulin sensitivity, beta-cell responsivity and overall disposition indices following a mixed meal tolerance test (MMTT) in GDM (n=40), non-pregnant type 2 diabetic (T2DM) (n=26) and healthy pregnant (n=40, MMTT only) women. At equivalent doses, glyburide plasma concentrations were ~50% lower in pregnancy compared to non-pregnant women. Average glyburide umbilical cord to maternal plasma concentration ratio at the time of delivery was 0.7 ± 0.4. Insulin sensitivity was ~5-fold lower in women with GDM compared to healthy pregnancy. Despite comparable beta-cell responsivity index, average beta-cell function corrected for insulin resistance was >3.5-fold lower in women with glyburide-treated GDM than healthy pregnancy. Women with GDM that fail glyburide may benefit from alternate medication selection or dosage escalation, though fetal safety should be considered.Corresponding Author and Reprint Requests: Mary F. Hebert, Pharm.D., FCCP, University of Washington, Department of Pharmacy, 1959 NE Pacific St., H-375 Health Science Center, Box 357630, Seattle WA 98195-7630, Phone: 206-616-5016, Fax: 206-543-3835, Email: E-mail: mhebert@u.washington.edu. * Current address: Pfizer Global Research and Development, San Diego CA CONFLICT OF INTEREST/DISCLOSURE At the time of study conduct and analysis, the authors declare no conflict of interest. However, since completion of the study, Dr. Vicini's affiliation has become Pfizer Global Research and Development. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2010 June 1. Published in final edited form as:Clin Pharmacol Ther. Gestational diabetes mellitus (GDM) complicates 5-12% of pregnancies and is associated with adverse pregnancy outcomes. Insulin has been the mainstay of pharmacotherapy for GDM. Glyburide's (GLY) advantages include easier route of administration and schedule as well as improved patient satisfaction and adherence. GLY's acceptance has been due to its comparable efficacy with insulin and limited transfer to the fetus.(1,2) However, the pharmacokinetics (PK) of GLY have not been studied in pregnancy and dosage strategies generally follow those used in non-pregnant patients with type 2 diabetes mellitus (T2DM). We hypothesized that the PK of GLY would be different during pregnancy, due to the expected changes in metabolism, protein binding, and body composition. In addition, the effects of GLY on the insulin sensitivity and secretion parameters have not been systematically studied. Our objectives were to compare GLY PK in women with GDM and non-pregnant T2DM, to measure fetal exposure to glyburide at delivery and to evaluate insulin sensitivity (SI), beta-cell responsivity index (Φ total ) and disposition index (DI) following a mixed meal tolerance test (MMTT) in women with GDM on GLY therapy, compared with gestational age-matched healthy pregnant ...

Effects of antidiabetic agents on pancreatic beta-cell function in gestational diabetes: is there enough evidence?

“…Of note, even the studies that reported some quantitative data on beta-cell function effects of treatment, which are summarized in Table 1, typically presented basic information, obtained by simple, empirical indices of beta-cell function, such as the insulinogenic index, or the HOMA beta-cell index. Only the study by Hebert et al [8] presented more accurate results on betacell function, based on mathematical modeling. However, even this study [8] had limitations, due to the relatively low number of the GDM women, and to the type of test performed, which was a mixed meal tolerance test instead of an OGTT.…”

“…Only the study by Hebert et al [8] presented more accurate results on betacell function, based on mathematical modeling. However, even this study [8] had limitations, due to the relatively low number of the GDM women, and to the type of test performed, which was a mixed meal tolerance test instead of an OGTT. In fact, OGTT is the standard procedure for diagnosing GDM, though it may be ethically questionable to repeat this examination in already diagnosed GDM women.…”

“…However, to our knowledge, few studied reported quantitative information on possible amelioration of beta-cell function. [8][9][10] The study by Hebert et al [8] included 40 women with GDM, 40 healthy pregnant and 26 non-pregnant women with type 2 diabetes. All women with GDM, and the majority of women with type 2 diabetes, were treated with glyburide twice daily.…”

“…This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. [8] 40 women Glyburide Model-based indices (beta-cell responsivity, disposition index), based on mixed meal test Glueck et al [9] 3 of 39 polycystic ovary syndrome women Metformin Empirical index (HOMA beta-cell)…”

Psychotropic Medications in Pregnancy and the Postpartum Period

“…11 Thus, physiological changes that accommodate the developing pregnancy can have profound impact on medications in pregnancy, potentially necessitating a higher dose of medication than would be commonly utilized for nonpregnant populations. 13,14 In addition, as each trimester passes, not only does the maternal physiology change but also the risks of taking medications change. In the first trimester, concern about teratogenicity and major fetal anomalies during the initial development of fetal organs and systems is present.…”