Pharmacodynamics of Glyburide, Metformin, and Glyburide/Metformin Combination Therapy in the Treatment of Gestational Diabetes Mellitus

Abstract

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β-cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed-meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β-cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β-cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.

Figure 1.. Glucose, insulin and C-peptide concentration-time profiles for all subjects with gestational diabetes mellitus (GDM) and healthy pregnant subjects who completed the study and were adherent to study procedures.

Shown are mean concentrations at each time point with the standard deviation represented by unidirectional error bars. Time since initiation of the MMTT and dose in minutes is listed on the x axis and the concentration of C-peptide (pmol/L), glucose (mg/dL), or insulin (μU/mL) is on the y axis. Data for SD1 are shown with filled circles (means), solid lines, and upper error bars (standard deviation); data for SD2 are shown with open circles, dashed lines, and lower error bars. Treatment arms are represented by COMBO = metformin/glyburide combination therapy group (green), MET = metformin monotherapy group (purple), GLY = glyburide monotherapy group (blue) and HP = healthy pregnancy group (black). Significance is indicated by asterisks.

Figure 2.. Effect of gestational age on the mean disposition index in healthy pregnant subjects.

Only paired data for healthy pregnant subjects who completed study day 1 (SD1) and study day 2 (SD2) are included (n=28). Insulin sensitivity is depicted on the x axis, and total β cell responsivity is depicted on the y, and points depict the mean total β-cell responsivity and mean SI on SD1 (filled circle) and SD2 (open circle) for the HP group. The hyperbolas shown depict the calculated total β-cell responsivity given the range of SI values shown for HP on SD1 (solid line) and SD2 (dashed line) where total β-cell responsivity $=\frac{DI}{SI}$ and the DI value used was the mean total β-cell responsivity times the mean SI.

Figure 3.. Pharmacodynamic effects of GLY, MET and GLY/MET Combo therapies.

Gray line depicts the mean baseline disposition index for all adherent subjects with GDM who completed the study. The black line depicts the mean baseline disposition index for all healthy pregnant subjects who completed the study. The vectors depict the mean pharmacodynamic effect of GLY (blue arrow), MET (purple arrow) and GLY/MET combination therapy (green arrow). Solid dots represent mean baseline disposition index (study day 1) and open circles represent study day 2 mean disposition index adjusted for mean gestational age-dependent change.

Figure 4.. Effects of a splice variant of multidrug and toxin extrusion transporter 2 (MATE2-K) and organic cation transporter 2 (OCT2) genotype on metformin response and dose in women with GDM who were adherent and completed the study.

Figure 4A depicts a Tukey boxplot of the effects of MATE2-K genotype (rs12943590; AA, AG and GG) on metformin pharmacologic activity (i.e. change in insulin sensitivity between study day 1 and study day 2, adjusted for gestational age dependent changes) in women receiving metformin monotherapy. Figure 4B depicts a Tukey boxplot of the effects of PMAT genotype (rs2685753; AG and GG) on change in peak glucose concentrations in women receiving metformin monotherapy. Figure 4C depicts a Tukey boxplot of the effects of OCT2 genotype (rs316019, AC vs CC) on metformin dose on study day 2 in women receiving metformin monotherapy. *: p<0.05, **: p<0.01 and ***: p<0.001.