Kirsten Grabowska - UBC Department of Obstetrics & Gynaecology

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Jacobson et al 123and 3 bone injuries. Mean birth weights for injuredneonates in the insulin group was 4048 g and 3906 g inthe glyburide group. No infants in the ING group hadidentified birth injuries.Chart review did not reveal the reasons 80 eligiblewomen who had GDM diagnosed in 2001 through 2002were initially treated with insulin instead of glyburide(ING group). The glyburide and ING groups weresimilar (data not shown) with a few notable exceptions:women in the ING group had higher mean BMI (33.9 vs30.6 kg/m 2 , P = .003), were less likely to identifythemselves as Asian (24%, 37%, P = .02), and had ahigher mean fasting on GTT (108.7 vs 102.4 mg/dL,P = .001).Maternal and neonatal outcomes in the glyburide andING groups were similar (data not shown), includingbirth weight (3661 G 629 g vs 3608 G 564 g, P = .48),preeclampsia (12%, 5%, P = .06), and phototherapy(9%, 4%, P = .11). Admission rates to the NICU weresimilar (15%, 10%, P = .27), though length of staywas longer for the glyburide group (8.0 G 10.1 days vs2.8 G 2.8 days, P = .01).Comparison of all women who received diagnoses in1999 through 2000 (insulin group) with all women whoreceived diagnoses in 2001 through 2002 (glyburide andING groups) demonstrated no significant differences indemographic or descriptive variables (data not shown)with 1 exception. Women who had GDM diagnosed in1999 through 2000 were less likely to identify themselvesas Asian (24%, 34%, P = .008) and more likely toidentify themselves as white (43%, 28%, P ! .001),There was an 18% increase in the number of womenmeeting study diagnostic criteria over the 2 periods.CommentOur retrospective study suggests that glyburide can beeffectively introduced for the treatment of women withGDM and fasting plasma glucose 140 mg/dL or less onGTT, into a large and diverse managed-care populationachieving results similar to insulin therapy. We found nosignificant differences in birth weight or rates of LGA.In addition, women treated with glyburide achievedbetter glycemic control, a finding that remained significantafter adjusting for characteristics that differedbetween the groups, including BMI, ethnicity, degreeof glucose intolerance, and gestational age at diagnosisof GDM. Although it is possible that women onglyburide had better compliance than those on insulin,among women with retrievable BS values, daily testingrates were similar between the 2 groups suggestingsimilar levels of compliance.Our study had several findings not previously reported.The glyburide group had a higher incidence ofpreeclampsia compared with the insulin group even aftercontrolling for confounders such as BMI and ethnicity.Although metformin, a biguanide, has been associatedwith increased risk of preeclampsia, this has not beennoted with the sulfonylureas. 7 Animal studies suggestglyburide inhibits vascular smooth muscle ATP-sensitivepotassium channel activity and increases systemic vascularresistance, and human in vitro studies suggest thatglyburide antagonizes cicletanine-induced relaxation inarteries from women with preeclampsia and thereforemay effect the natural vasodilatory substances of pregnancy.8,9Another unexpected finding was the higher rate ofphototherapy in the glyburide group. Paradoxically,both groups had similar rates of hyperbilirubinemia.The higher NICU admission rate in the insulin groupmay be due to practitioners selectively admitting infantsborn to women on insulin for a short observationperiod; however, the low rate of NICU admission inthe ING group would argue against this. Of concern isthe longer NICU length of stay in the glyburide groupthat could be due to their higher rate of phototherapy. Itis reassuring that all groups had similar rates of assistedventilation suggesting similar rates of respiratory distresssyndrome between the groups. The higher rate ofbirth injuries in the glyburide group, although notstatistically significant, warrants further investigation.The retrospective nature of our study lends itself toinherent biases. Comparison of patients treated in 1999through 2000 (insulin group) with those treated in 2001through 2002 (glyburide and ING groups) suggestedthere was a clear demographic change in the populationreflected by decreased white and increased Asian ethnicitiesover time. Although all patients identified in2001 through 2002 were eligible for glyburide, only 75%were initially treated with glyburide. Comparison of theglyburide with the ING group suggests a selection biasfor administration of glyburide, women receiving glyburidehad lower BMIs, lower mean fasting on GTT,and were more likely to be Asian. Logistic regressionmodeling controlling for ethnicity and these clinicalvariables still found a higher rate of preeclampsia, needfor phototherapy, and lower NICU admission rate inthe glyburide group. However, adjusted analysis maynot completely account for differences in the groups thatoccur because of population differences due to ourretrospective study design.Our study includes significantly more patients thanother studies published since the publication by Langeret al. 10-15 Our patient population is particularly diversewith Hispanics and Asians, although only 4% wereblack. Twelve percent of the glyburide group wereswitched to insulin and another 5% discontinued glyburideand never started insulin. Overall, this is significantlymore than the 4% reported by Langer et al, butmuch closer to current reports. 9-12 However, unlike thecontrolled trial of Langer et al with a strict dosing
124 Jacobson et alprotocol, management may not have been consistentamong physicians in our retrospective study.Although we found no significant differences in meanbirth weights and rates of LGA and macrosomiabetween our groups, our overall birth weights and rateswere greater in our study than Langer et al reports.However, several studies since have reported higherrates of LGA and macrosomia. 10,11,13-15 There areseveral possible explanations. Our sample includedmore women with risk factors such as family historyof DM and history of GDM as well as greater maternalage. Our study included more women with greaterglucose intolerance as evidenced by mean GLT valuesand by our use of NDDG cut-offs, reflected in ourhigher mean fasting, 1-hour, and 2-hour values on GTT.Langer’s group had lower fasting and postprandial BSgoals and their mean daily glyburide and insulin dosesappear higher than doses in our patients. It is possiblethat lower birth weights in the study by Langer et alreflect inadequate dosing in our retrospective study.However, our actual mean posttreatment BSs appearsimilar to the actual fasting means by Langer et al, andamong our subgroup that used 2-hour postprandialtesting, the means were less than their goal of 120 mg/dL.We found no significant difference in the rate of neonatalhypoglycemia between the groups, and although ouroverall rate was higher than Langer et al reported, it issimilar to that reported by others. 5,11 In addition, Langeret al used a strict laboratory definition for neonatalhypoglycemia and we used a definition based ondischarge summary data.Glyburide appears to be a safe and effective alternativeto insulin for the treatment of GDM in women withfasting plasma glucose 140 mg/dL or less on GTT andwho fail dietary therapy. Although potentially avoidingthe need for self-injection, the rate of discontinuation ina nonresearch setting warrants investigation into alternativeadministration protocols to improve compliance.Larger randomized trials are needed to investigate lessfrequent complications such as preeclampsia, NICUadmission, need for phototherapy, and birth injury.AcknowledgmentsWe thank Dayakar Beeravolu, Susan M. Shaheen, andIsaac J. Ergas for their assistance in database abstraction.References1. Coustan DR. Gestational diabetes. Washington: American Collegeof Obstetricians and Gynecologists; 2001. ACOG Practice Bulletin,Number 30.2. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. Acomparison of glyburide and insulin in women with gestationaldiabetes mellitus. N Engl J Med 2000;343:1134-8.3. Gabbe SG, Graves CR. Management of diabetes mellitus complicatingpregnancy. Obstet Gynecol 2003;102:857-68.4. Gabbe SG, Gregory RP, Power ML, Williams SB, Schulkin J.Management of diabetes mellitus by obstetrician-gynecologists.Obstet Gynecol 2004;103:1229-34.5. National Diabetes Data Group. Classification and diagnosis ofdiabetes mellitus and other categories of glucose intolerance.Diabetes 1979;28:1039-57.6. Shapiro SS, Wilk MD. An analysis of variance test for normality(complete samples). Biometrika 1965;52:591-611.7. Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemicagents in 118 diabetic pregnancies. Diabet Med 2000;17:507-11.8. Keyes L, Rodman DM, Curran-Everett D, Morris K, Moore LG.Effect of KCATP channel inhibition on total and regionalvascular resistance in guinea pig pregnancy. Am J Physiol1998;275:H680-8.9. Ebeigbe AB, Cabanie M. In vitro vascular effects of cicletanine inpregnancy-induced hypertension. Br J Pharmacol 1991;103:1992-6.10. Gilson G, Murphy N. Comparison of oral glyburide with insulinfor the management of gestational diabetes mellitus in AlaskaNative women. Am J Obstet Gynecol 2002;187:S152.11. Velazquez MD, Bolnick J, Cloakey D, Gonzalez JL, Curet LB.The use of glyburide in the management of gestational diabetes.Obstet Gynecol 2003;101(4 suppl):88S.12. Conway DL, Gonzales O, Skiver D. Use of glyburide for thetreatment of gestational diabetes: the San Antonio experience.J Matern Fetal Neonatal Med 2004;15:51-5.13. Fines VL, Moore TR, Castle SL. A comparison of glyburide andinsulin treatment in gestational diabetes mellitus on infant birthweight and adiposity. Am J Obstet Gynecol 2003;189:S161.14. Chmait R, Dinise T, Moore T. Prospective observational study toestablish predictors of glyburide success in women with gestationaldiabetes mellitus. J Perinat 2004;10:617-22.15. Kremer CJ, Duff P. Glyburide for the treatment of gestationaldiabetes. Am J Obstet Gynecol 2004;190:1438-9.
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Kirsten Grabowska - UBC Department of Obstetrics & Gynaecology

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