COMPARISON OF GLYBURIDE WITH METFORMIN IN TREATING
GESTATIONAL DIABETES MELLITUS: A SYSTEMATIC REVIEW AND METAANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Muhammad Amin1,*, Naeti Suksomboon2, #, Nalinee Poolsup3
1
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand,
Master of Science in Pharmacy (Clinical Pharmacy), Pakistan.
2
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
3
Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon-Pathom,
Thailand.
*ameen_hunzai@yahoo.com, #naeti.suk@mahidol.ac.th
Abstract
Objective: To compare the efficacy and safety of glyburide with metformin in treating
gestational diabetes mellitus.
Methods: We conducted a systematic review and meta-analysis of randomized controlled
trials (RCTs) that compared efficacy and safety of glyburide with metformin in gestational
diabetes mellitus (GDM) patients. We used electronic databases to conduct the literature search
for study identification along with a hand search of pertinent journals and conference
proceedings.
Results: 3 studies involving 421 patients met inclusion criteria for our review. A
significant increase in the risk for large for gestational age (LGA) babies (RR, 2.32; 95% CI,
1.23-4.37, p-value = 0.009) was observed in glyburide group compared to metformin, whereas a
non-significant increase in the risk for macrosomia (RR, 2.05; 95% CI, 0.67-6.27) and neonatal
hypoglycemia (RR, 1.09; 95% CI, 0.61-1.97) was noticed. Results remained non-significant for
preterm births and caesarean section. On the other hand, a significant decrease in fasting glucose
levels (MD, -2.67 mg/dl; 95% CI, -5.19,-0.16; p-value = 0.04) was noticed with glyburide, while
difference was non-significant for postprandial glucose levels.
Conclusion: Treating GDM with glyburide is likely to increase risk for LGA births.
Keywords: Gestational diabetes, glyburide, metformin, systematic review, meta-analysis.
Introduction
Gestational diabetes mellitus (GDM) has been defined as a condition in women who have
carbohydrate intolerance with onset or recognition during pregnancy.1 Incidence of GDM varies
among ethnic groups as women with certain ethnicities like Asian, African American, Hispanic,
Native American and Pacific Islanders are considered to be at higher risk for GDM.1 It has been
estimated that about 1-14% of women suffer from GDM depending upon diagnostic criteria used
and ethnicities studied.2 Complications of GDM are manifold as both mother and fetus are
affected. The main adverse perinatal outcomes of GDM are macrosomia, large for gestational
age (LGA) babies, shoulder dystocia, birth trauma, delayed motor development, premenopausal
breast cancer and diabetes later in life.3-10 Maternal adverse outcomes are caesarean section,
gestational hypertension, pre-eclampsia, labor induction and increase in risk for type 2 diabetes
mellitus following child birth.3-5, 11 Pre-eclampsia also has long term consequences due to its
association with cardiovascular events.12 Mostly, there is agreement that GDM should be treated
with medical nutrition therapy and insulin therapy is to be initiated if desired glycemic targets
are not achieved by dietary intervention.1, 13 However, controversy surrounds the efficacy and
safety of oral antidiabetic drugs for use in GDM. The 2008 National Institute for Health and Care
Excellence (NICE) clinical guidelines on diabetes in pregnancy,13 and after a long confusion, the
2013 American College of Obstetricians and Gynecologists (ACOG) clinical management
guidelines on GDM,1 recommend glyburide and metformin to be used as alternative to insulin if
dietary intervention fails but American Diabetes Association (ADA) has no specific
recommendation for treating GDM.2, 14 Individual trials on the topic are very limited and are of
small size; therefore a firm conclusion on their efficacy and safety cannot be drawn.15-17
Nonetheless, these studies have reported both metformin and glyburide as equally effective. In
view of this ambiguity, we conducted this systematic review and meta-analysis to identify any
difference in efficacy and safety parameters of glyburide and metformin in comparison with each
other.
Methodology
We conducted this study according to Cochrane Handbook for Systematic Reviews of
Interventions 18.
Eligibility Criteria
In this review we included randomized controlled trials (RCTs) comparing efficacy and
safety of glyburide against metformin or vice versa in GDM patients reporting at least one
outcome of interest. We did not make any restriction regarding language. We accepted
individual study definitions of GDM and diagnostic criteria used to identify such patients. We
included women with no restriction of age, gravida and parity. However, studies including
patients with pre-existing diabetes were not considered eligible. Interventions included glyburide
or metformin administered on top of routine antenatal care if dietary intervention failed to
control glycemic levels.
Outcomes of Interest
We included both perinatal and maternal outcomes in our review. The perinatal outcomes
of interest were macrosomia, LGA births, shoulder dystocia, birth trauma, neonatal
hypoglycemia, and preterm births while maternal outcomes comprised of caesarean section,
gestational hypertension, pre-eclampsia and glycemic levels (fasting and postprandial).
Literature Search for Study Identification
To identify relevant studies we used electronic databases Medline (PubMed), Cochrane
Central Register of Controlled Trials (CENTRAL), http://clinicaltrials.gov register,
http://clinicaltrialsresults.gov register, Cumulative Index to Nursing and Allied Health Literature
(CINAHL), Latin American and Caribbean Health Sciences Literature (LILACS), Scopus and
Web of Science for reports of RCTs published from inception up to October 2013 without any
language restriction. In addition, hand search for journals and conference proceedings was also
conducted.
Search terms used were gestational diabetes, pregnancy, macrosomia, large for
gestational age, glyburide and metformin. “Diabetes, Gestational” was the MeSH term for our
search strategy.
Data Collection
Data was extracted from the studies which included information on patient
characteristics, diagnostic criteria, interventions used, perinatal and maternal outcomes and
methodological quality of each RCT.
Risk of Bias
Cochrane Risk of Bias Tool was used for risk of bias assessment.18 Each study was
judged for bias by considering the domains of sequence generation, allocation concealment,
blinding of participants/ personnel and outcome assessors, incomplete outcome data, selective
outcome reporting and other risk of bias. Studies were classified as at low, uncertain and high
risk of bias according to the criteria defined in the Cochrane Handbook for Systematic Reviews
of Interventions18.
Statistical Analysis
We used Review Manager Software (Rev Man 5.2) for carrying out statistical analysis.
Fixed effects method was used for pooling data in the absence of significant heterogeneity and
random effects method was used if heterogeneity was significant. Risk ratio was the effect
measure used to present the results with 95% confidence interval (CI). I² and Chi² statistics were
used to assess heterogeneity between studies. Heterogeneity was regarded substantial if the value
for I² was > 50% or a P value < 0.10 in the Chi² test for heterogeneity.18
Results
Our literature search identified 799 studies initially. We reviewed titles and abstracts of
each study and selected 30 studies for detailed screening. We thoroughly analyzed these studies
by mutual discussion and finally included 3 RCTs involving 421 patients in our review which
met inclusion criteria. Characteristics of these studies are presented in Table 1.
Figure 1: Flow chart of study selection.
Studies identified as a result of literature search
(n = 799)
Studies removed after reviewing titles and abstracts
(n = 769)
Studies selected for thorough evaluation
(n = 30)
Studies removed after thorough evaluation (n=27):




Studies not included GDM patients (n=10)
Not Randomized Controlled Trials (n=5)
Studies comparing glyburide and metformin to insulin (n=10)
Duplicates removed: (n=2)
Trials meeting inclusion criteria
(n = 3)
Risk of Bias in the Included Studies
All the three studies included in the review had adopted adequate method for sequence
generation.15-17 Allocation was properly concealed in one study,15 and in remaining two it
remained unclear.16, 17 No study was double blinded therefore remained at high risk of
performance and detection bias. We observed attrition in two studies, 15, 16 whereas one study
was at low risk of attrition bias.17 We did not observe any reporting and other risk of bias in
included studies. According to Cochrane risk of bias tool18, we performed the risk of bias graph
and summary and the same has been shown in Figure 2 and 3, respectively.
Figure 2: Risk of bias graph.
Figure 3: Risk of bias summary.
+ Low risk of bias. ? Unclear risk of bias. – High risk of bias.
Table 1: Characteristics of the included studies.
Study
N
Moore 201015
USA
149
Silva 201016
Brazil
72
Mean
Age Yrs.
(SD)
30.3
(7.4)
Mean
BMI
(SD)
32.7
(6.4)
32.5
(5.6)
29.5
(5.7)
Diagnostic Criteria
100 g OGTT
2 or more abnormal:
F ≥ 95 mg/dl,
1 h ≥ 180 mg/dl,
2 h ≥ 155 mg/dl,
3 h ≥ 140 mg/dl
75 g OGTT
Any abnormal:
F ≥ 126 mg/dl
2 h ≥ 140 mg/dl
200
31.9
28.6
75 g OGTT
Silva 201217
(5.4)
(5.6)
Any abnormal:
Brazil
F ≥ 126 mg/dl
2 h ≥ 140 mg/dl
Yrs.: Years. OGTT: Oral glucose tolerance test. F: Fasting
Threshold Glycemic levels
for
Initiating
Medical
Intervention
F > 105 mg/dl
2 h > 120 mg/dl
F > 90 mg/dl
2 h > 120 mg/dl
F > 90 mg/dl
2h > 120 mg/dl
Perinatal and Maternal Outcomes
We analyzed studies in the review for macrosomia, LGA births, neonatal hypoglycemia,
preterm births, caesarean section and maternal glycemic levels. We noticed a significant increase
in risk for LGA births in glyburide group as compared to metformin (RR, 2.32; 95% CI, 1.234.37, p-value = 0.009) (Figure 4). Risk for macrosomia (RR, 2.05; 95% CI, 0.67-6.27) and
neonatal hypoglycemia (RR, 1.09; 95% CI, 0.61-1.97) was also high in glyburide group but
results remained statistically non-significant. We did not notice a significant difference in risk for
caesarean section and preterm births between the two groups. However, risk of preterm births
was likely to be lower, but not significantly so, with glyburide (RR, 0.78; 95% CI, 0.29-2.05)
(Figure 4). Fasting glucose levels were significantly lower in patients receiving glyburide
therapy (MD, -2.67 mg/dl; 95% CI, -5.19,-0.16; p-value = 0.04) while results for postprandial
glycemic levels remained non-significant statistically (MD, -0.15 mg/dl; 95% CI, -3.94, 3.65)
(Figure 5). Except for caesarean section, studies were consistent and heterogeneity remained
non-significant for rest of the outcomes.
Figure 4: Effects of Treatment on Perinatal and Maternal Pregnancy Outcomes.
Figure 5: Effects of Treatment on Maternal Glycemic Levels.
Discussion
Pharmacological interventions are initiated in the GDM management when life style
interventions which comprised of dietary interventions and exercise along with self-monitoring
of blood glucose (SMBG) fails to control desired glycemic levels during 1-2 weeks period.1, 13
The recommended targets for initiating pharmacotherapy is glucose levels consistently above
than 95 mg/dl at fasting, 1 hour postprandial glucose levels equal to or greater than 140 mg/dl or
2 hour postprandial glucose levels equal to or above then 120 mg/dl.1, 19 Mostly consensus exists
about use of human insulin if pharmacologic treatment is to be initiated due to its low
immunogenic potential; however use of insulin analogues is also on the rise.1, 13, 20 Interest
developed in the use of oral anti diabetic drugs (OADs) for a multiple reasons. Mainly OADs are
preferred over insulin due to ease in administration, low cost of therapy and adverse events like
hypoglycemia and weight gain are also unlikely. Glyburide was investigated in an in-vitro study
wherein minimal transfer of drug occurred across human placenta which made the grounds for
further trials in human subjects.21 On the other hand metformin crosses the placenta,22 but it did
not display any teratogenic effect in pregnant women.23, 24 Therefore further studies of metformin
were conducted mostly in comparison to human insulin,25, 26 and a few with glyburide.15-17 In
individual trials, both of these drugs reported efficacy comparable to human insulin,25, 27 and in
head to head trials both of these OADs displayed equivalent efficacy and safety profile in
comparison to each other.15-17 Based on the findings of these investigations, professional
organizations like NICE and ACOG recommend these two OADs for use in GDM patients
following failure of nutrition therapy and considered equally effective.1, 13 However, regulatory
authorities in the world including U.S. Food and Drug Administration (FDA) have not approved
any OAD for use in pregnant women.
In our review, we observed that glyburide increased risk for LGA births significantly.
Risk for macrosomia and neonatal hypoglycemia also increased but statistical significance was
not achieved. In addition, there was a non-significant difference in the risk for caesarean section.
According to Pedersen Hypothesis 28, glucose transfer across maternal placenta promotes insulin
secretion from fetal pancreas which plays a role in growth of adipose tissues in fetus.28 We
noticed significantly lower levels of maternal fasting glucose in glyburide group whereas
difference for postprandial glucose levels remained statistically non-significant. In GDM,
postprandial glucose levels are considered to have a strong association with adverse pregnancy
outcomes,29 and in our review, no significant increase for this outcome was observed. Therefore,
the most plausible reason behind significant increase in risk for LGA births in glyburide group
seems to be transfer of glyburide across placenta in minute quantities which owing to its inherent
characteristic might have promoted insulin secretion from fetal pancreas. Nonetheless, further
studies with large sample sizes are needed to confirm our findings and to identify any difference
in glucose control with both drugs. Similarly, we did not notice any significant increase in the
risk for preterm births in both groups. However, a recent meta-analysis comparing efficacy and
safety of metformin to insulin reported a significant increase in risk for preterm births in
metformin group.30 Risk of gestational hypertension and post prandial glycemic levels were low
in metformin treated patients for whom statistical significance was also achieved; however, it
cannot be ignored that a greater percentage of patients were switched to insulin therapy during
course of study in metformin group.30
Strengths and Limitations
Our review is the most updated review on the topic which includes all the three RCTs
available in medical literature. There was no significant heterogeneity for all the outcomes
except for caesarean section. However, this systematic review also has certain limitations. The
number of studies conducted on the topic was very few and available studies enrolled small
sample sizes. No study was double-blinded which made validity of data doubtful. Studies
included in the review did not furnish information on rate of many low incidence outcomes like
shoulder dystocia, birth trauma, pre-eclampsia and gestational hypertension. In addition, we
could not achieve statistical significance for outcomes like macrosomia, neonatal hypoglycemia
and preterm births partly due to small sample size, therefore a firm conclusion cannot be drawn
on the risk for these outcomes. Population source of included trials were from United States and
Brazil only, therefore extrapolation of these results to other populations is difficult.
Conclusion
Results of this review indicated that treatment of GDM with glyburide increases risk for
LGA births. Such infants are prone for pregnancy complications like shoulder dystocia, birth
trauma and birth asphyxia. Besides, rate of caesarean section is also expected to rise. Data from
another meta-analysis, report a higher incidence of preterm births in metformin treated GDM
patients. Based upon such findings, it seems that treating GDM with glyburide and metformin is
not free of harm. However, further studies of large sample sizes are required to confirm these
findings.
References:
1.
The American College of Obstetricians and Gynecologists. Gestational diabetes mellitus: Clinical
management guidelines for obstetricians–gynecologists. Obstet Gynecol. 2013;122(2):406-16.
2.
American Diabetes Association. Diagnosis and classification of diabetes mellitus, (Position Statement).
Diabetes Care. 2013;36 (Suppl. 1):s67-s74.
3.
Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and
adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991-2002.
4.
Ju H, Rumbold AR, Willson KJ, Crowther CA. Borderline gestational diabetes mellitus and pregnancy
outcomes. BMC Pregnancy Childbirth. 2008;8:31.
5.
Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: the consequences of not treating. Am J
Obstet Gynecol. 2005;192(4):989-97.
6.
Henriksen T. The macrosomic fetus: a challenge in current obstetrics. Acta Obstet Gynecol Scand.
2008;87(2):134-45.
7.
Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ. Childhood obesity and metabolic
imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30(9):2287-92.
8.
Slining M, Adair LS, Goldman BD, Borja JB, Bentley M. Infant overweight is associated with delayed
motor development. J Pediatr. 2010;157(1):20-5 e1.
9.
Ornoy A. Growth and neurodevelopmental outcome of children born to mothers with pregestational and
gestational diabetes. Pediatr Endocrinol Rev. 2005;3(2):104-13.
10.
Forman Mr CM, Ronckers C, Zhang Y. Through the looking glass at early-life exposures and breast cancer
risk. Cancer Invest. 2005;23(7):609-24.
11.
Reece EA, Leguizamon G, Wiznitzer A. Gestational diabetes: the need for a common ground. Lancet.
2009;373(9677):1789-97.
12.
Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and
cancer in later life: systematic review and meta-analysis. BMJ. 2007;335(7627):974.
13.
National Institute for Health and Clinical Excellence London. Diabetes in pregnancy: management of
diabetes and its complications from preconception to the postnatal period [www.nice.org.uk/CG063].
14.
American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2013;36(Suppl
1):S11-66.
15.
Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin compared with glyburide in gestational
diabetes: a randomized controlled trial. Obstet Gynecol. 2010;115(1):55-9.
16.
Silva JC, Pacheco C, Bizato J, De Souza BV, Ribeiro TE, Bertini AM. Metformin compared with glyburide
for the management of gestational diabetes. Int J Gynaecol Obstet. 2010;111(1):37-40.
17.
Silva JC, Fachin DR, Coral ML, Bertini AM. Perinatal impact of the use of metformin and glyburide for
the treatment of gestational diabetes mellitus. J Perinat Med. 2012;40(3):225-8.
18.
Higgins Jpt, editor. Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane
Collaboration, 2011 [www.handbook.cochrane.org].
19.
Metzger BE, Buchanan TA, Coustan DR, De Leiva A, Dunger DB, Hadden DR, et al. Summary and
recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care.
2007;30 Suppl 2:S251-60.
20.
Menon RK, Cohen RM, Sperling MA, Cutfield WS, Mimouni F, Khoury JC. Transplacental passage of
insulin in pregnant women with insulin-dependent diabetes mellitus. Its role in fetal macrosomia. N Engl J Med.
1990;323(5):309-15.
21.
Elliott BD, Schenker S, Langer O, Johnson R, Prihoda T. Comparative placental transport of oral
hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol. 1994;171(3):65360.
22.
Charles B, Norris R, Xiao X, Hague W. Population pharmacokinetics of metformin in late pregnancy. Ther
Drug Monit. 2006;28(1):67-72.
23.
Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a metaanalysis. Fertil Steril. 2006;86(3):658-63.
24.
Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social
development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome
who conceived on and continued metformin through pregnancy. Hum Reprod. 2004;19(6):1323-30.
25.
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of
gestational diabetes. N Engl J Med. 2008;358(19):2003-15.
26.
Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in
the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract.
2012;98(3):422-9.
27.
Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in
women with gestational diabetes mellitus. N Engl J Med. 2000;343(16):1134-8.
28.
Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh).
1954;16(4):330-42.
29.
De Veciana M, Major CA, Morgan MA, Asrat T, Toohey JS, Lien JM, et al. Postprandial versus
preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl
J Med. 1995;333(19):1237-41.
30.
Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: a meta-analysis.
PLoS One. 2013;8(5):e64585.