Clin Drug Investig DOI 10.1007/s40261-015-0289-3
Comparison of Glyburide with Metformin in Treating Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis Muhammad Amin1,2 • Naeti Suksomboon1 • Nalinee Poolsup3 • Obaidullah Malik2
Ó Springer International Publishing Switzerland 2015
Abstract Background and Objective Controversy has surrounded the treatment of gestational diabetes mellitus (GDM) for a long time. Although the use of both glyburide and metformin are recommended as an alternate to insulin if dietary therapy fails in GDM patients, it remains unclear whether both drugs are equally safe and efficacious. Therefore, in this review we compared the efficacy and safety of glyburide with metformin in treating GDM. Methods A systematic review and meta-analysis of randomized controlled trials was conducted that compared the efficacy and safety of glyburide with metformin in GDM patients. Electronic databases were used to conduct the literature search for study identification along with a hand
& Muhammad Amin [email protected]
Naeti Suksomboon [email protected]
Nalinee Poolsup [email protected]
Obaidullah Malik [email protected]
Division of Clinical Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
Pharmaceutical Evaluation and Registration Division, Drug Regulatory Authority of Pakistan, TF Complex,G-9/4, Islamabad, Pakistan
Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon-Pathom, Thailand
search of pertinent journals and conference proceedings. The effect measure used to present the results was risk ratio (RR) with 95 % confidence interval (CI). A fixed-effects model was used to pool the data if no significant heterogeneity was reported and a random-effects model was used in the case of significant heterogeneity being reported for an outcome. Results Three studies involving 508 patients met the inclusion criteria of this review. A significant increase in the risk of the composite outcome, i.e., macrosomia and large for gestational age (LGA) births (RR 1.94; 95 % CI 1.03–3.66, p = 0.04), was observed in the glyburide group, whereas a non-significant increase in the risk of neonatal hypoglycemia (RR 1.92; 95 % CI 0.31–12.02) was also noticed. Results remained statistically non-significant for preterm births (RR 0.65; 95 % CI 0.24–1.77), neonatal birth weight (mean difference (MD) 120.63 g; 95 % CI 62.08 to 303.33), and cesarean section (RR 0.86; 95 % CI 0.55–1.34). A significant decrease in fasting glucose levels (MD -2.40 mg/dL; 95 % CI -4.60 to -0.21; p = 0.03) was noticed in glyburide group while the difference was non-significant for postprandial glucose levels (MD 0.84 mg/dL; 95 % CI -4.03 to 2.35). Conclusion Metformin seems to be a superior choice to glyburide if oral antidiabetic drug therapy is to be initiated in GDM patients.
M. Amin et al.
Key Points Glyburide significantly increased the risk of the composite outcome, i.e., macrosomia and large for gestational age births, in comparison with metformin and the risk of neonatal hypoglycemia was also likely to increase. These effects of glyburide seem to be attributed to transfer of the drug to infants’ circulation, thus promoting fetal insulin secretion and eliciting associated harmful effects. Metformin seems to be a better alternative to glyburide in treating gestational diabetes mellitus if the patient is to be placed on oral antidiabetic drug therapy following failure of dietary modification.
1 Introduction Gestational diabetes mellitus (GDM) is defined as a condition in women who have a carbohydrate intolerance, the onset or recognition of which takes place during pregnancy . The incidence of GDM varies among certain ethnic groups, with Asian, African American, Hispanic, Native American, and Pacific Island women considered to be at a higher risk for GDM . Depending on the diagnostic criteria used and ethnicities studied, it is estimated that about 1–14 % of women suffer from GDM . 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, and birth asphyxia. In addition, such infants are prone to disease conditions such as delayed motor development, obesity, and diabetes later in life [3–8]. Furthermore, women with a history of macrosomia have an up to fivefold increased risk for development of premenopausal breast cancer. Similarly, LGA births are also reported to increase the risk of breast cancer . Maternal adverse outcomes are cesarean section, gestational hypertension, pre-eclampsia, labor induction, and an increase in the risk of developing type 2 diabetes [3, 4, 10, 11]. Pre-eclampsia also has long-term consequences due to its association with cardiovascular events . Generally, 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 (OADs) for use in GDM. National Institute for Health and Care Excellence (NICE) clinical guidelines on diabetes in pregnancy  recommend the use of metformin and, after a long discussion, the new American College of Obstetricians and Gynecologists (ACOG) clinical management guidelines on GDM  recommend use of glyburide and metformin as an alternative to insulin therapy if dietary intervention fails, but the American Diabetes Association (ADA) has no specific recommendation for treating GDM [2, 14]. Although the use of these two OADs in GDM is recommended, there is no specific recommendation on the superiority of either drug. Thus, it remains unclear as to how different these two drugs are in affecting the pregnancy outcomes of a patient with GDM. Individual trials on the topic are very limited and are of small sample size; therefore, a firm conclusion on their efficacy and safety cannot be drawn [15–17]. In view of this ambiguity, this systematic review and metaanalysis was carried out to identify any difference in the efficacy and safety parameters of glyburide and metformin in comparison with each other.
2 Methodology This study was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions  and the results were presented according to the PRISMA statement . 2.1 Eligibility Criteria Included in this review were randomized controlled trials (RCTs) comparing the efficacy and safety of glyburide against metformin, or vice versa, in GDM patients. To be eligible for inclusion, studies had to report at least one outcome of interest. No restriction was imposed regarding language. Individual study definitions of GDM and diagnostic criteria used to identify such patients were accepted. Women were included with no restriction regarding age, gravida, and parity. However, studies including patients with pre-existing diabetes were not considered eligible. Interventions included glyburide and metformin if dietary intervention failed to control glycemic levels in GDM patients. A composite outcome of macrosomia and LGA births was used in the review due to the paucity of data on these outcomes in individual trials. Macrosomia was defined according to individual study definitions, whereas LGA was defined as birth weight above the 90th percentile. Neonatal hypoglycemia was defined as glucose levels below 40 mg/dL and preterm birth as birth before the 37th week of gestation.
Glyburide vs. Metformin in GDM Treatment
2.2 Outcomes of Interest
2.6 Statistical Analysis
In this review, both perinatal and maternal outcomes were included. The perinatal outcomes of interest were macrosomia, LGA births, shoulder dystocia, birth trauma, neonatal hypoglycemia, preterm births, and birth weight, while maternal outcomes were comprised of cesarean section, gestational hypertension, preeclampsia, and glycemic levels (fasting and postprandial).
Review Manager Software (RevMan 5.2.7, Cochrane Collaboration, Oxford, UK) was used to carry out the statistical analysis. A fixed-effects method was used to pool the data in the absence of significant heterogeneity and a random-effects method was used if heterogeneity was significant. Risk ratio (RR) was the effect measure used to present the results with the 95 % confidence interval (CI). I2 and Chi-squared (v2) statistics were used to assess heterogeneity between studies. Heterogeneity was regarded substantial if the value for I2 was [50 % or p \ 0.10 in the v2 test for heterogeneity .
2.3 Literature Search for Study Identification To identify relevant studies, the electronic databases MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), the http://clinicaltrials. gov register, the 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 were used to find reports of RCTs published from each database’s inception up to January 2015. In addition, a hand search of journals and conference proceedings was also conducted. Search terms used were gestational diabetes, pregnancy, macrosomia, large for gestational age, glyburide, and metformin. 2.4 Data Collection Data were extracted from the studies that included information on patient characteristics, diagnostic criteria, interventions used, perinatal and maternal outcomes, and the methodological quality of each RCT.
3 Results Initially, 799 studies were identified as a result of the literature search. The titles and abstracts of each study were reviewed and 30 studies were selected for detailed screening. These studies were thoroughly analyzed by mutual discussion and three RCTs involving 508 patients that met the inclusion criteria were finally included in this review. A flow chart of study selection is given in Fig. 1 and characteristics of the studies are presented in Table 1. Citations retrieved as a result of literature search (n = 799)
Reports excluded after review of title and abstract (n = 769)
Reports identified for detailed evaluation (n = 30)
2.5 Risk of Bias The Cochrane Risk of Bias Tool was used for the risk of bias assessment . 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 Interventions . Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines were used to assess the quality of evidence for treating GDM with glyburide and metformin . The GRADE profiler was used to retrieve data and to create a GRADE evidence profile.
Reports Excluded after detailed 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)
Studies fulfilling inclusion criteria (n = 3)
Fig. 1 Flow chart of study selection
M. Amin et al. Table 1 Characteristics of the included studies Study, location
Age (years) [mean (SD)]
BMI (kg/m2) [mean (SD)]
Threshold glycemic levels for initiating medical intervention
Therapeutic failure (%)a
George et al. , India Glyburide
100 g OGTT
F C99 mg/dL to B130 mg/dL
2 or more abnormal:
2 h C120 to B250 mg/dL
F C95 mg/dL 1 h C180 mg/dL 2 h C155 mg/dL 3 h C140 mg/dL Moore et al. , USA Glyburide
29.6 (7.8) 31 (7.1)
100 g OGTT
F [105 mg/dL
2 or more abnormal:
2 h [120 mg/dL
F C95 mg/dL, 1 h C180 mg/dL, 2 h C155 mg/dL, 3 h C140 mg/dL Silva et al. (2012) , Brazil Glyburide Metformin
75 g OGTT
F [90 mg/dL
2 h [120 mg/dL
F C126 mg/dL 2 h C140 mg/dL BMI body mass index, F fasting, NA not available, OGTT oral glucose tolerance test, SD standard deviation a
Percentage of patients requiring insulin therapy in the glyburide and metformin groups who could not achieve desired glycemic control
3.1 Risk of Bias in the Included Studies
3.2 Perinatal and Maternal Outcomes
All three studies included in the review had adopted an adequate method for sequence generation [15–17]. Allocation was properly concealed in two studies [15, 17] and in the remaining one study information on this domain remained unclear . No study was double-blinded and therefore they remained at high risk of performance and detection bias, especially for an outcome such as cesarean section. However, lack of blinding of outcome assessment was not considered a serious threat to the validity of data for outcomes other than cesarean section and they were assigned a low risk of detection bias. Attrition was observed in one study , whereas two studies were at low risk of attrition bias [16, 17]. No reporting bias and other risk of bias was observed in the included studies. For risk of bias across studies, we assigned a low risk of bias for the outcomes other than cesarean section as most of the information came from studies at low risk of bias. For cesarean section, a high risk of bias was assigned as this outcome was at high risk of detection bias in all of the studies. The risk of bias graph and summary was performed according to the Cochrane Risk of Bias Tool , and these are shown in Figs. 2 and 3, respectively. Assessment of the quality of evidence using the GRADE recommendations is presented in Table 2.
For the composite outcome of macrosomia and LGA births, a significant increase in risk was noticed in the glyburide group compared with metformin (RR 1.94; 95 % CI 1.03–3.66; p = 0.04) (Fig. 4). The risk of neonatal hypoglycemia (RR 1.92; 95 % CI 0.31–12.02) was also high in the glyburide group but results remained statistically nonsignificant (Fig. 5). Further, our analysis was hindered by significant heterogeneity reported for this outcome. Similarly, significant heterogeneity was noticed for cesarean section and neonatal birth weight. No significant difference was observed in the risk of cesarean section (RR 0.86; 95 % CI 0.55–1.34) (Fig. 6) and neonatal birth weight (MD 120.63 g; 95 % CI -62.08 to 303.33) (Fig. 7) between the two groups. Likewise, the difference in the risk of preterm births was statistically non-significant (RR 0.65; 95 % CI 0.24–1.77) between the two groups (Fig. 8). However, the risk of preterm births was likely to be lower with glyburide. Fasting glucose levels were significantly lower in patients receiving glyburide therapy (MD -2.40 mg/dL; 95 % CI -4.60 to -0.21; p = 0.03) (Fig. 9) while the results for postprandial glycemic levels remained statistically non-significant (MD -0.84 mg/dL; 95 % CI 4.03 to 2.35) (Fig. 10).
Glyburide vs. Metformin in GDM Treatment Fig. 2 Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies
Fig. 3 Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. (?) Low risk of bias, (-) high risk of bias, (?) unclear risk of bias
4 Discussion Pharmacological therapy is initiated in GDM patients when lifestyle interventions comprised of dietary interventions and exercise along with self-monitoring of blood glucose fails to achieve the desired glycemic levels during a 1- to 2-week period [1, 13]. The recommended targets for initiating pharmacotherapy are glucose levels consistently above 95 mg/dL at fasting, 1-h postprandial glucose levels C140 mg/dL or 2-h postprandial glucose levels C120 mg/
dL [1, 21]. Consensus mostly exists regarding the use of insulin if pharmacologic treatment is to be initiated; however, use of OADs is also on the rise [1, 13]. Interest has developed in the use of OADs for multiple reasons. OADs are mainly preferred over insulin due to the ease of administration, the low cost of therapy, and adverse events such as hypoglycemia and weight gain being unlikely. Initially, glyburide was investigated in an in vitro study wherein minimal transfer of drug occurred across the human placenta, which formed the grounds for further trials in human subjects . On the other hand, metformin crosses the placenta , but it did not display any teratogenic effect in pregnant women [24–26]. These results are based on studies of women with polycystic ovary syndrome treated with metformin during pregnancy. Therefore, further studies of metformin were conducted, mostly in comparison with insulin [27, 28] and a few with glyburide [15–17]. Although a considerable percentage of patients needed supplemental insulin therapy due to the failure to achieve the desired glycemic targets, especially in patients receiving metformin compared with glyburide [15, 27, 29–31], both of these drugs reported efficacy comparable to insulin [27, 32]. Also, in head-to-head trials, both of these OADs displayed an equivalent efficacy and safety profile [15, 16]. Based on the findings of these investigations, professional organizations such as NICE recommend metformin and ACOG recommends both metformin and glyburide for use in GDM patients following failure of nutrition therapy, and they are considered equally effective [1, 13]. However, regulatory authorities around the globe including the US Food and Drug Administration have not approved any OAD for use in GDM patients. It is pertinent to mention that in GDM both fasting and postprandial glucose levels are associated with adverse pregnancy outcomes [3, 33]. In GDM patients, postprandial excursions are not a simple rise and fall phenomenon of glucose as the fetus is considered to recirculate glucose peaks through amniotic fluid, thus exhibiting an extended effect . Therefore, a drug with rapid onset of action is required to blunt the postprandial glucose spikes
Important Low 60 fewer per 1000 (from 192 fewer to 145 more) 0.86 (0.55–1.34) 110/258 (42.6) 96/250 (38.4) None Imprecise Direct Inconsistent
CI confidence interval, LGA large for gestational age, RCT randomized controlled trial, RR relative risk
Low RCT 3
6/250 (2.4) None Imprecise Direct Consistent
Inconsistent Low RCT 3
Cesarean section 3 RCT
Important 14 fewer per 1000 (from 29 fewer to 30 more) 0.65 (0.24–1.77) 10/258 (3.9)
12/258 (4.7) 23/250 (9.2) None Imprecise Direct
Direct Consistent Low RCT 3
Macrosomia and LGA
Critical 43 more per 1000 (from 32 fewer to 513 more)
1.94 (1.03–3.66) 14/258 (5.4) 26/250 (10.4) None Precise
Imprecision Indirectness Inconsistency Risk of bias Design
51 more per 1000 (from 2 more to 144 more)
Absolute RR (95 % CI) Glyburide vs. metformin Other considerations No. of studies
Effect Patients [n (%)] Quality assessment
Table 2 GRADE (Grading of Recommendations Assessment, Development and Evaluation) evidence profile
M. Amin et al.
. Theoretically, OADs do not fit into this scenario due to their delayed onset and peak times. However, as mentioned earlier, in individual trials both metformin and glyburide have shown no significant difference in the efficacy and safety parameters compared with insulin, but with a considerable percentage of therapeutic failure requiring supplemental insulin doses. In this review, a significant increase in the risk of the composite outcome, i.e., macrosomia and LGA, was observed with glyburide treatment in comparison with metformin. The risk of neonatal hypoglycemia also increased, but statistical significance was not achieved. According to the Pedersen Hypothesis , glucose transfer across the placental barrier promotes insulin secretion from the fetal pancreas, which plays a role in the growth of adipose tissues in the fetus . Increased insulin secretion from the fetal pancreas also means increased utilization of glucose by the fetus, thus promoting fetal growth. However, postprandial glucose levels which are considered to have strong association with adverse pregnancy outcomes , indicated no significant increase in the glyburide arm. Further, significantly lower levels of maternal fasting glucose were noticed in the glyburide group. Another important determinant of an increase in the incidence of large babies is maternal adiposity , which was also non-significantly different in both study groups in individual trials. Therefore, the most plausible reason behind the significant increase in risk of the composite outcome, i.e., LGA and macrosomia, in the glyburide group seems to be transfer of glyburide across the placenta, which, owing to its inherent characteristics, might have promoted insulin secretion from the fetal pancreas, causing fetal growth. Our analysis is also corroborated by a recent pharmacokinetic study in women with GDM, where glyburide was reported to cross the placental barrier and umbilical cord concentrations of the drug were reported to be 70 % of that of maternal circulation . In addition, a recent meta-analysis indicated a significant increase in the risk of macrosomia and neonatal hypoglycemia with glyburide use in comparison with insulin, which corresponds with the findings of this review . Nonetheless, further studies with large sample sizes are needed to confirm these findings and to identify any difference in glucose control with both drugs. Similarly, no significant increase in the risk of preterm births was noticed in both groups. However, two recent meta-analysis reports comparing the efficacy and safety of metformin with insulin produced mixed results by reporting a significant increase in the risk of preterm births and a significant decrease in the risk of gestational hypertension and postprandial glycemic levels in the metformin group [38, 39]. For the rest of the outcomes, no significant difference was noticed between the two groups. Nonetheless, it cannot be ignored that a greater percentage of patients
Glyburide vs. Metformin in GDM Treatment Fig. 4 Effect of glyburide and metformin treatment on the composite outcome (macrosomia and large for gestational age). CI confidence interval, df degrees of freedom, IV inverse variance
Fig. 5 Effect of glyburide and metformin treatment on neonatal hypoglycemia. CI confidence interval, df degrees of freedom, IV inverse variance
Fig. 6 Effect of glyburide and metformin treatment on cesarean section. CI confidence interval, df degrees of freedom, IV inverse variance
Fig. 7 Effect of glyburide and metformin treatment on neonatal birth weight. CI confidence interval, df degrees of freedom, IV inverse variance, SD standard deviation
Fig. 8 Effect of glyburide and metformin treatment on preterm births. CI confidence interval, df degrees of freedom, IV inverse variance
Fig. 9 Effect of glyburide and metformin treatment on fasting plasma glucose levels. CI confidence interval, df degrees of freedom, IV inverse variance, SD standard deviation
receiving metformin were switched to insulin therapy during the course of the study . Also for cesarean section, the results remained statistically non-significant
between the two groups in this review; however, analysis of this outcome was limited by the significant heterogeneity detected for this outcome. The most likely reason
M. Amin et al. Fig. 10 Effect of glyburide and metformin treatment on postprandial glucose levels. CI confidence interval, df degrees of freedom, IV inverse variance, SD standard deviation
for significant heterogeneity was differences in the reporting method for this outcome in individual trials. Moore et al.  reported only non-elective cesarean section cases, whereas Silva et al.  and George et al.  seem to have reported both elective and non-elective cesarean section deliveries. Interestingly, the rate of non-elective cesarean sections was significantly higher in the metformin group in the study conducted by Moore et al. , which was unexplainable and warrants further investigation. Our review is the most up-to-date review on the topic and includes all three RCTs available in the medical literature. The results for most of the outcomes were consistent and heterogeneity was reported for few outcomes. There was no significant difference in the baseline data of the patients in both study groups and, thus, was comparable. However, this systematic review also has certain limitations. Few studies have been conducted on the topic and the available studies enrolled small sample sizes. No study was double-blinded, which made the validity of the data doubtful, especially for cesarean section. This outcome was considered at high risk of detection bias as suspected macrosomia is likely to increase the rate of cesarean section . However, the rest of the outcomes were not considered at high risk of detection bias. Studies included in the review did not furnish information on the risk of many important outcomes such as shoulder dystocia, birth trauma, pre-eclampsia, and gestational hypertension. In addition, statistical significance was not achieved for outcomes such as neonatal hypoglycemia and preterm births, partly due to the small sample size; therefore, a firm conclusion cannot be drawn on the difference in risk for these outcomes.
5 Conclusion This review compared perinatal and maternal impacts of treating GDM with glyburide and metformin. The results indicate that treatment of GDM with glyburide increases the risk of higher birth weight among infants. Such infants are prone to pregnancy complications such as shoulder dystocia, birth trauma, and birth asphyxia. Also, the rate of cesarean section and labor induction is expected to rise. Based on such findings, it seems that metformin is an efficacious and better choice than glyburide in treating GDM
if OAD therapy is considered a therapeutic option following failure of dietary modification. However, further studies of large sample sizes with long-term follow-up are required to confirm these findings and to identify any other effects of OAD therapy on maternal or infant health. Disclosure statement No source of funding was used to prepare this review. The authors have no conflicts of interest that are directly relevant to the content of this article.
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