With the increase in obesity and sedentary lifestyles, the incidence of diabetes among reproductive-aged women is rising globally. Providers are expected to care for a growing number of women with gestational diabetes (GDM) in the coming decades. Traditionally, insulin has been considered the standard for management of GDM, when diet and exercise fail to achieve tight maternal glucose control without the risk of transfer of insulin across the placenta. Understanding the effectiveness and safety of the use of oral diabetes agents during pregnancy for both maternal and neonatal outcomes as an alternative management option is essential to the care of women with GDM and their offspring. In this review, our objectives were to (1) summarise the available evidence on the efficacy these medications, (2) review available data on adverse effect, (3) discuss current gaps in research, outlining limitations in current study designs that deserve attention and (4) summarise key points for the practicing clinician.
Understanding the effectiveness and safety of the use of oral diabetes agents during pregnancy for both maternal and neonatal outcomes is essential for the care of women with gestational diabetes (GDM) and their offspring. The incidence of GDM depends on the diagnostic criteria used and varies widely between racial groups. Overall incidence is reported as 3–6%, but has steadily increased over time, ranging from 2% in South America to 5% in the United States to 15% in India. GDM is associated with foetal complications, including macrosomia, hypoglycaemia and birth trauma. Maternal complications include risk of caesarean delivery and hypertensive disease. Efforts to promote maternal well-being and to avoid adverse neonatal outcomes are based on recommendations for diagnosis and treatment by the American College of Obstetricians and Gynecologists (ACOG), American Diabetes Association (ADA) and several international professional societies. These guidelines emphasise the importance of maternal glucose control to minimise the risk of macrosomia and its associated morbidities.
Traditionally, insulin has been considered the standard for management of GDM, when diet and exercise fail to achieve tight maternal glucose control without the risk of transfer of insulin across the placenta. Insulin therapy can be difficult for pregnant women to adhere to, due in part to the multiple injections required for therapy. Both women and their clinicians often experience frustration, and, to some degree, anxiety, over the lack of compliance and potential effects of suboptimal control on intrauterine foetal development. Oral diabetes medications (i.e., glyburide and metformin) are being used increasingly in women with GDM, despite continued concerns about their efficacy and safety, and the fact that their use is not approved by the United States Food and Drug Administration (FDA) for treatment of GDM. Women with GDM prefer, and are often more compliant with, oral medications compared with insulin. Further, the convenience of an oral medication, simple dosages as well as their low cost, increases the likelihood of their use, particularly in low-resource countries and settings. However, the lack of endorsement by national and international medical societies for use during pregnancy influences provider confidence when counselling patients about oral diabetes agents as an alternative to insulin therapy.
Although lack of adequate glucose control in GDM is associated with higher maternal and neonatal morbidity, little is known about the comparative effectiveness and safety of glyburide or metformin compared with insulin or to each other. Much of the concern over the use of oral diabetes medications is over the lack of data regarding the extent to which they cross the placenta and the potential risk of foetal hyperinsulinaemia, which can lead to macrosomia and prolonged neonatal hypoglycaemia. Potential effects regarding foetal metabolism or newborn growth and development are relatively understudied. As such, the use of these medications remains a topic of debate and ongoing research. There are several available oral diabetes medications although glyburide and metformin are the two most commonly used agents in the United States and Europe. In this review, our objectives are to (1) summarise the available evidence on the efficacy of these medications, (2) review available data on adverse effect, (3) discuss current gaps in research and outline limitations in current study designs that deserve attention and (4) summarise key points for the practicing clinician.
Brief summary of available oral diabetes medications
This review focusses on the second-generation sulphonylureas (glyburide and glibenclamide) and metformin, the two classes of drugs that are most commonly used in pregnancy and included in clinical trials of oral diabetes medications in the management of GDM. We summarise the mechanism of action for these two drug categories and provide a brief description on other oral diabetes medications that have been considered for use in pregnancy. Glyburide (or glibenclamide) is a second-generation sulphonylurea. Metformin is in the biguanide class of agents. Glyburide binds to pancreatic beta-cell adenosine triphosphate (ATP)-calcium channel receptors to increase insulin secretion and insulin sensitivity of peripheral tissues. There are conflicting studies regarding transfer of glyburide across the placenta. In vitro studies show minimal transfer of glyburide, but the foetal response to various dosages of the drug is not completely understood. Two first-generation sulphonylureas, namely tolbutamide and chlorpropamide are not recommended in women with GDM because these drugs cross the placenta and can adversely affect foetal metabolism. Metformin inhibits hepatic gluconeogenesis and glucose absorption and stimulates glucose uptake in peripheral tissues. Metformin does cross the placenta, but, as it acts as an insulin sensitiser for peripheral tissues rather that an insulin analogue, it is thought that it is less likely to affect foetal metabolism.
Acarbose, an alpha glucosidase inhibitor, has been used sparingly. Preliminary studies have suggested efficacy in reducing postprandial hyperglycaemia in GDM, but its use has been limited due to the frequency of abdominal cramping. As a small proportion of this drug may be absorbed systemically, further studies are necessary to better evaluate potential transplacental passage. Use of thiazolidinediones, glitinides (e.g., repaglinide and nateglinide) and glucagon-like peptide-1 (GLP-1 ) during pregnancy is considered experimental. There are no controlled data available in pregnancy.
Materials and methods
We originally conducted this systematic review as part of a comprehensive report for the Agency for Healthcare Research and Quality on therapeutic management, risk factors and post-partum screening of women with GDM. Details of that report can be viewed in full at http://www.ahrq.gov . The information included in this review includes an interim literature search of randomised controlled trials (RCTs) only, that compare a currently used oral diabetes medication (i.e., metformin and glyburide) with insulin or to another diabetes medication, that have been published since our original review in 2009. We hand-searched the references of these three RCTs for additional studies that were relevant to the current review. Search terms included various MeSH and text terms for GDM and oral diabetes agents or insulin. Articles were excluded if they were not written in English, did not include human data, contained no original data or less than 90% of the sample was diagnosed with GDM, did not compare an oral diabetes agent with insulin or another oral diabetes agent, did not use an oral glucose tolerance test (OGTT) to confirm diagnosis of GDM (either a 3-h, 100-g OGTT or a 2- h 75-g OGTT) or was a case report or case series. We then sequentially abstracted information on the characteristics of the studies and outcomes. Two investigators independently applied the Jadad criteria to assess the quality o f each randomised trial, which included the appropriateness of the randomisation scheme and blinding, description of withdrawals and a report of participants who were lost to follow-up. We conducted a meta-analysis for infant birth weight between insulin and glyburide treatment groups because there were a sufficient number of trials (three or more) and the trials were relatively homogeneous with respect to population characteristics, study duration and drug dosage. We used the random effects model of DerSimonian and Laird to derive weighted mean differences with respect to infant birth weight.
Materials and methods
We originally conducted this systematic review as part of a comprehensive report for the Agency for Healthcare Research and Quality on therapeutic management, risk factors and post-partum screening of women with GDM. Details of that report can be viewed in full at http://www.ahrq.gov . The information included in this review includes an interim literature search of randomised controlled trials (RCTs) only, that compare a currently used oral diabetes medication (i.e., metformin and glyburide) with insulin or to another diabetes medication, that have been published since our original review in 2009. We hand-searched the references of these three RCTs for additional studies that were relevant to the current review. Search terms included various MeSH and text terms for GDM and oral diabetes agents or insulin. Articles were excluded if they were not written in English, did not include human data, contained no original data or less than 90% of the sample was diagnosed with GDM, did not compare an oral diabetes agent with insulin or another oral diabetes agent, did not use an oral glucose tolerance test (OGTT) to confirm diagnosis of GDM (either a 3-h, 100-g OGTT or a 2- h 75-g OGTT) or was a case report or case series. We then sequentially abstracted information on the characteristics of the studies and outcomes. Two investigators independently applied the Jadad criteria to assess the quality o f each randomised trial, which included the appropriateness of the randomisation scheme and blinding, description of withdrawals and a report of participants who were lost to follow-up. We conducted a meta-analysis for infant birth weight between insulin and glyburide treatment groups because there were a sufficient number of trials (three or more) and the trials were relatively homogeneous with respect to population characteristics, study duration and drug dosage. We used the random effects model of DerSimonian and Laird to derive weighted mean differences with respect to infant birth weight.
Results
In this updated review and summary, we identified eight RCTs that examined the benefits and potential risks of oral diabetes medications: four RCTs compared glyburide and insulin, with a total of 575 participants; two RCTs compared metformin and insulin, with a total of 1396 participants, and two RCTs (with 221 participants) compared metformin and glyburide.
Population characteristics of eight RCTs with oral diabetes medications
The eight RCTs were published between 2000 and 2010 and were conducted in diverse countries and populations ( Table 1 ). Four trials were conducted in the United States, two in Brazil, one in India and one in Australia and New Zealand. The dosage of glyburide used in the glyburide versus insulin trials ranged from 5 mg to 20 mg daily. In the two trials comparing glyburide with metformin, the maximum glyburide dose was 20 mg daily; the maximum daily metformin dose was 2500 mg. Five of the six studies compared an oral diabetes medication with insulin and reported the percentage of participants initially placed on an oral medication who ultimately required insulin. Two of the five studies reported no participants requiring supplementation with insulin. Three of the five studies reported a wide range of participants who required insulin, ranging from 4% to 6% to 47%. The average gestational age at screening and diagnosis of GDM varied across studies from 22 to 25 gestational weeks.
| Author | Country | Interventions | Patients on OHA | Patients on insulin | Dose of OHA | OHA group requiring insulin | Criteria for starting medical treatment | |
|---|---|---|---|---|---|---|---|---|
| Fasting mg/dL | 2h, mg/dL | |||||||
| Rowan et al. | Australia, New Zealand | Metformin vs insulin | 363 | 970 | Metformin 1750-2500 | 168 (46.6%) | 97.2 | 120.6 |
| Moore et al. | United States | Metformin vs insulin | 32 | 31 | Not reported | 0 (0%) | 105 | 120 |
| Ogunyemi et al. | United States | Glyburide vs insulin | 48 | 49 | Glyburide 5 mg | 3 (6.25%) | 95 | 120 |
| Anjalakshi et al. | India | Glyburide vs insulin | 10 | 13 | Not reported | 0 (0%) | 120 | |
| Langer et al. | United States | Glyburide vs insulin | 201 | 203 | Glyburide 9 ± 6 mg | 8 (4%) | 95 | 120 |
| Bertini et al. | Brazil | Glyburide vs insulin | 27 | |||||
| Patients on Glyburide | Patients on metformin | |||||||
| Moore | United States | Glyburide vs metformin | 74 | 75 | Max daily dose of 20 mg vs. 2000 mg | 12 vs 26 | 105 | 120 |
| Silva et al. | Brazil | Glyburide vs metformin | 40 | 32 | Max daily dose of 20 mg vs. 2500 mg | 10 vs 8 | 90 | 120 |
Quality assessment of RCTs
Six of the RCTs described the randomisation scheme. None of the trials were blinded. Four of the trials reported and described participant withdrawals or the reasons for loss to follow-up. Only two studies reported an intention-to-treat analysis.
RCTs comparing insulin to glyburide: maternal outcomes
Clinical trials assess the efficacy of glyburide on glucose control, but there is limited data on any adverse effects of glyburide compared with insulin ( Table 2 ). Four RCTs compared the effects of insulin and glyburide on five different maternal outcomes ( Table 2 ). Three RCTs evaluated caesarean delivery. Four RCTs evaluated glycaemic control (fasting blood glucose (FBG), 2-h postprandial and average daily glucose). Only one RCT examined maternal weight. Only two adverse maternal outcomes were evaluated. Three RCTs evaluated maternal hypoglycaemia and one RCT evaluated pre-eclampsia. Langer and colleagues reported findings from the largest RCT, in which they randomly assigned 404 women to receive insulin or glyburide. They reported no statistically significant differences in mean final FBG or 2-h postprandial glucose levels between those receiving insulin and those taking glyburide. Two smaller RCTs also reported no differences in 2-h postprandial levels between women on insulin compared with women on glyburide. The most recent study, however, reported higher mean FBG (FBG) 89 ± 13.2 vs. 95.6 ± 13. 4 mg dl −1 ( p = 0.02) and 2-hour postprandial levels (132 ± 35 vs. 116 ± 17 mg dl −1 in women on glyburide compared with women on insulin, respectively.
| Author | Treatment | Pre-eclampsia | Cesarean Delivery | Weight (kg) | Glycemic Control during Pregnancy (mg/dL) | Hypoglycemia |
|---|---|---|---|---|---|---|
| Anjalakshi et al. 2006 | G1: Insulin: 13 | 2-h PG: B 175 ± 31; F 93 ± 10 | ||||
| G2: Glibenclamide: 10 | 2-h PG: B 167 ± 23; F 95 ± 7 | |||||
| Bertini et al. 2005 | G1: Insulin: 27 | 12 (44) | Maternal F-B 11.5 ± 3.8 | FBG: B 108 ± 26 F 95 ± 16 a | Requiring hospital admission: 0 (0) | |
| G2: Glyburide: 24 | 12 (50) | 10 ± 5.2 | 0 (0) | |||
| G3: Acarbose: 19 | 10 (52) | 10.6 ± 3.2 P = 0.46 b | 0 (0) | |||
| Preprandial glucose: B 107 ± 23; F 97 ± 14 a | FSG less than 40 mg/dL 41 (20) | |||||
| Langer et al. 2000 | G1: Insulin: 203 | 12 (6) | 49 (24) | 2-h PPG: B 129 ± 27; F 112 ± 15 a | ||
| Combined glucose: B 116 ± 22 c ; F 105 ± 18 | ||||||
| FBG: B104 ± 25; P = 0.12 d ; F 98 ± 13 a ; P = 0.17 d | ||||||
| Preprandial glucose: B 104 ± 20; P = 0.16 d ; F 95 ± 15 a ; P = 0.17 d | FSG less than 40 mg/dL 4 (2); P = 0.03 | |||||
| G2: Glyburide: 201 | 12 (6) | 46 (23) | 2-h PPG; B 130 ± 25; P = 0.69 d ; F 113 ± 22 a ; P = 0.6 d | |||
| Combined glucose: B 114 ± 19 c ; P = 0.33 d F 105 ± 16; P = 0.99 d | ||||||
| Ogunyemi et al. 2007 | G1: Insulin: 49 | 25 (56) | FBG: 89. ± 13.2 2-hPPG: 116.3 ± 16.6 | 15 (31) | ||
| G2: Glyburide: 48 | 18 (42) P = .20 | FBG: 95.6. ± 1342, 2-hPPG: 132.6 ± 35.0; P = .02 | 18 (38) P = .66 | |||
| Rowan et al. 2008 | G1: Metformin: 363 | 20 (5.5) | 131 (36) | F-B 0.4 ± 3 | FBG a : 93.6 ± 11 2-h PPG: 111.6 ± 11 | |
| G2: insulin: 370 | 26 (7.0) | 142(38) P = 0.5 | F-B 2.0 ± 3; P < 0.001 | FBG a : 93.6 ± 11 P = 0.24 d 2-h PPG: 115.2 ± 16 P = 0.003 | ||
| Moore et al. 2007 | G1: Metformin: 32 | 7 | B 104.28 ± 25.45 | FBG: 92.6 ± 10.0 | ||
| G2: Insulin: 31 | 10; P = .102 | B 67.49 ± 19.5 | FBG: 96.8 ± 92.6, P = .400 | |||
| Moore et al. 2010 | G1: Glyburide: 74 | 3 (4) | 2 | FBG: 90.9 ± 13 | ||
| G2: Metformin: 75 | 2 (2.7) P = >.5 | 11 P = .02 | 94.3 ± 15; P = .23 | |||
| Silva et al. 2010 | G1: Glyburide: 40 | 28 (70) | ||||
| G2: Metformin: 32 | 22 (68.7); P = .91 |
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