Editorial Opinion
Glyburide for Gestational Diabetes Time for a Pause for Thought Richard I. G. Holt, PhD, FRCP
Gestational diabetes mellitus (GDM) remains a major clinical challenge and is likely to remain so as the numbers of women with hyperglycemia in pregnancy continue to increase. The rising incidence has followed the changing demographic characteristics of pregnant women, such as Related article page 452 older age and inc reasing body mass index, coupled with new stricter diagnostic criteria.1 While one may debate whether it is appropriate to medicalize the pregnancies of such a large proportion of women, a more pertinent question is how to manage their hyperglycemia to reduce fetal and maternal morbidity. Even relatively modest hyperglycemia in pregnancy is associated with exaggerated fetal growth and an associated increased risk of interventional delivery, shoulder dystocia, and birth trauma. The risk of adverse outcomes increases with the degree of maternal hyperglycemia in a linear manner,2 and 2 large randomized clinical trials in women with GDM have shown the benefit of treating maternal hyperglycemia.3,4 Consequently, current recommendations are that women with GDM should aim for normoglycemia during pregnancy.5,6 If dietary and lifestyle measures fail to maintain glucose targets, insulin has been the recommended treatment of choice.5,6 However, this approach adds a considerable burden for both pregnant women and their health care teams, and other strategies using oral agents have been explored. Early studies indicated that sulfonylurea treatment was associated with an increased risk of congenital abnormalities and neonatal hypoglycemia, although confounding by maternal hyperglycemia should not be discounted.7,8 Nevertheless, it was well recognized that sulfonylurea drugs cross the placenta and potentially stimulate fetal insulin secretion, thereby causing the very same fetal complications treatment seeks to avoid. The publication of a randomized clinical trial by Langer et al9 regenerated interest in the use of glyburide in 2000. Following basic science experiments using a single cotyledon model that indicated that, unlike other sulfonylurea drugs, glyburide did not cross the placenta,10 404 women with GDM were randomly assigned to receive insulin or glyburide. There was a high treatment success rate with glyburide, with only 4% of women needing to switch to insulin. Overall, there were no differences in glycemic control between the 2 groups but hypoglycemia rates were higher in those treated with insulin. There were no other differences in maternal or perinatal outcomes. Importantly, cord insulin concentrations suggested no difference in fetal insulinemia, and glyburide was not detected in the cord serum samples. These findings led to a change in clinical practice. Several guideline bodies, including the American College of Obstet-
rics and Gynecology6 and the UK National Institute for Health and Care Excellence,5 endorsed the use of glyburide. However, other associations such as the American Diabetes Association were more cautious. In the United States among women with private health insurance, glyburide is now used more commonly than insulin to treat GDM; between 2000 and 2011, the use of glyburide increased from 7.4% of pharmacological treatment to 64.5%, superseding insulin as the most common treatment in 2007.11 More recent observational and experimental studies have generally confirmed that glyburide is effective and well tolerated, but caveats about safety have begun to emerge.8 Although not all studies have shown differences in fetal and maternal outcomes between glyburide and insulin, there have been reports of increased rates of preeclampsia, neonatal jaundice requiring phototherapy, longer stay in the neonatal intensive care unit, macrosomia, and neonatal hypoglycemia following treatment with glyburide.8 Furthermore, the very premise on which the use of glyburide is based, namely that it does not cross the placenta,10 has been challenged by a study of 40 women with GDM that found that fetal plasma glyburide concentrations were approximately 70% of maternal plasma levels.12 The major limitation with the current evidence has been the lack of power to demonstrate differences between insulin and glyburide, and this is particularly relevant for rare adverse events.8 The article by Camelo Castillo et al13 in this issue of JAMA Pediatrics is therefore a welcome addition to the debate. The article describes a large retrospective observational study of more than 9000 privately insured women with GDM treated with either glyburide (n = 4982) or insulin (n = 4191) and is nearly 2.5 times larger than the Sweet Success California Diabetes and Pregnancy Program, which is the next largest analysis with 2073 women treated with glyburide.14 Similar to the Sweet Success California Diabetes and Pregnancy Program, it shows that there is an increase in adverse fetal outcomes in women treated with glyburide. After adjusting for baseline differences, infants of women treated with glyburide had a 41% higher risk for neonatal intensive care unit admission, a 63% higher risk of respiratory distress, a 40% higher risk of hypoglycemia, and a 35% higher risk of birth injury compared with infants born to women treated with insulin.13 The absolute increase in risk associated with glyburide was 3.0% for neonatal intensive care unit admission, 1.4% for large for gestational age, and 1.1% for respiratory distress. The corresponding numbers needed to treat to harm were 36 for neonatal intensive care unit admission, 71 for large for gestational age, and 96 for respiratory distress. Smaller differences between treatment groups were also found for obstetric trauma, jaundice, and preterm birth. Conversely, the risk of cesarean delivery was 3% lower in the glyburide group.
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(Reprinted) JAMA Pediatrics May 2015 Volume 169, Number 5
Copyright 2015 American Medical Association. All rights reserved.
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Opinion Editorial
The incidence rates of adverse events in this analysis were similar to the Sweet Success California Diabetes and Pregnancy Program14 and indeed to those of the study by Langer et al as the estimates for all outcomes lie within the confidence intervals of the original study.9 Importantly, however, the much larger sample of the current analysis provides much more power than the randomized clinical trial to detect any differences in outcome between women treated with glyburide or insulin and to characterize those differences with greater precision. The main limitation of this and other observational analyses is that the results may be affected by important confounding factors. While the authors have adjusted for important medical conditions, they have not adjusted for all relevant sociodemographic features. This is an important omission as previous studies found that women were more likely to be treated with glyburide than insulin if they were nulliparous, not overweight, or African American or Asian, had not attended college, and had a primary language that was not English, all of which may influence the outcome of the pregnancy.8 Nevertheless, the consistency of findings with previous studies raises ARTICLE INFORMATION Author Affiliation: Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, England. Corresponding Author: Richard I. G. Holt, PhD, FRCP, IDS Bldg (MP887), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, England ([email protected]). Published Online: March 30, 2015. doi:10.1001/jamapediatrics.2015.144. Conflict of Interest Disclosures: Prof Holt was a member of the 2008 National Institute for Health and Care Excellence diabetes and pregnancy guideline development group. No other disclosures were reported. REFERENCES 1. Metzger BE, Gabbe SG, Persson B, et al; International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-682. 2. Metzger BE, Lowe LP, Dyer AR, et al; HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991-2002. 3. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS)
428
cause for concern and the time has come to reconsider the place of glyburide in pregnancy. So, are there viable alternatives to glyburide? A number of observational studies and clinical trials have suggested that metformin hydrochloride may be a better choice.8,15 None of the studies of metformin in pregnancy have highlighted any serious safety concerns despite it crossing the placenta. Although again limited by small numbers, these studies are encouraging, showing at least equivalent neonatal outcomes for metformin compared with insulin while reporting reductions in maternal weight gain and hypoglycemia, improved treatment satisfaction, and less neonatal hypoglycemia. This latest study heightens residual concerns about the use of glyburide to treat GDM that need to be resolved before this drug should be recommended for continued use in pregnancy. As the authors rightly conclude, the “higher risk of neonatal outcomes associated with glyburide-treated women demands further attention”13 and more attention is needed to determine which women are most likely to benefit from glyburide or perhaps more importantly not be harmed. It is time for a pause for thought.
Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-2486.
hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol. 1994; 171(3):653-660.
4. Landon MB, Spong CY, Thom E, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339-1348.
11. Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000-2011. Obstet Gynecol. 2014;123(6):1177-1184.
5. National Collaborating Centre for Women's and Children's Health. Diabetes in Pregnancy: Management of Diabetes and Its Complications From Preconception to the Postnatal Period. London, England: RCOG Press; 2008. 6. Committee on Practice Bulletins–Obstetrics. Practice bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol. 2013;122(2, pt 1):406-416. 7. Ekpebegh CO, Coetzee EJ, van der Merwe L, Levitt NS. A 10-year retrospective analysis of pregnancy outcome in pregestational type 2 diabetes: comparison of insulin and oral glucose-lowering agents. Diabet Med. 2007;24(3): 253-258. 8. Holt RI, Lambert KD. The use of oral hypoglycaemic agents in pregnancy. Diabet Med. 2014;31(3):282-291. 9. 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):1134-1138.
12. Hebert MF, Ma X, Naraharisetti SB, et al; Obstetric-Fetal Pharmacology Research Unit Network. Are we optimizing gestational diabetes treatment with glyburide? the pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009;85(6):607-614. 13. Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes [published online March 30, 2015]. JAMA Pediatr. doi:10.1001/jamapediatrics.2015.74. 14. Cheng YW, Chung JH, Block-Kurbisch I, Inturrisi M, Caughey AB. Treatment of gestational diabetes mellitus: glyburide compared to subcutaneous insulin therapy and associated perinatal outcomes. J Matern Fetal Neonatal Med. 2012;25(4):379-384. 15. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(19):2003-2015.
10. Elliott BD, Schenker S, Langer O, Johnson R, Prihoda T. Comparative placental transport of oral
JAMA Pediatrics May 2015 Volume 169, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Tulane University User on 05/18/2015
jamapediatrics.com
Glyburide for Gestational Diabetes Time for a Pause for Thought Richard I. G. Holt, PhD, FRCP
Gestational diabetes mellitus (GDM) remains a major clinical challenge and is likely to remain so as the numbers of women with hyperglycemia in pregnancy continue to increase. The rising incidence has followed the changing demographic characteristics of pregnant women, such as Related article page 452 older age and inc reasing body mass index, coupled with new stricter diagnostic criteria.1 While one may debate whether it is appropriate to medicalize the pregnancies of such a large proportion of women, a more pertinent question is how to manage their hyperglycemia to reduce fetal and maternal morbidity. Even relatively modest hyperglycemia in pregnancy is associated with exaggerated fetal growth and an associated increased risk of interventional delivery, shoulder dystocia, and birth trauma. The risk of adverse outcomes increases with the degree of maternal hyperglycemia in a linear manner,2 and 2 large randomized clinical trials in women with GDM have shown the benefit of treating maternal hyperglycemia.3,4 Consequently, current recommendations are that women with GDM should aim for normoglycemia during pregnancy.5,6 If dietary and lifestyle measures fail to maintain glucose targets, insulin has been the recommended treatment of choice.5,6 However, this approach adds a considerable burden for both pregnant women and their health care teams, and other strategies using oral agents have been explored. Early studies indicated that sulfonylurea treatment was associated with an increased risk of congenital abnormalities and neonatal hypoglycemia, although confounding by maternal hyperglycemia should not be discounted.7,8 Nevertheless, it was well recognized that sulfonylurea drugs cross the placenta and potentially stimulate fetal insulin secretion, thereby causing the very same fetal complications treatment seeks to avoid. The publication of a randomized clinical trial by Langer et al9 regenerated interest in the use of glyburide in 2000. Following basic science experiments using a single cotyledon model that indicated that, unlike other sulfonylurea drugs, glyburide did not cross the placenta,10 404 women with GDM were randomly assigned to receive insulin or glyburide. There was a high treatment success rate with glyburide, with only 4% of women needing to switch to insulin. Overall, there were no differences in glycemic control between the 2 groups but hypoglycemia rates were higher in those treated with insulin. There were no other differences in maternal or perinatal outcomes. Importantly, cord insulin concentrations suggested no difference in fetal insulinemia, and glyburide was not detected in the cord serum samples. These findings led to a change in clinical practice. Several guideline bodies, including the American College of Obstet-
rics and Gynecology6 and the UK National Institute for Health and Care Excellence,5 endorsed the use of glyburide. However, other associations such as the American Diabetes Association were more cautious. In the United States among women with private health insurance, glyburide is now used more commonly than insulin to treat GDM; between 2000 and 2011, the use of glyburide increased from 7.4% of pharmacological treatment to 64.5%, superseding insulin as the most common treatment in 2007.11 More recent observational and experimental studies have generally confirmed that glyburide is effective and well tolerated, but caveats about safety have begun to emerge.8 Although not all studies have shown differences in fetal and maternal outcomes between glyburide and insulin, there have been reports of increased rates of preeclampsia, neonatal jaundice requiring phototherapy, longer stay in the neonatal intensive care unit, macrosomia, and neonatal hypoglycemia following treatment with glyburide.8 Furthermore, the very premise on which the use of glyburide is based, namely that it does not cross the placenta,10 has been challenged by a study of 40 women with GDM that found that fetal plasma glyburide concentrations were approximately 70% of maternal plasma levels.12 The major limitation with the current evidence has been the lack of power to demonstrate differences between insulin and glyburide, and this is particularly relevant for rare adverse events.8 The article by Camelo Castillo et al13 in this issue of JAMA Pediatrics is therefore a welcome addition to the debate. The article describes a large retrospective observational study of more than 9000 privately insured women with GDM treated with either glyburide (n = 4982) or insulin (n = 4191) and is nearly 2.5 times larger than the Sweet Success California Diabetes and Pregnancy Program, which is the next largest analysis with 2073 women treated with glyburide.14 Similar to the Sweet Success California Diabetes and Pregnancy Program, it shows that there is an increase in adverse fetal outcomes in women treated with glyburide. After adjusting for baseline differences, infants of women treated with glyburide had a 41% higher risk for neonatal intensive care unit admission, a 63% higher risk of respiratory distress, a 40% higher risk of hypoglycemia, and a 35% higher risk of birth injury compared with infants born to women treated with insulin.13 The absolute increase in risk associated with glyburide was 3.0% for neonatal intensive care unit admission, 1.4% for large for gestational age, and 1.1% for respiratory distress. The corresponding numbers needed to treat to harm were 36 for neonatal intensive care unit admission, 71 for large for gestational age, and 96 for respiratory distress. Smaller differences between treatment groups were also found for obstetric trauma, jaundice, and preterm birth. Conversely, the risk of cesarean delivery was 3% lower in the glyburide group.
jamapediatrics.com
(Reprinted) JAMA Pediatrics May 2015 Volume 169, Number 5
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Tulane University User on 05/18/2015
427
Opinion Editorial
The incidence rates of adverse events in this analysis were similar to the Sweet Success California Diabetes and Pregnancy Program14 and indeed to those of the study by Langer et al as the estimates for all outcomes lie within the confidence intervals of the original study.9 Importantly, however, the much larger sample of the current analysis provides much more power than the randomized clinical trial to detect any differences in outcome between women treated with glyburide or insulin and to characterize those differences with greater precision. The main limitation of this and other observational analyses is that the results may be affected by important confounding factors. While the authors have adjusted for important medical conditions, they have not adjusted for all relevant sociodemographic features. This is an important omission as previous studies found that women were more likely to be treated with glyburide than insulin if they were nulliparous, not overweight, or African American or Asian, had not attended college, and had a primary language that was not English, all of which may influence the outcome of the pregnancy.8 Nevertheless, the consistency of findings with previous studies raises ARTICLE INFORMATION Author Affiliation: Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, England. Corresponding Author: Richard I. G. Holt, PhD, FRCP, IDS Bldg (MP887), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, England ([email protected]). Published Online: March 30, 2015. doi:10.1001/jamapediatrics.2015.144. Conflict of Interest Disclosures: Prof Holt was a member of the 2008 National Institute for Health and Care Excellence diabetes and pregnancy guideline development group. No other disclosures were reported. REFERENCES 1. Metzger BE, Gabbe SG, Persson B, et al; International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-682. 2. Metzger BE, Lowe LP, Dyer AR, et al; HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991-2002. 3. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS)
428
cause for concern and the time has come to reconsider the place of glyburide in pregnancy. So, are there viable alternatives to glyburide? A number of observational studies and clinical trials have suggested that metformin hydrochloride may be a better choice.8,15 None of the studies of metformin in pregnancy have highlighted any serious safety concerns despite it crossing the placenta. Although again limited by small numbers, these studies are encouraging, showing at least equivalent neonatal outcomes for metformin compared with insulin while reporting reductions in maternal weight gain and hypoglycemia, improved treatment satisfaction, and less neonatal hypoglycemia. This latest study heightens residual concerns about the use of glyburide to treat GDM that need to be resolved before this drug should be recommended for continued use in pregnancy. As the authors rightly conclude, the “higher risk of neonatal outcomes associated with glyburide-treated women demands further attention”13 and more attention is needed to determine which women are most likely to benefit from glyburide or perhaps more importantly not be harmed. It is time for a pause for thought.
Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-2486.
hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol. 1994; 171(3):653-660.
4. Landon MB, Spong CY, Thom E, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339-1348.
11. Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000-2011. Obstet Gynecol. 2014;123(6):1177-1184.
5. National Collaborating Centre for Women's and Children's Health. Diabetes in Pregnancy: Management of Diabetes and Its Complications From Preconception to the Postnatal Period. London, England: RCOG Press; 2008. 6. Committee on Practice Bulletins–Obstetrics. Practice bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol. 2013;122(2, pt 1):406-416. 7. Ekpebegh CO, Coetzee EJ, van der Merwe L, Levitt NS. A 10-year retrospective analysis of pregnancy outcome in pregestational type 2 diabetes: comparison of insulin and oral glucose-lowering agents. Diabet Med. 2007;24(3): 253-258. 8. Holt RI, Lambert KD. The use of oral hypoglycaemic agents in pregnancy. Diabet Med. 2014;31(3):282-291. 9. 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):1134-1138.
12. Hebert MF, Ma X, Naraharisetti SB, et al; Obstetric-Fetal Pharmacology Research Unit Network. Are we optimizing gestational diabetes treatment with glyburide? the pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009;85(6):607-614. 13. Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes [published online March 30, 2015]. JAMA Pediatr. doi:10.1001/jamapediatrics.2015.74. 14. Cheng YW, Chung JH, Block-Kurbisch I, Inturrisi M, Caughey AB. Treatment of gestational diabetes mellitus: glyburide compared to subcutaneous insulin therapy and associated perinatal outcomes. J Matern Fetal Neonatal Med. 2012;25(4):379-384. 15. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(19):2003-2015.
10. Elliott BD, Schenker S, Langer O, Johnson R, Prihoda T. Comparative placental transport of oral
JAMA Pediatrics May 2015 Volume 169, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Tulane University User on 05/18/2015
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