BMJ 2015;350:h177 doi: 10.1136/bmj.h177 (Published 21 January 2015)
Page 1 of 2
Editorials
EDITORIALS Which oral hypoglycaemic for gestational diabetes? Latest evidence favours metformin over glibenclamide, but there’s more work to do on both agents David A Sacks associate investigator; clinical professor
12
Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA; 2Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, California, USA 1
Gestational diabetes constitutes over 80% of diabetes seen during pregnancy1 and is increasing in prevalence.2 That gestational diabetes is associated with specific adverse maternal, fetal, and neonatal outcomes has been clearly established.3 The care of the pregnant woman with gestational diabetes has long been based on the assumption of a causal or a co-varying relationship between maternal hyperglycaemia and these adverse outcomes.4 Balsells and colleagues’ meta-analysis (doi:10.1136/ bmj.h102) analyzes the consequences of contemporary efforts to minimize the adverse effects of maternal hyperglycaemia.5 Results were somewhat mixed, but, of the two oral agents, metformin had a significantly better risk-benefit profile that glibenclamide (glyburide). A progressive decrease in insulin sensitivity with advancing gestational age is a normal accompaniment of pregnancy. In contrast with their non-diabetic peers, women destined to develop gestational diabetes have significantly lower insulin sensitivity before conception despite maintaining normal glucose tolerance. During pregnancy, the amount of insulin that women with gestational diabetes release in response to a glucose load is significantly less than that released by pregnant women without gestational diabetes, and a glucose tolerance test becomes abnormal. Thus, two mechanisms contribute to maternal hyperglycaemia: exaggerated insulin resistance antedating pregnancy and inability of beta cells to compensate for this resistance during pregnancy.6
Because of the relationship between elevated maternal glucose concentrations and adverse pregnancy outcomes, lowering maternal glucose to specified target concentrations is standard practice in the care of women with gestational diabetes. Traditionally, care of these women starts with changes in dietary content and quantity accompanied by increases in physical activity. While these measures will achieve glycaemic targets in most cases, a minority of women with gestational diabetes will need supplemental drug treatments to achieve them. Initially, injected insulin was the sole agent used for achieving glycaemic goals.4 Subsequent studies suggested the safety and efficacy of oral agents in the treatment of gestational diabetes.7 8 Probably because of ease of administration, minimal side effects, efficacy in achieving glycaemic goals, and a rate of adverse
outcomes not in excess of those seen with traditional management, the use of oral hypoglycaemics in lieu of insulin in the care of women with gestational diabetes is now well accepted by women and their doctors.9
Metformin and glibenclamide are the two oral hypoglycaemics most widely used in the treatment of gestational diabetes. Balsells and colleagues report a large meta-analysis evaluating these agents for treatment of gestational diabetes using data obtained exclusively from randomized controlled trials.5 They compared relations between the use of these agents and important maternal and fetal outcomes during and immediately following pregnancy, including gestational weight gain, gestational age at birth, macrosomia, and neonatal hypoglycaemia. The study focused on three comparisons: insulin versus metformin, insulin versus glibenclamide, and metformin versus glibenclamide. Given the dramatic increase in use of oral hypoglycaemic agents for treatment of gestational diabetes, the most clinically relevant analyses are those comparing metformin with glibenclamide. The authors took great care to collect and control for confounders that may affect their outcomes of interest. Nonetheless, meta-analysis has its limitations. For example, among the 15 studies analyzed, five different sets of criteria were used to define gestational diabetes. Although the targeted glucose values were similar among studies, they were not identical, and timing of postprandial glucose tests also varied. Tests for heterogeneity cannot fully adjust for effects on outcomes driven by individual differences in patient adherence to study protocols or effects related to socioeconomic differences of subjects within each study.
One key finding was that metformin was associated with reduced maternal weight gain relative to both insulin and glibenclamide. It’s possible this result would have been different in analyses that expressed this outcome as a function of appropriate weight gain for prepregnancy weight and height.10 Importantly, the finding that between 10% and 46% of women in trials comparing metformin with insulin required insulin supplementation or substitution for metformin11 raises the question of whether the comparisons in these intention-to-treat analyses are really between metformin and insulin or between the combined effects
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BMJ 2015;350:h177 doi: 10.1136/bmj.h177 (Published 21 January 2015)
Page 2 of 2
EDITORIALS
of metformin and insulin with insulin alone. The finding of significantly less fetal overgrowth in the metformin group suggests a marked advantage of metformin compared with glibenclamide. However, more information is necessary before we accept the authors’ suggestion that glibenclamide should be abandoned in favour of metformin for women with gestational diabetes.
Several issues regarding the use of these oral hypoglycaemics in pregnancy have yet to be addressed adequately. For example, glibenclamide taken during pregnancy takes longer to reach peak concentration and is metabolized more rapidly than glibenclamide taken in the non-pregnant state. Earlier administration in relation to a meal, alteration in dosing, and pre-meal rather than once a day dosing may enhance the performance of this drug.12 Metformin is excreted intact through the renal tubules. Because of the progressive increase in renal filtration and active drug transport, maternal doses may need upward adjustment to improve efficacy with advancing pregnancy. Studies of alterations in dose and timing of administration of both drugs in the treatment of gestational diabetes seem prudent and necessary. Combined use of metformin and glibenclamide might also merit investigation. In addition, long term follow-up of both mothers and their offspring are needed to fully assess the safety as well as the benefits of these drugs when taken during pregnancy.13 Balsells and colleagues’ study adds knowledge about the associations between the use of metformin, glibenclamide, and insulin for women with gestational diabetes and important clinical outcomes. The investigators’ efforts will hopefully inspire further investigations into treatment of this highly prevalent disease of pregnancy.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare. Provenance and peer review: Commissioned, not peer reviewed. 1 2 3 4 5 6 7 8 9 10 11 12 13
Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. Diabetes Care 2008;31:899-904. Schneider S, Bock C, Wetzel M, Maul H, Loerbroks A. The prevalence of gestational diabetes in advanced economies. J Perinat Med 2012;40:511-20. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991-2002. Gabbe SG, Mestman JG, Freeman RK, Anderson GV, Lowensohn RI. Management and outcome of class A diabetes mellitus. Am J Obstet Gynecol 1977;127:465-9 Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015;350:h102. Catalano PM. Trying to understand gestational diabetes. Diabet Med 2014;31:273-81. 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;343:1134-8. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15. Camelo Castillo W, Boggess K, Sturmer 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;123:1177-84. Rasmussen K, Yaktine AL, eds; Committee to Reexamine IOM Pregnancy Weight Guidelines; Institute of Medicine; National Research Council. Weight gain during pregnancy: reexamining the guidelines . National Academies Press, 2009. Ryu RJ, Hays KE, Hebert MF. Gestational diabetes mellitus management with oral hypoglycemic agents. Semin Perinatol 2014;38:508-15. Caritis SN, Hebert MF. A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol 2013;121:1309-12. Ro TB, Ludvigsen HV, Carlsen SM, Vanky E. Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest 2012;72:570-5.
Cite this as: BMJ 2015;350:h177 © BMJ Publishing Group Ltd 2015
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Which oral hypoglycaemic for gestational diabetes? Latest evidence favours metformin over glibenclamide, but there’s more work to do on both agents David A Sacks associate investigator; clinical professor
12
Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA; 2Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, California, USA 1
Gestational diabetes constitutes over 80% of diabetes seen during pregnancy1 and is increasing in prevalence.2 That gestational diabetes is associated with specific adverse maternal, fetal, and neonatal outcomes has been clearly established.3 The care of the pregnant woman with gestational diabetes has long been based on the assumption of a causal or a co-varying relationship between maternal hyperglycaemia and these adverse outcomes.4 Balsells and colleagues’ meta-analysis (doi:10.1136/ bmj.h102) analyzes the consequences of contemporary efforts to minimize the adverse effects of maternal hyperglycaemia.5 Results were somewhat mixed, but, of the two oral agents, metformin had a significantly better risk-benefit profile that glibenclamide (glyburide). A progressive decrease in insulin sensitivity with advancing gestational age is a normal accompaniment of pregnancy. In contrast with their non-diabetic peers, women destined to develop gestational diabetes have significantly lower insulin sensitivity before conception despite maintaining normal glucose tolerance. During pregnancy, the amount of insulin that women with gestational diabetes release in response to a glucose load is significantly less than that released by pregnant women without gestational diabetes, and a glucose tolerance test becomes abnormal. Thus, two mechanisms contribute to maternal hyperglycaemia: exaggerated insulin resistance antedating pregnancy and inability of beta cells to compensate for this resistance during pregnancy.6
Because of the relationship between elevated maternal glucose concentrations and adverse pregnancy outcomes, lowering maternal glucose to specified target concentrations is standard practice in the care of women with gestational diabetes. Traditionally, care of these women starts with changes in dietary content and quantity accompanied by increases in physical activity. While these measures will achieve glycaemic targets in most cases, a minority of women with gestational diabetes will need supplemental drug treatments to achieve them. Initially, injected insulin was the sole agent used for achieving glycaemic goals.4 Subsequent studies suggested the safety and efficacy of oral agents in the treatment of gestational diabetes.7 8 Probably because of ease of administration, minimal side effects, efficacy in achieving glycaemic goals, and a rate of adverse
outcomes not in excess of those seen with traditional management, the use of oral hypoglycaemics in lieu of insulin in the care of women with gestational diabetes is now well accepted by women and their doctors.9
Metformin and glibenclamide are the two oral hypoglycaemics most widely used in the treatment of gestational diabetes. Balsells and colleagues report a large meta-analysis evaluating these agents for treatment of gestational diabetes using data obtained exclusively from randomized controlled trials.5 They compared relations between the use of these agents and important maternal and fetal outcomes during and immediately following pregnancy, including gestational weight gain, gestational age at birth, macrosomia, and neonatal hypoglycaemia. The study focused on three comparisons: insulin versus metformin, insulin versus glibenclamide, and metformin versus glibenclamide. Given the dramatic increase in use of oral hypoglycaemic agents for treatment of gestational diabetes, the most clinically relevant analyses are those comparing metformin with glibenclamide. The authors took great care to collect and control for confounders that may affect their outcomes of interest. Nonetheless, meta-analysis has its limitations. For example, among the 15 studies analyzed, five different sets of criteria were used to define gestational diabetes. Although the targeted glucose values were similar among studies, they were not identical, and timing of postprandial glucose tests also varied. Tests for heterogeneity cannot fully adjust for effects on outcomes driven by individual differences in patient adherence to study protocols or effects related to socioeconomic differences of subjects within each study.
One key finding was that metformin was associated with reduced maternal weight gain relative to both insulin and glibenclamide. It’s possible this result would have been different in analyses that expressed this outcome as a function of appropriate weight gain for prepregnancy weight and height.10 Importantly, the finding that between 10% and 46% of women in trials comparing metformin with insulin required insulin supplementation or substitution for metformin11 raises the question of whether the comparisons in these intention-to-treat analyses are really between metformin and insulin or between the combined effects
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h177 doi: 10.1136/bmj.h177 (Published 21 January 2015)
Page 2 of 2
EDITORIALS
of metformin and insulin with insulin alone. The finding of significantly less fetal overgrowth in the metformin group suggests a marked advantage of metformin compared with glibenclamide. However, more information is necessary before we accept the authors’ suggestion that glibenclamide should be abandoned in favour of metformin for women with gestational diabetes.
Several issues regarding the use of these oral hypoglycaemics in pregnancy have yet to be addressed adequately. For example, glibenclamide taken during pregnancy takes longer to reach peak concentration and is metabolized more rapidly than glibenclamide taken in the non-pregnant state. Earlier administration in relation to a meal, alteration in dosing, and pre-meal rather than once a day dosing may enhance the performance of this drug.12 Metformin is excreted intact through the renal tubules. Because of the progressive increase in renal filtration and active drug transport, maternal doses may need upward adjustment to improve efficacy with advancing pregnancy. Studies of alterations in dose and timing of administration of both drugs in the treatment of gestational diabetes seem prudent and necessary. Combined use of metformin and glibenclamide might also merit investigation. In addition, long term follow-up of both mothers and their offspring are needed to fully assess the safety as well as the benefits of these drugs when taken during pregnancy.13 Balsells and colleagues’ study adds knowledge about the associations between the use of metformin, glibenclamide, and insulin for women with gestational diabetes and important clinical outcomes. The investigators’ efforts will hopefully inspire further investigations into treatment of this highly prevalent disease of pregnancy.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare. Provenance and peer review: Commissioned, not peer reviewed. 1 2 3 4 5 6 7 8 9 10 11 12 13
Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. Diabetes Care 2008;31:899-904. Schneider S, Bock C, Wetzel M, Maul H, Loerbroks A. The prevalence of gestational diabetes in advanced economies. J Perinat Med 2012;40:511-20. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991-2002. Gabbe SG, Mestman JG, Freeman RK, Anderson GV, Lowensohn RI. Management and outcome of class A diabetes mellitus. Am J Obstet Gynecol 1977;127:465-9 Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015;350:h102. Catalano PM. Trying to understand gestational diabetes. Diabet Med 2014;31:273-81. 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;343:1134-8. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15. Camelo Castillo W, Boggess K, Sturmer 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;123:1177-84. Rasmussen K, Yaktine AL, eds; Committee to Reexamine IOM Pregnancy Weight Guidelines; Institute of Medicine; National Research Council. Weight gain during pregnancy: reexamining the guidelines . National Academies Press, 2009. Ryu RJ, Hays KE, Hebert MF. Gestational diabetes mellitus management with oral hypoglycemic agents. Semin Perinatol 2014;38:508-15. Caritis SN, Hebert MF. A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol 2013;121:1309-12. Ro TB, Ludvigsen HV, Carlsen SM, Vanky E. Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest 2012;72:570-5.
Cite this as: BMJ 2015;350:h177 © BMJ Publishing Group Ltd 2015
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