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Published in: Current Diabetes Reports 12/2019

01-12-2019 | Neonatal Hypoglycemia | Therapies and New Technologies in the Treatment of Diabetes (M Pietropaolo, Section Editor)

The Use of Non-insulin Agents in Gestational Diabetes: Clinical Considerations in Tailoring Therapy

Authors: Rachel A. Blair, Emily A. Rosenberg, Nadine E. Palermo

Published in: Current Diabetes Reports | Issue 12/2019

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Abstract

Purpose of Review

To assess evidence to date for use of non-insulin agents in treatment of gestational diabetes mellitus.

Recent Findings

There has been increasing interest in the use of non-insulin agents, primarily metformin and glyburide (which both cross the placenta). Metformin has been associated with less maternal weight gain; however, recent studies have shown a trend toward increased weight in offspring exposed to metformin in utero. Glyburide has been associated with increased neonatal hypoglycemia.

Summary

Glycemic control during pregnancy is essential to optimize both maternal and fetal outcomes. There are a myriad of factors to consider when designing treatment programs including patient preference, phenotype, and glucose patterns. While insulin is typically recommended as first-line, some women refuse or cannot afford insulin and in those cases, non-insulin agents may be used. Further studies are needed to assess treatment in pregnancy, perinatal outcomes, and particularly long-term metabolic profiles in mothers and offspring.
Literature
1.
go back to reference Guariguata L, Linnenkamp U, Beagley J, Whiting DR, Cho NH. Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin Pract. 2014 Feb;103(2):176–85.CrossRef Guariguata L, Linnenkamp U, Beagley J, Whiting DR, Cho NH. Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin Pract. 2014 Feb;103(2):176–85.CrossRef
3.
go back to reference • Committee on Practice Bulletins—Obstetrics: ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol 2018;131(2):e49–e64. Doi: https://doi.org/10.1097/AOG.0000000000002501. A detailed overview of recommendations for diagnosis and management of gestational diabetes in the USA. • Committee on Practice Bulletins—Obstetrics: ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol 2018;131(2):e49–e64. Doi: https://​doi.​org/​10.​1097/​AOG.​0000000000002501​. A detailed overview of recommendations for diagnosis and management of gestational diabetes in the USA.
4.
go back to reference • American Diabetes Association. Management of diabetes in pregnancy: standards of medical care in diabetes—2019. Diabetes care. 2019;42(Supplement 1):S165–72. The most recent guidelines from the American Diabetes Association briefly summarizing diagnosis and treatment of gestational diabetes. • American Diabetes Association. Management of diabetes in pregnancy: standards of medical care in diabetes—2019. Diabetes care. 2019;42(Supplement 1):S165–72. The most recent guidelines from the American Diabetes Association briefly summarizing diagnosis and treatment of gestational diabetes.
6.
go back to reference Landon MB, Carpenter MW, Wapner RJ, Thorp JM, Harper M, Sorokin Y, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;10. Landon MB, Carpenter MW, Wapner RJ, Thorp JM, Harper M, Sorokin Y, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;10.
8.
go back to reference Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin DKJ, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000–2011. Obstet Gynecol. 2014 Jun;123(6):1177–84.CrossRef Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin DKJ, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000–2011. Obstet Gynecol. 2014 Jun;123(6):1177–84.CrossRef
10.
go back to reference Barbour LA, Scifres C, Valent AM, Friedman JE, Buchanan TA, Coustan D, et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;219(4):367.e1–7.CrossRef Barbour LA, Scifres C, Valent AM, Friedman JE, Buchanan TA, Coustan D, et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;219(4):367.e1–7.CrossRef
11.
go back to reference Society for Maternal-Fetal Publications Committee. SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;218(5):B2–4.CrossRef Society for Maternal-Fetal Publications Committee. SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;218(5):B2–4.CrossRef
12.
go back to reference Song C, Li J, Leng J, Ma RC, Yang X. Lifestyle intervention can reduce the risk of gestational diabetes: a meta-analysis of randomized controlled trials: lifestyle intervention and GDM. Obes Rev. 2016;17(10):960–9.CrossRef Song C, Li J, Leng J, Ma RC, Yang X. Lifestyle intervention can reduce the risk of gestational diabetes: a meta-analysis of randomized controlled trials: lifestyle intervention and GDM. Obes Rev. 2016;17(10):960–9.CrossRef
13.
go back to reference Yamamoto JM, Kellett JE, Balsells M, García-Patterson A, Hadar E, Solà I, et al. Gestational diabetes mellitus and diet: a systematic review and meta-analysis of randomized controlled trials examining the impact of modified dietary interventions on maternal glucose control and neonatal birth weight. Diabetes Care. 2018;41(7):1346–61.CrossRef Yamamoto JM, Kellett JE, Balsells M, García-Patterson A, Hadar E, Solà I, et al. Gestational diabetes mellitus and diet: a systematic review and meta-analysis of randomized controlled trials examining the impact of modified dietary interventions on maternal glucose control and neonatal birth weight. Diabetes Care. 2018;41(7):1346–61.CrossRef
14.
15.
go back to reference • Feig DS, Berger H, Donovan L, Godbout A, Kader T, Keely E, et al. Diabetes and pregnancy. Can J Diabetes. 2018;42:S255–S282. A detailed guideline from Canada about treatment of gestational diabetes, with a helpful summary of evidence about dietary approaches. CrossRef • Feig DS, Berger H, Donovan L, Godbout A, Kader T, Keely E, et al. Diabetes and pregnancy. Can J Diabetes. 2018;42:S255–S282. A detailed guideline from Canada about treatment of gestational diabetes, with a helpful summary of evidence about dietary approaches. CrossRef
16.
go back to reference Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981;34:362–6.CrossRef Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981;34:362–6.CrossRef
17.
go back to reference Yamamoto JM, Kellett JE, Balsells M, García-Patterson A, Hadar E, Solà I, et al. Dietary intervention in patients with gestational diabetes mellitus: a systematic review and meta-analysis of randomized clinical trials on maternal and newborn outcomes. Diabetes Care. 2018;41:1346–61. https://doi.org/10.2337/dc18-0102.CrossRefPubMed Yamamoto JM, Kellett JE, Balsells M, García-Patterson A, Hadar E, Solà I, et al. Dietary intervention in patients with gestational diabetes mellitus: a systematic review and meta-analysis of randomized clinical trials on maternal and newborn outcomes. Diabetes Care. 2018;41:1346–61. https://​doi.​org/​10.​2337/​dc18-0102.CrossRefPubMed
18.
go back to reference Wei J, Heng W, Gao J. Effects of low glycemic index diets on gestational diabetes mellitus: a meta-analysis of randomized controlled clinical trials. Medicine (Baltimore). 2016;95(22):e3792.CrossRef Wei J, Heng W, Gao J. Effects of low glycemic index diets on gestational diabetes mellitus: a meta-analysis of randomized controlled clinical trials. Medicine (Baltimore). 2016;95(22):e3792.CrossRef
19.
go back to reference Coe DP, Conger SA, Kendrick JM, Howard BC, Thompson DL, Bassett DR, et al. Postprandial walking reduces glucose levels in women with gestational diabetes mellitus. Appl Physiol Nutr Metab. 2017;43(5):531–4.CrossRef Coe DP, Conger SA, Kendrick JM, Howard BC, Thompson DL, Bassett DR, et al. Postprandial walking reduces glucose levels in women with gestational diabetes mellitus. Appl Physiol Nutr Metab. 2017;43(5):531–4.CrossRef
20.
go back to reference National Institute for Health and Care Excellence. Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period. 2015. www.nice.org.uk/guidance/ng3. Accessed 15 June 2019. National Institute for Health and Care Excellence. Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period. 2015. www.​nice.​org.​uk/​guidance/​ng3. Accessed 15 June 2019.
21.
go back to reference Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017 Sep;60(9):1577–85.CrossRef Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017 Sep;60(9):1577–85.CrossRef
22.
go back to reference Rowan JA, Battin MR. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;13. Rowan JA, Battin MR. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;13.
23.
go back to reference Farrar D, Simmonds M, Bryant M, Sheldon TA, Tuffnell D, Golder S, et al. Treatments for gestational diabetes: a systematic review and meta-analysis. BMJ Open. 2017 Jun 1;7(6):e015557.CrossRef Farrar D, Simmonds M, Bryant M, Sheldon TA, Tuffnell D, Golder S, et al. Treatments for gestational diabetes: a systematic review and meta-analysis. BMJ Open. 2017 Jun 1;7(6):e015557.CrossRef
24.
go back to reference Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet Med J Br Diabet Assoc. 2017;34(1):27–36.CrossRef Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet Med J Br Diabet Assoc. 2017;34(1):27–36.CrossRef
25.
26.
go back to reference 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. 2015;21(350):h102. 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. 2015;21(350):h102.
28.
go back to reference Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RPV. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol. 2013 Jul;209(1):34.e1–7.CrossRef Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RPV. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol. 2013 Jul;209(1):34.e1–7.CrossRef
29.
go back to reference Løvvik TS, Carlsen SM, Salvesen Ø, Steffensen B, Bixo M, Gómez-Real F, et al. Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019 Apr 1;7(4):256–66.CrossRef Løvvik TS, Carlsen SM, Salvesen Ø, Steffensen B, Bixo M, Gómez-Real F, et al. Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019 Apr 1;7(4):256–66.CrossRef
30.
go back to reference •• Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res Care. 2018;6(1):e000456. This study demonstrated that offspring of women with GDM exposed to metformin in utero had several body measurements that were larger than offspring exposed to insulin when assessed at 7 to 9 years of age. CrossRef •• Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res Care. 2018;6(1):e000456. This study demonstrated that offspring of women with GDM exposed to metformin in utero had several body measurements that were larger than offspring exposed to insulin when assessed at 7 to 9 years of age. CrossRef
31.
go back to reference •• Hanem LGE, Stridsklev S, Júlíusson PB, Salvesen Ø, Roelants M, Carlsen SM, et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age: follow-up of two RCTs. J Clin Endocrinol Metab 2018 Apr 1;103(4):1612–21. This study showed that offspring of women with PCOS randomized to metformin (compared to placebo) had a higher BMI at 4 years of age. CrossRef •• Hanem LGE, Stridsklev S, Júlíusson PB, Salvesen Ø, Roelants M, Carlsen SM, et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age: follow-up of two RCTs. J Clin Endocrinol Metab 2018 Apr 1;103(4):1612–21. This study showed that offspring of women with PCOS randomized to metformin (compared to placebo) had a higher BMI at 4 years of age. CrossRef
32.
go back to reference Feig DS, Murphy K, Asztalos E, Tomlinson G, Sanchez J, Zinman B, et al. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial. BMC Pregnancy Childbirth. 2016 Jul 19;16(1):173.CrossRef Feig DS, Murphy K, Asztalos E, Tomlinson G, Sanchez J, Zinman B, et al. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial. BMC Pregnancy Childbirth. 2016 Jul 19;16(1):173.CrossRef
33.
go back to reference Corbould A, Swinton F, Radford A, Campbell J, McBeath S, Dennis A. Fasting blood glucose predicts response to extended-release metformin in gestational diabetes mellitus. Aust N Z J Obstet Gynaecol. 2013;53(2):125–9.CrossRef Corbould A, Swinton F, Radford A, Campbell J, McBeath S, Dennis A. Fasting blood glucose predicts response to extended-release metformin in gestational diabetes mellitus. Aust N Z J Obstet Gynaecol. 2013;53(2):125–9.CrossRef
34.
go back to reference Bressler R, Johnson DG. Pharmacological regulation of blood glucose levels in non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997 Apr 28;157(8):836–48.CrossRef Bressler R, Johnson DG. Pharmacological regulation of blood glucose levels in non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997 Apr 28;157(8):836–48.CrossRef
35.
go back to reference Elliot BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol. 1991;165(4):807–12.CrossRef Elliot BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol. 1991;165(4):807–12.CrossRef
36.
go back to reference 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 Oct 19;343(16):1134–8.CrossRef 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 Oct 19;343(16):1134–8.CrossRef
37.
go back to reference Hebert M, Ma X, Naraharisetti S, Krudys K, Umans J, Hankins G, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009 Jun;85(6):607–14.CrossRef Hebert M, Ma X, Naraharisetti S, Krudys K, Umans J, Hankins G, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009 Jun;85(6):607–14.CrossRef
38.
go back to reference • Sénat M-V, Affres H, Letourneau A, Coustols-Valat M, Cazaubiel M, Legardeur H, et al. Effect of glyburide vs subcutaneous insulin on perinatal complications among women with gestational diabetes: a randomized clinical trial. JAMA. 2018;319(17):1773. This trial showed that glyburide could not be concluded to be non-inferior to insulin on a composite outcome of neonatal hypoglycemia, macrosomia, and hyperbilirubinemia. CrossRef • Sénat M-V, Affres H, Letourneau A, Coustols-Valat M, Cazaubiel M, Legardeur H, et al. Effect of glyburide vs subcutaneous insulin on perinatal complications among women with gestational diabetes: a randomized clinical trial. JAMA. 2018;319(17):1773. This trial showed that glyburide could not be concluded to be non-inferior to insulin on a composite outcome of neonatal hypoglycemia, macrosomia, and hyperbilirubinemia. CrossRef
39.
go back to reference Song R, Chen L, Chen Y, Si X, Liu Y, Liu Y, et al. Comparison of glyburide and insulin in the management of gestational diabetes: a meta-analysis. PLoS One. 2017 Aug 3;12(8):e0182488.CrossRef Song R, Chen L, Chen Y, Si X, Liu Y, Liu Y, et al. Comparison of glyburide and insulin in the management of gestational diabetes: a meta-analysis. PLoS One. 2017 Aug 3;12(8):e0182488.CrossRef
40.
go back to reference Cheng YW, Chung JH, Block-Kurisch I, Inturrisi M, Caughey AB. Treatment of gestational diabetes mellitus: glyburide compared to subcutaneous insulin therapy and associated perinatal outcomes. J Matern Fetal Neonatol. 2012;25:379–84.CrossRef Cheng YW, Chung JH, Block-Kurisch I, Inturrisi M, Caughey AB. Treatment of gestational diabetes mellitus: glyburide compared to subcutaneous insulin therapy and associated perinatal outcomes. J Matern Fetal Neonatol. 2012;25:379–84.CrossRef
42.
go back to reference Bertini AM, Silva JC, Taborda W, Becker F, Lemos Bebber FR, Zucco Viesi JM, et al. Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat Med. 2005;33(6):519–23.CrossRef Bertini AM, Silva JC, Taborda W, Becker F, Lemos Bebber FR, Zucco Viesi JM, et al. Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat Med. 2005;33(6):519–23.CrossRef
43.
go back to reference Zárate A, Ochoa R, Hernández M, Basurto L. Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy. Ginecol Obstet Mex. 2000 Jan;68:42–5.PubMed Zárate A, Ochoa R, Hernández M, Basurto L. Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy. Ginecol Obstet Mex. 2000 Jan;68:42–5.PubMed
46.
go back to reference American Diabetes Association. Classification and diagnosis of diabetes: standards of medical Care in Diabetes—2019. Diabetes Care. 2019 Jan;42(Suppl 1):S165–72.CrossRef American Diabetes Association. Classification and diagnosis of diabetes: standards of medical Care in Diabetes—2019. Diabetes Care. 2019 Jan;42(Suppl 1):S165–72.CrossRef
47.
go back to reference American Diabetes Association. Prevention or delay of type 2 diabetes: standards of medical Care in Diabetes—2019. Diabetes Care. 2019 Jan;42(Suppl 1):S13–28.CrossRef American Diabetes Association. Prevention or delay of type 2 diabetes: standards of medical Care in Diabetes—2019. Diabetes Care. 2019 Jan;42(Suppl 1):S13–28.CrossRef
48.
go back to reference Briggs GG, Ambrose PJ, Nageotte MP, Padilla G, Wan S. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol. 2005;105:1437–41.CrossRef Briggs GG, Ambrose PJ, Nageotte MP, Padilla G, Wan S. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol. 2005;105:1437–41.CrossRef
49.
go back to reference Eyal S, Easterling TR, Carr D, Umans JG, Miodovnik M, Hankins GDV, et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos. 2010;38:833–40.CrossRef Eyal S, Easterling TR, Carr D, Umans JG, Miodovnik M, Hankins GDV, et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos. 2010;38:833–40.CrossRef
Metadata
Title
The Use of Non-insulin Agents in Gestational Diabetes: Clinical Considerations in Tailoring Therapy
Authors
Rachel A. Blair
Emily A. Rosenberg
Nadine E. Palermo
Publication date
01-12-2019
Publisher
Springer US
Published in
Current Diabetes Reports / Issue 12/2019
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-019-1243-1

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