, Volume 77, Issue 16, pp 1723–1732 | Cite as

Pharmacological Management of Gestational Diabetes Mellitus

Therapy in Practice


Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes in the setting of poor glycemic control. The initial management for GDM includes intensive lifestyle modification, which often requires behavioral and nutritional changes to optimize glycemic control. Pharmacotherapy for GDM is initiated when glycemic targets are not met. The rapid-acting bolus analogues aspart and lispro achieve postprandial targets with less hypoglycemia compared to regular insulin, with similar fetal outcomes. The long-acting insulin analogues glargine and detemir appear safe with similar maternal/fetal outcomes compared to NPH. While insulin has been the mainstay therapy for women with GDM to improve glycemic control when lifestyle modifications are insufficient, certain oral antihyperglycemic drugs (OADs) can be considered as alternative treatment options for GDM but continue to be controversial for use as first-line treatment options compared to insulin by many professional bodies. Metformin has good efficacy and short-term safety data but it freely crosses the placenta and long-term safety data are lacking. Glyburide has good efficacy and short-term data but it also crosses the placenta and may be associated with increased rates of large-for-gestational-age (LGA) infants and neonatal hypoglycaemia when compared with insulin. This review aims to give an overview of the pharmacological treatment for women with GDM including some of the known safety profiles of current therapeutic options.


Compliance with Ethical Standards

Conflict of interest

Dr. Mukerji has no conflict of interest. Dr. Feig is the Principal Investigator of the Metformin in Women with Type 2 Diabetes in Pregnancy trial. The trial receives metformin and placebo from Apotex Inc.


No funding has been received for this article.


  1. 1.
    Jovanovic L, Pettitt DJ. Gestational diabetes mellitus. JAMA. 2001;286(20):2516–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Sacks DA, et al. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care. 2012;35(3):526–8.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Feig DS, et al. Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: a large, population-based study in Ontario, Canada, 1996–2010. Diabetes Care. 2014;37(6):1590–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Savitz DA, et al. Ethnicity and gestational diabetes in New York City, 1995–2003. BJOG. 2008;115(8):969–78.PubMedCrossRefGoogle Scholar
  5. 5.
    Getahun D, Fassett MJ, Jacobsen SJ. Gestational diabetes: risk of recurrence in subsequent pregnancies. Am J Obstet Gynecol. 2010;203(5):467 e1–6.CrossRefGoogle Scholar
  6. 6.
    Lin PC, et al. The risk factors for gestational diabetes mellitus: a retrospective study. Midwifery. 2016;42:16–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Mitanchez D. Foetal and neonatal complications in gestational diabetes: perinatal mortality, congenital malformations, macrosomia, shoulder dystocia, birth injuries, neonatal complications. Diabetes Metab. 2010;36(6 Pt 2):617–27.PubMedCrossRefGoogle Scholar
  8. 8.
    Mukerji G, Chiu M, Shah BR. Impact of gestational diabetes on the risk of diabetes following pregnancy among Chinese and South Asian women. Diabetologia. 2012;55(8):2148–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Feig DS, et al. Risk of development of diabetes mellitus after diagnosis of gestational diabetes. CMAJ. 2008;179(3):229–34.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Mukerji G, Chiu M, Shah BR. Gestational diabetes mellitus and pregnancy outcomes among Chinese and South Asian women in Canada. J Matern Fetal Neonatal Med. 2013;26(3):279–84.PubMedCrossRefGoogle Scholar
  11. 11.
    Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care. 2008;31(8):1668–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hapo Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991–2002.CrossRefGoogle Scholar
  13. 13.
    Landon MB, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339–48.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Crowther CA, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477–86.PubMedCrossRefGoogle Scholar
  15. 15.
    International Association of D, et al. The diagnosis of gestational diabetes mellitus: new paradigms or status quo? J Matern Fetal Neonatal Med. 2012;25(12):2564–9.CrossRefGoogle Scholar
  16. 16.
    Lapolla A, et al. New International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: a retrospective study on pregnancy outcome. Diabet Med. 2011;28(9):1074–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Waugh N, Pearson D, Royle P. Screening for hyperglycaemia in pregnancy: consensus and controversy. Best Pract Res Clin Endocrinol Metab. 2010;24(4):553–71.PubMedCrossRefGoogle Scholar
  18. 18.
    International Association of D, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676–82.CrossRefGoogle Scholar
  19. 19.
    Griffin ME, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabet Med. 2000;17(1):26–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Canadian Diabetes Association Clinical Practice Guidelines Expert C, et al. Diabetes and pregnancy. Can J Diabetes. 2013;37(Suppl 1):S168–83.Google Scholar
  21. 21.
    Anjalakshi C, et al. A single test procedure to diagnose gestational diabetes mellitus. Acta Diabetol. 2009;46(1):51–4.PubMedCrossRefGoogle Scholar
  22. 22.
    American Diabetes Association. Management of diabetes in pregnancy. Diabetes Care. 2015;38(Suppl):S77–9.CrossRefGoogle Scholar
  23. 23.
    NICE guideline 3: Diabetes in pregnancy. Management of diabetes and its complications from preconception to the postnatal period. [cited February 25, 2015]. http://www.nice.org.uk/guidance/ng3/evidence/full-guideline-3784285.
  24. 24.
    Nankervis A, McIntyre HD, Moses R, Ross GP, Callaway L, Porter C, Jeffries W, De Vries B, Boorman C, McElduff A. For the Australasian Diabetes in Pregnancy Society. ADIPS Consensus Guidelines for the Testing and Diagnosis of Hyperglycaemia in Pregnancy in Australia and New Zealand. November 2014 [cited 2017 March 20, 2017]. http://adips.org/downloads/2014ADIPSGDMGuidelinesV18.11.2014_000.pdf.
  25. 25.
    Kjos SL, et al. A randomized controlled trial using glycemic plus fetal ultrasound parameters versus glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia. Diabetes Care. 2001;24(11):1904–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Challier JC, Hauguel S, Desmaizieres V. Effects of insulin on glucose uptake and metabolism in the human placenta. J Clin Endocrinol Metab. 1986;62(5):803–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Gg FR, editor. Drugs in pregnancy and lactation. 10th ed. Philadelphia: Wolters Kluwer; 2015. p. 2015.Google Scholar
  28. 28.
    Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174–83.PubMedCrossRefGoogle Scholar
  29. 29.
    Toledano Y, Hadar E, Hod M. Safety of insulin analogues as compared with human insulin in pregnancy. Expert Opin Drug Saf. 2016;15(7):963–73.PubMedCrossRefGoogle Scholar
  30. 30.
    Pettitt DJ, et al. Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mellitus. Diabet Med. 2007;24(10):1129–35.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Pettitt DJ, et al. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care. 2003;26(1):183–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Lv S, Wang J, Xu Y. Safety of insulin analogs during pregnancy: a meta-analysis. Arch Gynecol Obstet. 2015;292(4):749–56.PubMedCrossRefGoogle Scholar
  33. 33.
    Boskovic R, Feig DS, Derewlany L, et al. Transfer of insulin lispro across the human placenta: in vitro perfusion studies. Diabetes Care. 2003;26(5):1390–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Di Cianni G, et al. Maternal metabolic control and perinatal outcome in women with gestational diabetes mellitus treated with lispro or aspart insulin: comparison with regular insulin. Diabetes Care. 2007;30(4):e11.PubMedCrossRefGoogle Scholar
  35. 35.
    Jovanovic L, et al. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care. 1999;22(9):1422–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Doder Z, Vanechanos D, Oster M, Landgraf W, Lin S. Insulin glulisine in pregnancy—experience from clinical trials and post-marketing surveillance. Eur Endocrinol. 2015;11(1):17–20.CrossRefGoogle Scholar
  37. 37.
    Lambert K, Holt RI. The use of insulin analogues in pregnancy. Diabetes Obes Metab. 2013;15(10):888–900.PubMedCrossRefGoogle Scholar
  38. 38.
    Koren R, Toledano Y, Hod M. The use of insulin detemir during pregnancy: a safety evaluation. Expert Opin Drug Saf. 2015;14(4):593–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Suffecool K, et al. Insulin detemir does not cross the human placenta. Diabetes Care. 2015;38(2):e20–1.PubMedCrossRefGoogle Scholar
  40. 40.
    Herrera KM, et al. Randomized controlled trial of insulin detemir versus NPH for the treatment of pregnant women with diabetes. Am J Obstet Gynecol. 2015;213(3):426.e1–7.CrossRefGoogle Scholar
  41. 41.
    Pollex EK, et al. Insulin glargine safety in pregnancy: a transplacental transfer study. Diabetes Care. 2010;33(1):29–33.PubMedCrossRefGoogle Scholar
  42. 42.
    Kurtzhals P, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;49(6):999–1005.PubMedCrossRefGoogle Scholar
  43. 43.
    Pollex E, et al. Safety of insulin glargine use in pregnancy: a systematic review and meta-analysis. Ann Pharmacother. 2011;45(1):9–16.PubMedCrossRefGoogle Scholar
  44. 44.
    Valentine WJ, et al. Cost-effectiveness of basal insulin from a US health system perspective: comparative analyses of detemir, glargine, and NPH. Adv Ther. 2006;23(2):191–207.PubMedCrossRefGoogle Scholar
  45. 45.
    Goetzl L, Wilkins I. Glyburide compared to insulin for the treatment of gestational diabetes mellitus: a cost analysis. J Perinatol. 2002;22(5):403–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Castillo WC, et al. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000–2011. Obstet Gynecol. 2014;123(6):1177–84.PubMedCentralCrossRefGoogle Scholar
  47. 47.
    Markowicz-Piasecka M, et al. Is metformin a perfect drug? Updates in pharmacokinetics and pharmacodynamics. Curr Pharm Des. 2016;23:2532–50.Google Scholar
  48. 48.
    Mulherin AJ, et al. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011;152(12):4610–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Vanky E, et al. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005;83(5):1575–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Charles B, et al. Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit. 2006;28(1):67–72.PubMedCrossRefGoogle Scholar
  51. 51.
    Eyal S, et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos. 2010;38(5):833–40.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    de Oliveira Baraldi C, et al. Metformin pharmacokinetics in nondiabetic pregnant women with polycystic ovary syndrome. Eur J Clin Pharmacol. 2011;67(10):1027–33.PubMedCrossRefGoogle Scholar
  53. 53.
    Rowan JA, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(19):2003–15.PubMedCrossRefGoogle Scholar
  54. 54.
    Balsells M, et al. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. Bmj. 2015;350:h102.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Jiang YF, et al. Comparative efficacy and safety of OADs in management of GDM: network meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2015;100(5):2071–80.PubMedCrossRefGoogle Scholar
  56. 56.
    Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: a meta-analysis. PLoS One. 2013;8(5):e64585.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kitwitee P, et al. Metformin for the treatment of gestational diabetes: an updated meta-analysis. Diabetes Res Clin Pract. 2015;109(3):521–32.PubMedCrossRefGoogle Scholar
  58. 58.
    Li G, et al. Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs. Arch Gynecol Obstet. 2015;292(1):111–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Rowan JA, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care. 2011;34(10):2279–84.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Barrett HL, et al. Maternal and neonatal circulating markers of metabolic and cardiovascular risk in the metformin in gestational diabetes (MiG) trial: responses to maternal metformin versus insulin treatment. Diabetes Care. 2013;36(3):529–36.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wouldes TA, et al. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes. Arch Dis Child Fetal Neonatal Ed. 2016;101:F488–93.CrossRefGoogle Scholar
  62. 62.
    Ijas H, et al. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. BJOG. 2015;122(7):994–1000.PubMedCrossRefGoogle Scholar
  63. 63.
    Podhorecka M, Ibanez B, Dmoszynska A. Metformin—its potential anti-cancer and anti-aging effects. Postepy Hig Med Dosw (Online). 2017;71:170–5.CrossRefGoogle Scholar
  64. 64.
    Griss T, et al. Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS Biol. 2015;13(12):e1002309.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Sacco F, et al. The cell-autonomous mechanisms underlying the activity of metformin as an anticancer drug. Br J Cancer. 2016;115(12):1451–6.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Riedmaier AE, et al. Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol Sci. 2013;34(2):126–35.CrossRefGoogle Scholar
  67. 67.
    Salomaki H, et al. Prenatal metformin exposure in a maternal high fat diet mouse model alters the transcriptome and modifies the metabolic responses of the offspring. PLoS One. 2014;9(12):e115778.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Carlsen SM, Martinussen MP, Vanky E. Metformin’s effect on first-year weight gain: a follow-up study. Pediatrics. 2012;130(5):e1222–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Malek R, Davis SN. Pharmacokinetics, efficacy and safety of glyburide for treatment of gestational diabetes mellitus. Expert Opin Drug Metab Toxicol. 2016;12(6):691–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Rumboldt Z, Bota B. Favorable effects of glibenclamide in a patient exhibiting idiosyncratic hepatotoxic reactions to both chlorpropamide and tolbutamide. Acta Diabetol Lat. 1984;21(4):387–91.PubMedCrossRefGoogle Scholar
  71. 71.
    Caritis SN, Hebert MF. A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol. 2013;121(6):1309–12.PubMedCrossRefGoogle Scholar
  72. 72.
    Jaber LA, et al. Comparison of pharmacokinetics and pharmacodynamics of short- and long-term glyburide therapy in NIDDM. Diabetes Care. 1994;17(11):1300–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Peterson KE, et al. Design of an intervention addressing multiple levels of influence on dietary and activity patterns of low-income, postpartum women. Health Educ Res. 2002;17(5):531–40.PubMedCrossRefGoogle Scholar
  74. 74.
    Guardado-Mendoza R, et al. The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus. Arch Med Sci. 2013;9(5):936–43.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Fuhlendorff J, et al. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes. 1998;47(3):345–51.PubMedCrossRefGoogle Scholar
  76. 76.
    Elliott BD, et al. Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol. 1994;171(3):653–60.PubMedCrossRefGoogle Scholar
  77. 77.
    Hebert MF, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009;85(6):607–14.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Schwartz RA, et al. Glyburide transport across the human placenta. Obstet Gynecol. 2015;125(3):583–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Gedeon C, et al. Breast cancer resistance protein: mediating the trans-placental transfer of glyburide across the human placenta. Placenta. 2008;29(1):39–43.PubMedCrossRefGoogle Scholar
  80. 80.
    Gedeon C, et al. Investigating the potential role of multi-drug resistance protein (MRP) transporters in fetal to maternal glyburide efflux in the human placenta. J Obstet Gynaecol. 2008;28(5):485–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Tertti K, et al. Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs). Eur J Pharm Sci. 2011;44(3):181–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Langer O, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343(16):1134–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Song R, et al. Comparison of glyburide and insulin in the management of gestational diabetes: a meta-analysis. PLoS One. 2017;12(8):e0182488.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Diaz P, Dimasuay K, Koele-Schmidt L, et al. Glyburide treatment in gestational diabetes is associated with increased placental glucose transporter 1 expression and higher birth weight. Placenta. 2017;57:52–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Conway DL, Gonzales O, Skiver D. Use of glyburide for the treatment of gestational diabetes: the San Antonio experience. J Matern Fetal Neonatal Med. 2004;15(1):51–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Chmait R, Dinise T, Moore T. Prospective observational study to establish predictors of glyburide success in women with gestational diabetes mellitus. J Perinatol. 2004;24(10):617–22.PubMedCrossRefGoogle Scholar
  87. 87.
    Nachum Z, et al. Glyburide versus metformin and their combination for the treatment of gestational diabetes mellitus: a randomized controlled study. Diabetes Care. 2017;40(3):332–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Mollar-Puchades MA, et al. Use of repaglinide on a pregnant woman during embryogenesis. Diabetes Obes Metab. 2007;9(1):146–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Zarate A, et al. Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy. Ginecol Obstet Mex. 2000;68:42–5.PubMedGoogle Scholar
  90. 90.
    Bertini AM, et al. Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat Med. 2005;33(6):519–23.PubMedCrossRefGoogle Scholar
  91. 91.
    Chan LY, Yeung JH, Lau TK. Placental transfer of rosiglitazone in the first trimester of human pregnancy. Fertil Steril. 2005;83(4):955–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Holmes HJ, Casey BM, Bawdon RE. Placental transfer of rosiglitazone in the ex vivo human perfusion model. Am J Obstet Gynecol. 2006;195(6):1715–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 180: gestational diabetes mellitus. Obstet Gynecol. 2017;130(1):e17–37.Google Scholar
  94. 94.
    Cheng AY. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Introduction. Can J Diabetes. 2013;37(Suppl 1):S1–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.University of TorontoTorontoCanada
  2. 2.Women’s College HospitalTorontoCanada
  3. 3.Mount Sinai HospitalTorontoCanada

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