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Pharmacological Management of Gestational Diabetes Mellitus

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Abstract

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.

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References

  1. Jovanovic L, Pettitt DJ. Gestational diabetes mellitus. JAMA. 2001;286(20):2516–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  4. Savitz DA, et al. Ethnicity and gestational diabetes in New York City, 1995–2003. BJOG. 2008;115(8):969–78.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  6. Lin PC, et al. The risk factors for gestational diabetes mellitus: a retrospective study. Midwifery. 2016;42:16–20.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  9. Feig DS, et al. Risk of development of diabetes mellitus after diagnosis of gestational diabetes. CMAJ. 2008;179(3):229–34.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hapo Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991–2002.

    Article  Google Scholar 

  13. Landon MB, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Crowther CA, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477–86.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. Anjalakshi C, et al. A single test procedure to diagnose gestational diabetes mellitus. Acta Diabetol. 2009;46(1):51–4.

    Article  CAS  PubMed  Google Scholar 

  22. American Diabetes Association. Management of diabetes in pregnancy. Diabetes Care. 2015;38(Suppl):S77–9.

    Article  Google Scholar 

  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. 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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  27. Gg FR, editor. Drugs in pregnancy and lactation. 10th ed. Philadelphia: Wolters Kluwer; 2015. p. 2015.

    Google Scholar 

  28. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174–83.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  32. Lv S, Wang J, Xu Y. Safety of insulin analogs during pregnancy: a meta-analysis. Arch Gynecol Obstet. 2015;292(4):749–56.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  35. Jovanovic L, et al. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care. 1999;22(9):1422–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  37. Lambert K, Holt RI. The use of insulin analogues in pregnancy. Diabetes Obes Metab. 2013;15(10):888–900.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  39. Suffecool K, et al. Insulin detemir does not cross the human placenta. Diabetes Care. 2015;38(2):e20–1.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  41. Pollex EK, et al. Insulin glargine safety in pregnancy: a transplacental transfer study. Diabetes Care. 2010;33(1):29–33.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  49. Vanky E, et al. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005;83(5):1575–8.

    Article  PubMed  Google Scholar 

  50. Charles B, et al. Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit. 2006;28(1):67–72.

    Article  CAS  PubMed  Google Scholar 

  51. Eyal S, et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos. 2010;38(5):833–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  53. Rowan JA, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(19):2003–15.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  64. Griss T, et al. Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS Biol. 2015;13(12):e1002309.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  71. Caritis SN, Hebert MF. A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol. 2013;121(6):1309–12.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schwartz RA, et al. Glyburide transport across the human placenta. Obstet Gynecol. 2015;125(3):583–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  88. Mollar-Puchades MA, et al. Use of repaglinide on a pregnant woman during embryogenesis. Diabetes Obes Metab. 2007;9(1):146–7.

    Article  CAS  PubMed  Google Scholar 

  89. Zarate A, et al. Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy. Ginecol Obstet Mex. 2000;68:42–5.

    CAS  PubMed  Google Scholar 

  90. Bertini AM, et al. Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat Med. 2005;33(6):519–23.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  93. Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 180: gestational diabetes mellitus. Obstet Gynecol. 2017;130(1):e17–37.

  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.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Toronto, Toronto, ON, Canada

    Geetha Mukerji & Denice S. Feig

  2. Women’s College Hospital, Toronto, ON, Canada

    Geetha Mukerji

  3. Mount Sinai Hospital, Toronto, ON, Canada

    Denice S. Feig

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  1. Geetha Mukerji
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Correspondence to Denice S. Feig.

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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.

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Mukerji, G., Feig, D.S. Pharmacological Management of Gestational Diabetes Mellitus. Drugs 77, 1723–1732 (2017). https://doi.org/10.1007/s40265-017-0807-0

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