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

  • Therapies and New Technologies in the Treatment of Diabetes (M Pietropaolo, Section Editor)
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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.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 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.

    Article  CAS  Google Scholar 

  2. Wexler DJ, Powe CE, Barbour LA, Buchanan T, Coustan DR, Corcoy R, et al. Research gaps in gestational diabetes mellitus: executive summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop. Obstet Gynecol. 2018;132(2):496–505. https://doi.org/10.1097/AOG.0000000000002726.

    Article  PubMed  PubMed Central  Google Scholar 

  3. • 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. • 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.

  5. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991–2002. https://doi.org/10.1056/NEJMoa0707943.

    Article  Google Scholar 

  6. 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.

  7. Brown J, Martis R, Hughes B, Rowan J, Crowther CA. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. Cochrane Database Syst Rev. 2017;1:CD011967. https://doi.org/10.1002/14651858.CD011967.pub2.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. Goh JEL, Sadler L, Rowan J. Metformin for gestational diabetes in routine clinical practice. Diabetic Med. 2011;28:1082–7. https://doi.org/10.1111/j.1464-5491.2011.03361.x.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. Society for Maternal-Fetal Publications Committee. SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;218(5):B2–4.

    Article  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. Institute of Medicine and National Research Council Committee to reexamine IOM pregnancy weight guidelines. Weight gain during pregnancy: reexamining the guidelines. Washington, DC: National Academies Press; 2009. Available from: http://www.ncbi.nlm.nih.gov/books/NBK32813/. Accessed 15 June 2019.

  15. • 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.

    Article  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    Article  Google Scholar 

  20. 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. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017 Sep;60(9):1577–85.

    Article  CAS  Google Scholar 

  22. Rowan JA, Battin MR. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;13.

  23. 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.

    Article  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. • Priya G, Kalra S. Metformin in the management of diabetes during pregnancy and lactation. Drugs Context 2018;7:212523. doi: https://doi.org/10.7573/dic.212523. A comprehensive summary of primary studies and meta-analyses of metformin in gestational diabetes mellitus.

    Article  Google Scholar 

  26. 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.

  27. Committee on Practice Bulletins—Obstetrics: ACOG Practice Bulletin No. 156: Obesity in pregnancy. Obstet Gynecol 2015;126(6): e112–e126. doi: https://doi.org/10.1097/AOG.0000000000001211

  28. 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.

    Article  CAS  Google Scholar 

  29. 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.

    Article  Google Scholar 

  30. •• 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.

    Article  Google Scholar 

  31. •• 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.

    Article  Google Scholar 

  32. 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.

    Article  Google Scholar 

  33. 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.

    Article  Google Scholar 

  34. 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.

    Article  CAS  Google Scholar 

  35. 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.

    Article  Google Scholar 

  36. 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.

    Article  CAS  Google Scholar 

  37. 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.

    Article  CAS  Google Scholar 

  38. • 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.

    Article  Google Scholar 

  39. 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.

    Article  Google Scholar 

  40. 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.

    Article  CAS  Google Scholar 

  41. Caritis SN, Hebert MF. A pharmacologic approach to the use of glyburide in pregnancy [internet]. Obstet Gynecol. 2013;121:1309–12. https://doi.org/10.1097/AOG.0b013e31829007f0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Article  CAS  Google Scholar 

  43. 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  Google Scholar 

  44. Alexopoulos AS, Blair R, Peters AL. Management of preexisting diabetes in pregnancy: a review. JAMA. 2019;321(18):1811–9. https://doi.org/10.1001/jama.2019.4981.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Powe CE, Allard C, Battista M-C, Doyon M, Bouchard L, Ecker JL, et al. Heterogeneous contribution of insulin sensitivity and secretion defects to gestational diabetes mellitus. Diabetes Care. 2016;39(6):1052–5. https://doi.org/10.2337/dc15-2672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical Care in Diabetes—2019. Diabetes Care. 2019 Jan;42(Suppl 1):S165–72.

    Article  Google Scholar 

  47. 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.

    Article  Google Scholar 

  48. 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.

    Article  CAS  Google Scholar 

  49. 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.

    Article  CAS  Google Scholar 

  50. Pregnancy and Lactation Labeling (Drugs) Final Rule. Food and Drug Administration https://www.fda.gov/drugs/labeling/pregnancy-and-lactation-labeling-drugs-final-rule. Accessed 15 June 2019.

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Correspondence to Nadine E. Palermo.

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Blair, R.A., Rosenberg, E.A. & Palermo, N.E. The Use of Non-insulin Agents in Gestational Diabetes: Clinical Considerations in Tailoring Therapy. Curr Diab Rep 19, 158 (2019). https://doi.org/10.1007/s11892-019-1243-1

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