Metformin for gestational diabetes study: metformin vs insulin in gestational diabetes: glycemic control and obstetrical and perinatal outcomes: randomized prospective trial

Published:April 19, 2021DOI:


      Gestational diabetes that is not properly controlled with diet has been commonly treated with insulin. In recent years, several studies have published that metformin can lead to, at least, similar obstetrical and perinatal outcomes as insulin. Nevertheless, not all clinical guidelines endorse its use, and clinical practice is heterogeneous.


      This study aimed to test whether metformin could achieve the same glycemic control as insulin and similar obstetrical and perinatal results, with a good safety profile, in women with gestational diabetes that is not properly controlled with lifestyle changes.

      Study Design

      The metformin for gestational diabetes study was a multicenter, open-label, parallel arms, randomized clinical trial performed at 2 hospitals in Málaga (Spain), enrolling women with gestational diabetes who needed pharmacologic treatment. Women at the age of 18 to 45 years, in the second or third trimesters of pregnancy, were randomized to receive metformin or insulin (detemir or aspart). The main outcomes were (1) glycemic control (mean glycemia, preprandial and postprandial) and hypoglycemic episodes and (2) obstetrical and perinatal outcomes and complications (hypertensive disorders, type of labor, prematurity, macrosomia, large for gestational age, neonatal care unit admissions, respiratory distress syndrome, hypoglycemia, jaundice). Outcomes were analyzed on an intention-to-treat basis.


      Between October 2016 and June 2019, 200 women were randomized, 100 to the insulin-treated group and 100 to the metformin-treated group. Mean fasting and postprandial glycemia did not differ between groups, but postprandial glycemia was significantly better after lunch or dinner in the metformin-treated-group. Hypoglycemic episodes were significantly more common in the insulin-treated group (55.9% vs 17.7% on metformin; odds ratio, 6.118; 95% confidence interval, 3.134–11.944; P=.000). Women treated with metformin gained less weight from the enrollment to the prepartum visit (36–37 gestational weeks) (1.35±3.21 vs 3.87±3.50 kg; P=.000). Labor inductions (45.7% [metformin] vs 62.5% [insulin]; odds ratio, 0.506; 95% confidence interval, 0.283–0.903; P=.029) and cesarean deliveries (27.6% [metformin] vs 52.6% [insulin]; odds ratio, 0.345; 95% confidence interval, 0.187–0.625; P=.001) were significantly lower in the metformin-treated group. Mean birthweight, macrosomia, and large for gestational age and babies’ complications were not different between treatment groups. The lower cesarean delivery rate for women treated with metformin was not associated with macrosomia, large or small for gestational age, or other complications of pregnancy.


      Metformin treatment was associated with a better postprandial glycemic control than insulin for some meals, a lower risk of hypoglycemic episodes, less maternal weight gain, and a low rate of failure as an isolated treatment. Most obstetrical and perinatal outcomes were similar between groups.

      Key words

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        • Brown J.
        • Grzeskowiak L.
        • Williamson K.
        • Downie M.R.
        • Crowther C.A.
        Insulin for the treatment of women with gestational diabetes.
        Cochrane Database Syst Rev. 2017; 11: CD012037
        • Løvvik T.S.
        • Carlsen S.M.
        • Salvesen Ø.
        • 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; 7: 256-266
        • Given J.E.
        • Loane M.
        • Garne E.
        • et al.
        Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study.
        BMJ. 2018; 361: k2477
        • Rowan J.A.
        • Hague W.M.
        • Gao W.
        • Battin M.R.
        • Moore M.P.
        • MiG Trial Investigators
        Metformin versus insulin for the treatment of gestational diabetes.
        N Engl J Med. 2008; 358: 2003-2015
        • Rowan J.A.
        • Gao W.
        • Hague W.M.
        • McIntyre H.D.
        Glycemia and its relationship to outcomes in the metformin in Gestational Diabetes Trial.
        Diabetes Care. 2010; 33: 9-16
        • Ijäs H.
        • Vääräsmäki M.
        • Morin-Papunen L.
        • et al.
        Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study.
        BJOG. 2011; 118: 880-885
        • Niromanesh S.
        • Alavi A.
        • Sharbaf F.R.
        • Amjadi N.
        • Moosavi S.
        • Akbari S.
        Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial.
        Diabetes Res Clin Pract. 2012; 98: 422-429
        • Hassan J.A.
        • Karim N.
        • Sheikh Z.
        Metformin prevents macrosomia and neonatal morbidity in gestational diabetes.
        Pak J Med Sci. 2012; 28: 384-389
        • Tertti K.
        • Ekblad U.
        • Koskinen P.
        • Vahlberg T.
        • Rönnemaa T.
        Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin.
        Diabetes Obes Metab. 2013; 15: 246-251
        • Spaulonci C.P.
        • Bernardes L.S.
        • Trindade T.C.
        • Zugaib M.
        • Francisco R.P.V.
        Randomized trial of metformin vs insulin in the management of gestational diabetes.
        Am J Obstet Gynecol. 2013; 209: 34.e1-34.e7
        • Mesdaghinia E.
        • Samimi M.
        • Homaei Z.
        • Saberi F.
        • Moosavi S.G.A.
        • Yaribakht M.
        Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: a randomised blinded trial.
        Int J Prev Med. 2013; 4: 327-333
        • Ruholamin S.
        • Eshaghian S.
        • Allame Z.
        Neonatal outcomes in women with gestational diabetes mellitus treated with metformin in compare with insulin: a randomized clinical trial.
        J Res Med Sci. 2014; 19: 970-975
        • Ainuddin J.
        • Karim N.
        • Hasan A.A.
        • Naqvi S.A.
        Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial.
        Diabetes Res Clin Pract. 2015; 107: 290-299
        • Borg H.
        • Ezat S.
        Metformin opposed to insulin in the management of gestational diabetes.
        Res Obstet Gynecol. 2016; 4: 17-26
        • Ashoush S.
        • El-Said M.
        • Fathi H.
        • Abdelnaby M.
        Identification of metformin poor responders, requiring supplemental insulin, during randomization of metformin versus insulin for the control of gestational diabetes mellitus.
        J Obstet Gynaecol Res. 2016; 42: 640-647
        • 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
        • Jiang Y.F.
        • Chen X.Y.
        • Ding T.
        • Wang X.F.
        • Zhu Z.N.
        • Su S.W.
        Comparative efficacy and safety of OADs in management of GDM: network meta-analysis of randomized controlled trials.
        J Clin Endocrinol Metab. 2015; 100: 2071-2080
        • 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. 2017; 34: 27-36
        • Mousa A.
        • Løvvik T.
        • Hilkka I.
        • et al.
        Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis.
        BMJ Open. 2020; 10e036981
        • Hanem L.G.E.
        • Salvesen Ø.
        • Juliusson P.B.
        • et al.
        Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5-10 year follow-up of the PregMet randomised controlled trial.
        Lancet Child Adolesc Health. 2019; 3: 166-174
        • Rowan J.A.
        • Rush E.C.
        • Plank L.D.
        • 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; 6e000456
        • Tarry-Adkins J.L.
        • Aiken C.E.
        • Ozanne S.E.
        Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: a systematic review and meta-analysis.
        PLoS Med. 2019; 16e1002848
      1. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group.
        Diabetes. 1979; 28: 1039-1057
        • National Institute for Health and Care Excellence
        Diabetes in pregnancy: management from preconception to the postnatal period.
        (Available at:)
        Date: 2015
        Date accessed: December 20, 2020
      2. American Diabetes Association. 6. Glycemic targets: standards of medical care in Diabetes-2021.
        Diabetes Care. 2021; 44: S73-S84
      3. Carrascosa A, Ferrández A, Yeste D, et al. Estudio transversal español de crecimiento 2008: Valores de peso y longitud en 9.362 (4.884 varones, 4.478 niñas) recién nacidos de 26-42 semanas de edad gestacional. tables from. Ann Pediatr (Barc) 2008;68:544–551.

        • Medicina Fetal Barcelona
        (Available at:) (Accessed June 8, 2021)
        • SEGO, Sociedad Española de Ginecología y Obstetricia
        Control de bienestar fetal anteparto.
        (Available at:)
        • Ricart W.
        • López J.
        • Mozas J.
        • et al.
        Potential impact of American Diabetes Association (2000) criteria for diagnosis of gestational diabetes mellitus in Spain.
        Diabetologia. 2005; 48: 1135-1141
      4. American Diabetes Association. 14. Management of diabetes in pregnancy: standards of medical care in diabetes-2021.
        Diabetes Care. 2021; 44: S200-S210
        • Society of Maternal-Fetal Medicine (SMFM) Publications committee. Electronic address: [email protected]
        SMFM statement: pharmacological treatment of gestational diabetes.
        Am J Obstet Gynecol. 2018; 218: B2-B4
        • Kumar R.
        • Lowe J.
        • Thompson-Hutchison F.
        • et al.
        Implementation and evaluation of the “Metformin first” protocol for management of gestational diabetes.
        Can J Diabetes. 2019; 43: 554-559
        • Cesta C.E.
        • Cohen J.M.
        • Pazzagli L.
        • et al.
        Antidiabetic medication use during pregnancy: an international utilization study.
        BMJ Open Diabetes Res Care. 2019; 7: e000759
        • Goh J.E.L.
        • Sadler L.
        • Rowan J.
        Metformin for gestational diabetes in routine clinical practice.
        Diabet Med. 2011; 28: 1082-1087
        • Pazzagli L.
        • Abdi L.
        • Kieler H.
        • Cesta C.E.
        Metformin versus insulin use for treatment of gestational diabetes and delivery by caesarean section: a nationwide Swedish cohort study.
        Eur J Obstet Gynecol Reprod Biol. 2020; 254: 271-276
        • Guo L.
        • Ma J.
        • Tang J.
        • Hu D.
        • Zhang W.
        • Zhao X.
        Comparative Efficacy and Safety of Metformin, Glyburide, and Insulin in Treating Gestational Diabetes Mellitus: A Meta-Analysis.
        J Diabetes Res. 2019; 2019: 9804708
        • Khin M.O.
        • Gates S.
        • Saravanan P.
        Predictors of metformin failure in gestational diabetes mellitus (GDM).
        Diabetes Metab Syndr. 2018; 12: 405-410
      5. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in Diabetes-2021.
        Diabetes Care. 2021; 44: S15-S33

      Supplemental References

        • Aroda V.R.
        • Edelstein S.L.
        • Goldberg R.B.
        • et al.
        Long-term Metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study.
        J Clin Endocrinol Metab. 2016; 101: 1754-1761
        • Ryckman K.K.
        • Spracklen C.N.
        • Smith C.J.
        • Robinson J.G.
        • Saftlas A.F.
        Maternal lipid levels during pregnancy and gestational diabetes: a systematic review and meta-analysis.
        BJOG. 2015; 122: 643-651
        • Barbour A.
        • Hernandez T.L.
        Maternal non-glycemic contributors to Fetal Growth in Obesity and Gestational Diabetes: Spotlight on Lipids.
        Curr Diab Rep. 2018; 18: 37
        • Barbour L.A.
        • Hernandez T.L.
        Maternal lipids and fetal overgrowth: making fat from fat.
        Clin Ther. 2018; 40: 1638-1647
        • Huhtala M.S.
        • Tertti K.
        • Rönnemaa T.
        Serum lipids and their association with birth weight in metformin and insulin treated patients with gestational diabetes.
        Diabetes Res Clin Pract. 2020; 170: 108456

      Linked Article

      • Gestational diabetes, metformin, and the risk of hypoglycemia
        American Journal of Obstetrics & GynecologyVol. 225Issue 3
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          Picón-César et al1 published a study aimed at determining if metformin could reach the same glycemic control and other outcomes as insulin in patients with gestational diabetes not properly controlled with lifestyle changes. The authors concluded that metformin treatment was associated with a better postprandial glycemic control than insulin for some meals, a low risk for hypoglycemic episodes, less maternal weight gain, and a low rate of failure as isolated treatment. Most obstetrical and perinatal results were similar between groups.
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