By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: The administration of metformin in the early stages of gestational diabetes did not demonstrate superiority over placebo in relation to the need to start insulin therapy prior to delivery, or on fasting blood glucose concentrations ≥ 5.1 mmol/L at either the 32nd or 38th weeks of gestation (composite primary outcome).
SOURCE: Dunne F, Newman C, Alvarez-Iglesias A, et al. Early metformin in gestational diabetes: A randomized clinical trial. JAMA 2023;330:1547-1556.
Gestational diabetes mellitus (GDM) is a prevalent metabolic condition associated with pregnancy and characterized by hyperglycemia first recognized during pregnancy.1 Presently, the prevalence of GDM ranges from 2% to 10% in the United States.2 There is a growing body of evidence indicating that GDM is linked to various adverse maternal, fetal, and neonatal outcomes, including an increased risk of preeclampsia, cesarean delivery, and an elevated future susceptibility to developing type 2 diabetes, and increased rates of miscarriages, neonatal mortality, stillbirths, congenital anomalies, macrosomia, shoulder dystocia, hyperbilirubinemia, respiratory distress syndrome, and neonatal hypoglycemia.1,3 Thus, timely identification and effective control of GDM is of paramount importance in mitigating potential consequences and adverse outcomes.
At present, the management of GDM involves the implementation of lifestyle interventions of nutritional therapy and exercise as the first-line primary approach. Pharmacotherapy is considered only for patients who fail to achieve adequate glycemic control with lifestyle interventions. Metformin, a widely used oral hypoglycemic medication for the treatment of type 2 diabetes, has shown promise as a potential therapeutic approach for the management of GDM diagnosed in early pregnancy. Metformin augments glucose consumption by peripheral tissues within the framework of GDM, hence leading to improved regulation of blood glucose levels. In addition, metformin possesses the distinctive characteristic of not inducing insulin secretion, therefore diminishing its likelihood of inducing hypoglycemia.
Numerous studies have been conducted to examine the effectiveness of metformin in the treatment of GDM, particularly when administered during the early stages of pregnancy. In 2008, the New England Journal of Medicine published a randomized controlled trial (RCT) comparing the efficacy of metformin and insulin for the treatment of GDM, and demonstrated similar glycemic outcomes in both groups, implying that metformin may serve as a viable substitute for insulin in the management of hyperglycemia during pregnancy.4 One drawback of the present therapeutic approach in the management of GDM, which involves administering medications only after lifestyle interventions have proven ineffective, is that it leads to a significant duration of hyperglycemia during pregnancy for a considerable percentage (about 50%) of pregnant women. The implementation of metformin at the time of diagnosis may lead to enhanced glycemic control, decreased reliance on insulin therapy, and potential additional benefits beyond glycemic control, such as mitigating gestational weight gain. Based on this hypothesis, Dunne and colleagues postulated that the administration of metformin on diagnosis would be correlated with enhanced clinical outcomes in pregnant women diagnosed with GDM.5
This was a Phase III, double-blind RCT conducted at two sites in Ireland.5 Pregnant women met inclusion criteria if they had a singleton gestation up to 28w6d gestational age, were between 18-50 years of age; and were diagnosed with GDM based on the World Health Organization (WHO) 2013 plasma glucose levels criteria (fasting, ≥ 5.1 mmol/L; one-hour, ≥ 10 mmol/L; or two-hour, ≥ 8.5 mmol/L). Pregnant women were excluded from the trial if they were diagnosed with established pre-gestational diabetes, had a fasting blood sugar (FBS) of ≥ 7 mmol/L, or a two-hour glucose level of 11.1 mmol/L on oral glucose tolerance testing.
Eligible pregnant women were randomly assigned to the metformin or placebo groups (500 mg daily tablets in each group) in a 1:1 ratio. The dosage was incrementally increased every two days over a span of 10 days, reaching a maximum daily intake of 2,500 mg. To assure random sequence and allocation concealment, a secure and interactive web-based randomization system was implemented in a centralized manner. The participating sites were provided with treatment numbers and participant identification numbers following the verification of eligibility. The allocation of treatment was concealed from the investigators at the site, the personnel at the site, the participants, and the assessors of the outcomes.
The primary outcome of interest, assessed on the birth of the newborn, was a combination of two factors: the commencement of insulin treatment prior to delivery, or an FBS level ≥ 5.1 mmol/L at either the 32nd or 38th week of gestation. The secondary maternal outcomes included the time it took for insulin initiation, the amount of insulin required, the occurrence of pregnancy-induced hypertension or preeclampsia, antepartum and postpartum hemorrhage, any type of bleeding, the mode and timing of delivery (with a specific focus on the number of preterm births < 37 weeks of gestation), gestational weight gain from the time of randomization to delivery and from randomization to 12 weeks postpartum, self-reported capillary glycemic control, and treatment satisfaction.
Secondary neonatal outcomes included infant birth weight, length, and head circumference with derived measures for large for gestational age > 90th percentile, small for gestational age < 10th percentile, macrosomia > 4 kg, low birth weight < 2.5 kg, proportion of infants with neonatal morbidities including the need for neonatal intensive care, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, Apgar score < 7 at five minutes, and neonatal hypoglycemia (< 2.6 mmol/L on one or more occasions within 60 minutes post-delivery). Based on approximately 40% of individuals requiring insulin during the study, the trial’s target sample size was determined. At a two-tailed type-1 error rate of 0.05 and an attrition rate of 5%, a sample size of 550 (275 per group) would have 80% power to detect a 30% difference in the primary outcome between groups.
After investigators screened 2,308 pregnancies, 535 pregnant women were randomized and enrolled between June 2017 and September 2022. Of these, 268 pregnant women (50%) received metformin and 267 participants received placebo. Baseline characteristics were comparable between both groups. For the primary composite endpoint, there was no statistically significant difference in insulin initiation or FBS ≥ 5.1 mmol/L at gestational weeks 32 or 38 (risk ratio [RR] 0.89; 95% confidence interval [CI], 0.78, 1.02; P = 0.13). Of the secondary maternal outcomes, three favored the metformin group: time to insulin initiation (RR, 0.66; 95% CI, 0.51, 0.85; P = 0001), self-reported capillary glycemic control (mean difference [MD], -0.2; 95% CI, -0.47, -0.04; P = 0.02), and gestational weight gain (MD, -1.2 kg; 95% CI, -1.99, -0.42; P = 0.003). Secondary neonatal outcomes differed significantly by group, with smaller neonates (lower mean birth weights [3,393 g vs. 3,506 g; MD, -113 g; 95% CI, -201, -24; P = 0.005], a lower proportion weighing > 4 kg [7.6% vs. 14.8%; MD, -7.2%; 95% CI, -12.6%, -1.8%; P < 0.05], a lower proportion of neonates in the > 90th percentile [6.5% vs. 14.9%; MD, -8.4%; 95% CI, -13.7%, -3.2%; P = 0.003], and smaller crown-heel length [51.0 cm vs. 51.7 cm; MD, -0.7 cm; 95% CI, -1.3, -0.2; P = 0.02]) in the metformin group. There were no statistically significant differences between the two groups with respect to all other secondary outcomes.
COMMENTARY
The results of this trial demonstrate that metformin has potential as a viable approach for the treatment of early GDM, since it effectively regulates blood glucose concentrations while exhibiting a positive safety profile.5 The attractiveness of this alternative to insulin lies in its potential to enhance maternal and fetal outcomes while offering healthcare practitioners increased flexibility in customizing treatment strategies to meet the unique needs of each pregnant patient.
Although several RCTs have provided evidence for the effectiveness of metformin in lowering glucose levels for the management of GDM, including a lower risk of neonatal hypoglycemia and lower maternal weight gain during pregnancy, metformin is not recommended as a first-line treatment option for GDM.4,6-8 This is because of the fact that metformin can pass through the placenta, and there are some concerns over the long-term safety of its use for the health of the offspring. For example, the exposure to metformin in the Metformin in Gestational Diabetes Offspring Follow-Up (MiG TOFU) study was associated with an increased body mass index (BMI) in children 7-9 years of age.9 The use of metformin in pregnant women with chronic hypertension or preeclampsia, or those susceptible to intrauterine growth restriction, should be avoided because of the possibility of acidosis and stunted growth that can arise from placental insufficiency.10,11
When using metformin for blood glucose control in GDM, fasting and postprandial blood glucose monitoring are recommended to achieve optimal glucose levels. Glucose targets are fasting plasma glucose < 95 mg/dL and either one-hour postprandial glucose < 140 mg/dL or two-hour postprandial glucose < 120 mg/dL. Although there are insufficient data to support the use of continuous glucose monitoring in the setting of GDM, findings from the Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy (CONCEPTT) RCT indicate that incorporating real-time continuous glucose monitoring alongside standard care (which includes optimizing pre- and postprandial glucose targets) can be beneficial for pregnant women with diabetes.12 This approach demonstrated a modest reduction in hemoglobin A1c levels without an associated rise in hypoglycemia incidents. Additionally, it resulted in reductions in the occurrence of large-for-gestational-age births, length of hospital stays, and neonatal hypoglycemia.12 The importance of obtaining a referral to a nutritionist lies in the establishment of a comprehensive diet plan, determination of an appropriate insulin-to-carbohydrate ratio, and the identification of weight gain objectives.
In summary, this study demonstrated that metformin was effective in improving maternal and neonatal outcomes in pregnant women with GDM without any significant short-term adverse effects. Therefore, metformin can be an alternative to insulin in select pregnant women who require medication therapy but have challenges in safely and successfully using insulin as the result of factors such as financial constraints, language problems, limited understanding, or cultural pressures. The American College of Obstetricians and Gynecologists continues to recommend insulin as the first-line therapy for the pharmacologic management of GDM in the United States.1
REFERENCES
- [No authors listed]. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet Gynecol 2018;131:e49-e64.
- Akinyemi OA, Weldeslase TA, Odusanya E, et al. Profiles and outcomes of women with gestational diabetes mellitus in the United States. Cureus 2023;15:e41360.
- Holmes VA, Young IS, Patterson CC, et al. Optimal glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes in the diabetes and pre-eclampsia intervention trial. Diabetes Care 2011;34:1683-1688.
- Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-2015.
- Dunne F, Newman C, Alvarez-Iglesias A, et al. Early metformin in gestational diabetes: A randomized clinical trial. JAMA 2023;330:1547-1556.
- Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: A meta-analysis. PloS One 2013;8:e64585.
- Balsells M, García-Patterson A, Solà I, et al. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: A systematic review and meta-analysis. BMJ 2015;350:h102.
- Jiang YF, Chen XY, Ding T, et al. Comparative efficacy and safety of OADs in management of GDM: Network meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2015;100:2071-2080.
- Rowan JA, Rush EC, Plank LD, 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:e000456.
- Barbour LA, Scifres C, Valent AM, et al. A cautionary response to SMFM statement: Pharmacological treatment of gestational diabetes. Am J Obstet Gynecol 2018;219:367.e1-367.e7.
- Barbour LA, Feig DS. Metformin for gestational diabetes mellitus: Progeny, perspective, and a personalized approach. Diabetes Care 2019;42:396-399.
- Feig DS, Donovan LE, Corcoy R, et al. Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): A multicentre international randomised controlled trial. Lancet 2017;390:2347-2359.
