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Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy

Treatment with metformin plus insulin people with preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome in a randomized clinical trial of 794 pregnant adults (18–45 years). One positive result — reduction in odds of a large-for-gestational-age infant — warrants further study of metformin plus insulin in these patients.

Between Apr. 2019 and Nov. 2021 at 17 U.S. centers, pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed before 23 weeks’ gestation were treated with insulin and randomized to metformin 1000 mg twice daily or placebo from the date of enrollment to delivery.

Based on a primary outcome of a composite of neonatal complications (perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy), the investigators found: “Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants’ mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group.”

Editorial: “In the short term, the plurality of data supports a role for metformin in individuals with gestational diabetes and type 2 diabetes during pregnancy,” writes an editorialist. “The results of EMERGE suggest a potential role for the early use of metformin soon after the diagnosis of gestational diabetes. The results of MOMPOD suggest that although still useful in reducing births of large-for-gestational-age infants and improving glycemic control, other benefits of metformin use in those with type 2 diabetes during pregnancy may be diminished in some populations. An individual participant data meta-analysis using MiTy and MOMPOD data is planned, which will hopefully provide a deeper understanding of the effects of metformin in the population of individuals with type 2 diabetes. In addition, there are conflicting data regarding the long-term impact on offspring of individuals with gestational diabetes exposed to metformin in utero, with some studies showing an increase in adiposity in late childhood and others not. Follow-up of offspring of participants with type 2 diabetes in MiTy Kids has shown no difference in BMI z score at 24 months between those exposed to metformin and those not exposed. Further follow-up of these children in MiTy Tykes and the children of participants in both the MOMPOD and EMERGE trials is planned and will be essential to fully understand the long-term risks and benefits of metformin and allow clinicians to more confidently guide the treatment of individuals with gestational diabetes and type 2 diabetes in pregnancy.”

Source: JAMA