The effect of metformin on perinatal outcomes in pregnant women with type 2 diabetes differs by baseline insulin requirements

Background Metformin works by increasing insulin sensitivity, which may aid in the management of insulin-treated type 2 diabetes in pregnancy. However, large trials have found that adjunctive metformin did not reduce composite adverse neonatal outcomes in this population. Objective Our objective was to determine if baseline insulin requirements modified the effect of metformin on adverse neonatal and maternal outcomes. Study Design We performed a secondary analysis of the Medical Optimization and Management of Pregnancies with Overt Type 2 Diabetes trial, a randomized controlled trial of metformin vs placebo in insulin-treated type 2 diabetes or diabetes diagnosed in early pregnancy. We included participants who took ≥1 dose of study drug and had baseline insulin data available. Our primary outcome was a composite of adverse neonatal outcomes, as defined by the parent trial. Secondary outcomes included cesarean delivery, maternal gestational weight gain, and change in insulin requirements during pregnancy, among others. Total daily dose of insulin at randomization was evaluated as an effect modifier of the relationship between metformin and the primary outcome using a likelihood ratio test with P <.10 as significant. To illustrate effect modification, we subsequently evaluated the association between metformin and outcomes among subgroups with total daily dose <30 U, >60 U, and >90 U using multivariable Poisson regression with robust error variance and ordinary least squares regression. Results Of the 794 participants included in the parent trial analysis, 785 (99%) met criteria for our study. The median total daily dose at randomization was 62 U (interquartile range, 35, 88) with 155 (20%) using <30 U, 225 (29%) using 30 to 60 U, 222 (28%) using 60 to 90 U, 100 (13%) using 91 to 120 U, and 83 (10%) using >120 U. There was a significant interaction between metformin and total daily dose of insulin in relation to the primary composite adverse neonatal outcome ( P =.089). For participants with total daily dose of insulin <30 U, adjunctive metformin was associated with a lower risk of the composite adverse neonatal outcome, compared with placebo (44% vs 55%; adjusted relative risk, 0.76; 95% confidence interval, 0.59–0.98). There were no differences in the composite adverse neonatal outcome among participants with total daily dose of insulin >60 U or >90 U. However, for participants with total daily dose of insulin >60 U and >90 U, adjunctive metformin was associated with a smaller increase in insulin requirements during pregnancy, compared with placebo (total daily dose >60 U: mean difference, −13 units; 95% confidence interval, −26 to 1; total daily dose >90 U: mean difference, −27 units; 95% confidence interval, −50 to 5). Conclusion The effect of metformin on maternal and neonatal outcomes in the Medical Optimization and Management of Pregnancies with Overt Type 2 Diabetes trial cohort differed by baseline insulin requirements. In pregnant women with pregestational type 2 diabetes or diabetes diagnosed early in pregnancy, adjunctive metformin was associated with a lower risk of the composite adverse neonatal outcome, preterm birth, large for gestational age, neonatal intensive care unit admission, and less neonatal fat mass among participants with low baseline insulin requirements, when compared with placebo. Conversely, metformin may help mitigate increases in insulin requirements during pregnancy for those with high baseline insulin requirements. Further studies are needed to confirm our findings and investigate the mechanisms underlying the differential effects of metformin based on baseline insulin requirements in pregnancy. © 2026 Elsevier Inc.