Early metformin therapy falls short in curbing gestational diabetes woes

In a recent study published in the journal JAMA Network, researchers conducted a randomized clinical trial to investigate whether early metformin therapy can reduce insulin dependence and improve glycemic control in pregnant women who present symptoms of gestational diabetes. Their findings did not find outcome improvements in diabetes symptoms, contrasting previous scientific and medical beliefs. Secondary outcomes of metformin use, including benefits on maternal weight and infant weight gain, were mixed and form the basis for future studies tailored to investigate these associations.

Study: Early Metformin in Gestational Diabetes. Image Credit: Arturs Budkevics / Shutterstock

Gestational diabetes and the history of metformin therapy

Gestational diabetes mellitus (GDM) is a global health problem characterized by hyperglycemia due to carbohydrate intolerance at pregnancy initiation. It is a common problem, estimated to affect almost 3 million to-be-mothers annually, causing significant health and economic burdens to those affected. These burdens are especially pronounced in low- and middle-income regions, given the high cost of medical intervention in confirmed cases.

Gestational diabetes can been shown to be directly linked to numerous detrimental pregnancy outcomes, including increased risk of type 2 diabetes for both the mother and her child, maternal weight gain, preeclampsia, and the need for cesarean delivery. Fetal risks are also increased, notably birth injuries and infant respiratory distress, both of which require expensive neonatal intensive care unit (ICU) admissions.

Research has found that improved glycemic control can significantly mitigate the risks associated with GDM. However, the optimal management approach to achieve these pregnancy outcomes remains elusive. Currently, management involves medical, nutritional therapy, and physical exercise, failing which pharmacotherapy using insulin supplementation is initiated. Studies have found that insulin helps blunt GDM, thereby improving perinatal outcomes. However, it is independently associated with excess gestational weight gain, increased maternal and infant hypoglycemia risk, and infant treatment in neonatal ICUs.

In recent years, scientists have been exploring metformin, a US Food and Drug Administration (FDA) approved antidiabetic, as an alternative to insulin, especially early in pregnancy. Metformin acts by crossing the placenta and activating the AMP-activated protein kinase (AMPK) pathway, leading to alterations in rapamycin pathways, the latter of which regulates placental amino acid transport. Early initiation of pharmacotherapy involving metformin may alleviate the need for insulin therapy and potentially reduce gestational weight gain, though these assumptions have never been scientifically verified.

About the study

In the present study, researchers conducted a placebo-controlled, double-blind study with the working hypothesis that metformin pharmacotherapy at the time of GDM diagnosis would be statistically associated with improved pregnancy outcomes for both mothers and infants. Outcomes were determined to infant birth and were defined as primary – laboratory-determined fasting blood glucose values of at least 5.1 mmol/L at both weeks 32 and 38 of gestation. Secondary outcomes were divided into maternal and neonatal.

“Secondary maternal outcomes were time to insulin initiation, insulin dose required, development of pregnancy-induced hypertension or preeclampsia, antepartum and postpartum hemorrhage, any bleeding, mode and time of delivery with determination of numbers with preterm birth before 37 weeks of gestation, gestational weight gain from randomization to delivery and from randomization to 12 weeks’ postpartum, self-reported capillary glycemic control, and treatment satisfaction.”

Neonatal secondary outcomes comprised morphometric measurements (birth weight, head length, and circumference), neonatal morbidities (ICU admission, jaundice, and major congenital anomalies), and Apgar scores below 7. Neonatal hypoglycemia was additionally measured.

The study population comprised 510 Irish women aged between 18 and 50 who were confirmed GDM but devoid of diagnosed diabetes (type 1, type 2, monogenic, or secondary) enrolled in the effectiveness of early metformin in addition to usual care in the reduction of gestational diabetes effects (EMERGE) study. EMERGE is a phase 3, randomized, placebo-controlled, double-blind study of metformin intervention in addition to routine exercise and nutrition therapy.

Study procedures involved randomly assigning either a placebo or metformin in addition to normal care.

“Metformin (or matched placebo, identical in taste, smell, appearance, and packing to metformin) was started at 500 mg daily, and titrated upwards every 2 days over 10 days, to a maximum of 2500 mg daily (5 tablets) in 2 doses (1500 mg in the morning and 1000 mg in the evening), taken until delivery.”

If severe hyperglycemia requiring insulin intervention was observed in any participant, supplemental insulin dosage was determined using maternal weight and gestational week of initiation. Outcome evaluation involved laboratory tests (fasting blood glucose and hemoglobin A_1C) conducted at gestational weeks 32 and 38 and completion of the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at week 12. Researchers further visited a newborn infant within 72 of delivery to determine and record maternal and fetal outcomes. A final follow-up phone conversation was recorded for fetal morbidity confirmation 12 weeks following delivery.

Study findings

This study was unable to find statistical differences between fasting glucose levels or insulin requirements of metformin and placebo cohorts (5.1 mmol/L) at either 32 or 38 weeks of gestation. Insulin initiation occurred in 134 (51.1%) placebo participants and 101 (38.4%) metformin cohort individuals. An alternative time-to-event analysis revealed a significantly reduced insulin initiation probability in the metformin group (hazard ratio, 0.66 [95% CI, 0.51-0.85]; P = .001).

Participants in the metformin group showed reduced weight gain between the time of randomization and delivery (0.8 [3.3] kg vs. 2.0 [3.6] kg; difference, −1.2 kg [95% CI, −1.99 to −0.42]; P = .003). Pregnancy-induced hypertension, antepartum, and preeclampsia risks did not differ between study cohorts. Similarly, induction of labor, postpartum hemorrhage, and cesarean birth did not differ between groups.

“During the treatment period, no participant deaths occurred. However, one birthing parent in the metformin group died at 12 weeks postpartum due to a large pulmonary embolus.”

Neonatal secondary outcomes differed slightly between cohorts, with the metformin group infants depicting lower mean weights than the placebo group (3393 [527] g vs. 3506 [510] g). These differences, however, were not statistically different. ICU admissions and the condition breakup for these admissions did not differ between cohorts.

“…intensive care unit admission (15.6% vs. 12.5%), respiratory distress requiring support (9.2% vs. 6.9%), jaundice requiring phototherapy (0.4% vs. 0%), Apgar below 7 at 5 minutes (0.4% vs. 0.4%), hypoglycemia less than 2.6 mmol/L (13.7% vs. 13.0%), and major congenital anomalies (3.8% vs. 2.7%)”

Conclusions

The present study investigated the assumption that metformin intervention early during gestation may alleviate risks associated with gestational diabetes mellitus. A significant (510 individuals) double-blind, randomized clinical trial was unable to reveal the statistical superiority of this assumption, with no differences found between prospective mothers who consumed metformin supplements compared to those on placebo treatments.

“The mixed results of the prespecified secondary outcomes suggest areas of focus for future research, including some of the secondary neonatal outcomes. In addition, the findings of this study support benefits of metformin on maternal weight gain, which has been reported in previous clinical trials.”

“Although metformin is considered a suitable first-line therapy by National Institute for Health and Care Excellence guideline recommendations, the American Diabetes Association does not consider metformin as first-line therapy, particularly in pregnant individuals with hypertension or preeclampsia or those at risk for intrauterine growth restriction.”