Gestational diabetes is glucose intolerance during pregnancy, leading to elevated blood glucose levels. Gestational diabetes increases the risk of weight gain, cesarean section, preeclampsia, and adverse outcomes for the fetus, requiring admission to the neonatal intensive care unit. Furthermore, after gestational diabetes, mothers and their children have an increased risk of developing type 2 diabetes in the long term. Gestational diabetes is diagnosed in approximately 2.93 million pregnant women worldwide every year.
The first-line treatment for gestational diabetes is dietary therapy and physical exercise. Pharmacotherapy with insulin is initiated if these lifestyle changes do not improve glycemic control. However, insulin is associated with increased hypoglycemia in mothers and infants, excessive gestational weight gain, a higher likelihood of cesarean section, and neonatal intensive care unit admission.
An alternative treatment for gestational diabetes is metformin therapy. Compared to insulin, metformin reduced the frequency of severe hypoglycemia in infants but increased the frequency of spontaneous preterm birth and small-for-gestational-age infants.
Metformin for the Treatment of Gestational Diabetes – Clinical Trial
In 2023, Irish researchers investigated whether early initiation of metformin, starting immediately after the diagnosis of gestational diabetes, could improve glycemic control, reduce the need for insulin therapy, and limit gestational weight gain.
The study involved 535 pregnant women: 268 in the metformin group and 267 in the placebo group. The gestational age was up to 28 weeks. The diagnosis of gestational diabetes corresponded to glucose values: fasting ≥5.1 mmol/L and <7 mmol/L, 1-hour ≥10 mmol/L, or 2-hour ≥8.5 mmol/L in the oral glucose tolerance test. Metformin and placebo were used in addition to dietary therapy and physical exercise recommendations. According to Irish national guidelines, insulin was prescribed if two or more glucose readings between clinic visits exceeded the target values: fasting ≤5.1 mmol/L, 1-hour ≤7 mmol/L. If insulin was initiated, the metformin or placebo treatment continued. At 32 and 38 weeks of pregnancy, study participants underwent blood tests for glycated hemoglobin (A1c) and fasting blood glucose levels. The maximum metformin dose was 2500 mg. 92% of participants adhered to the prescribed treatment: either metformin or placebo. 5% of participants discontinued metformin due to severe gastrointestinal side effects. For the same reason, 24% of participants required a dose reduction in the metformin group. Only 4% of participants in the placebo group experienced gastrointestinal side effects requiring dose reduction.
Study Results
- Early metformin did not outperform placebo in terms of the combination of starting insulin therapy and fasting blood glucose levels ≥5.1 mmol/L at 32 or 38 weeks of pregnancy.
- Metformin reduced the likelihood of insulin initiation. In the metformin group, insulin was prescribed to 38% of pregnant women, compared to 51% in the placebo group.
- The average insulin requirement was 19.8 IU in the metformin group compared to 22.8 IU in the placebo group.
- Participants in the metformin group gained less weight.
- The frequency of preterm births within two weeks differed slightly: 0.7% in the metformin group and 3.33% in the placebo group.
- The frequency of pregnancy-induced hypertension, preeclampsia, antepartum and postpartum hemorrhage, labor induction, and cesarean section did not differ between the groups.
- There were no deaths during the treatment period. However, one woman in the metformin group died 12 weeks after childbirth due to pulmonary artery thromboembolism.
- The average birth weight of infants was 113 g lower in the metformin group. Additionally, in the metformin group, fewer large-for-gestational-age infants weighing over 4000 g and more infants weighing less than 2500 g. In the metformin group, infant height was significantly shorter by 0.7 cm. Head circumference was the same between the groups.
- The need for admission to the neonatal intensive care unit did not differ significantly between the groups. One neonatal death due to genetic pathology was registered in the metformin group, and one intrauterine death due to antepartum hemorrhage was recorded in the placebo group.
Conclusion
Metformin, when initiated immediately after the diagnosis of gestational diabetes, did not affect the combination of starting insulin therapy and fasting blood glucose levels ≥5.1 mmol/L at 32 or 38 weeks of pregnancy.
Metformin reduced the proportion of large infants for gestational age or had a birth weight of over 4 kg. Minimizing excessive intrauterine growth reduces the increased risk of developing diabetes, obesity, and hypertension in adulthood. However, metformin increased the proportion of small-for-gestational-age infants with a birth weight of less than 2.5 kg, which is essential because metformin inhibits the mechanistic target of the rapamycin complex. This protein complex regulates amino acid transport across the placenta and may contribute to reduced muscle mass. In the long term, reduced muscle mass can contribute to obesity. Therefore, the impact of metformin on infant growth and weight requires further, more extended study.
Inadequate glycemic control and excessive weight gain during pregnancy increase the risk of developing diabetes and cardiovascular diseases. Metformin reduced weight gain in pregnant women, which could be associated with reduced insulin use and the direct influence of metformin on food consumption.
Despite metformin being considered first-line therapy, the American Diabetes Association does not consider metformin as first-line therapy, especially in pregnant women with hypertension or preeclampsia or those at risk of intrauterine growth restriction.
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Reference
Early Metformin in Gestational Diabetes
