Metformin use during pregnancy for T2DM tied to better maternal and neonatal outcomes: Lancet

Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but for women who have insulin resistance, gestational diabetes worsens the pregnancy, by increasing their insulin requirements, leading to weight gain, painful injections, high cost, and noncompliance.

As there is much less information on metformin's benefits and risks in pregnancy, the MiTy trial (Metformin in women with type 2 diabetes in pregnancy) was conducted with an aim to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes.

It was a prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial. Researchers recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks' gestation. Participants were randomly assigned to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks of gestation. The mean A1c level at randomization was 47 mmol/mol (6.5%) in both groups. Participants with type 2 diabetes with single viable pregnancy between 6 and 22 weeks plus 6 days' gestation and who were on insulin were included in the trial. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 hours after each meal. Follow up visits were scheduled monthly and the participants were seen every 1–4 weeks and when ever needed for standard clinical care. Blood pressure was monitored during the study visit and the researchers asked participants about tolerance to pills, hospitalisations, insulin doses, and severe hypoglycaemia events. The glucometer readings were recorded and stored in the central coordinating centre. Researchers determined a composite of fetal and neonatal outcomes as a primary outcome of the trial. Secondary outcomes included several relevant maternal and neonatal outcomes.

KEY FINDINGS OF THE TRIAL WERE:

• Researchers found no significant difference in the primary composite neonatal outcome between the metformin and placebo groups (40% vs 40%)
• However, women in metformin group reached better glycemic control at 34 weeks' gestation (HbA1C: 43·2 mmol/mol ) [6.1%]than that of placebo group (41·0 mol/mol ) [(5.9%)] and gained less weight of about 7·2 kg when compared with placebo of 9·0 kg.
• There was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, cord c-peptide, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours
• Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day.
• The most common adverse events were gastrointestinal complications (38 events in the metformin group and 38 events in the placebo group)
• There were no significant differences between the metformin and placebo groups in rates of pregnancy loss
• Researchers also found the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb)
• Metformin group was also associated with an increased risk of small for gestational age babies, at 12.9% versus 6.6% with placebo

The authors concluded "We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants"

"Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy" the authors further added.For more information:

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30310-7/fulltext