Mixed Bag for Early Metformin in Gestational Diabetes

HAMBURG, Germany — Giving metformin early on to women with gestational diabetes failed to show a statistically significant benefit for the phase III EMERGE trial’s primary endpoint, but secondary outcomes did appear to favor the intervention.

For the study’s primary composite outcome — insulin initiation or a fasting glucose level of ≥5.1 mmol/L (91.9 mg/dL) at gestation weeks 32 or 38 — no significant difference was seen between women assigned to either metformin or placebo on top of usual care (56.8% vs 63.7%; P=0.13), Fidelma Dunne, PhD, of the University of Galway in Ireland, reported here.

But “metformin did have a positive impact on important prespecified maternal metabolic and neonatal secondary outcomes,” she said in presenting the findings at the European Association for the Study of Diabetes (EASD) annual meeting. The study were simultaneously published in JAMA as well.

As well, Dunne explained that when the primary composite outcome was isolated to week 38, there was a lower risk in the metformin arm (41.8% vs 53.3%; P<0.001). And looking at insulin initiation alone also favored the intervention, with 38.4% of women on metformin starting insulin during the study versus 51.1% of those assigned to placebo (RR 0.75, 95% CI 0.62-0.91, P=0.004).

Though a modest difference, average fasting glucose was lower for the metformin group at both time points:

• Week 32: 4.9 vs 5.0 mmol/L (88.2 vs 90.0 mg/dL, P=0.03)
• Week 38: 4.5 vs 4.7 mmol/L (81.0 vs 84.6 mg/dL, P<0.001)

Around a quarter of metformin-treated women experienced gastrointestinal side effects, while only 4.1% of the placebo group did. Before delivery, the metformin-treated group were on an average of 20.4 IU of insulin versus 24.2 IU for the placebo group.

Secondary maternal outcomes favoring the metformin arm included a shorter time to insulin initiation, lower self-reported capillary glycemic control, and less gestational weight gain, while no differences were seen for maternal morbidity, preterm birth, or mode of delivery.

“[T]he findings of this study support benefits of metformin on maternal weight gain, which has been reported in previous clinical trials,” the researchers wrote. “Lower weight gain in the metformin group is likely to be due to less insulin use and a direct effect of metformin on food intake.”

Secondary neonatal outcomes revealed smaller neonates born to women in the metformin group, with no differences between groups when it came to the need for neonatal intensive care, respiratory support for respiratory distress, phototherapy for jaundice requiring, or outcomes such as major congenital anomalies, neonatal hypoglycemia, or the proportion with 5-minute Apgar scores less than 7.

“Metformin was not associated with any increase in maternal or neonatal morbidities,” Dunne added. “I feel that short-term pregnancy benefits from metformin are consistent and convincing in terms of maternal weight gain, glycemic control, birth weight, neonatal hypoglycemia, and large-for-gestational-age.”

Dunne referenced a 2008 trial published in the New England Journal of Medicine that found metformin yielded similar neonatal and maternal outcomes as insulin when given in gestational diabetes (weeks 20 to 33), plus metformin was associated with less hypoglycemia. She added that a slew of open-label studies looking at metformin’s effect in gestational diabetes followed, but none included a randomized trial against placebo, bringing us to the current trial.

This two-center trial enrolled participants from one tertiary hospital and one smaller regional hospital in Ireland. This included 510 individuals representing 535 pregnancies that were diagnosed with gestational diabetes according to the World Health Organization 2013 criteria. Participants were followed through 12 weeks postpartum.

The average age was 34, around 80% were white, and the median BMI at baseline was 30. The median gestation at randomization was week 27.

“EMERGE confirms that metformin is an alternative and safe treatment option with no increase in preterm birth or adverse perinatal outcomes. Caution, however, should continue with metformin,” Dunne added in regards to small-for-gestational-age babies, especially for women with nephropathy and hypertension.

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