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15-01-2025 | Gestational Diabetes | Editor's Choice | News

Sequential oral glucose-lowering agents do not equal insulin in gestational diabetes

Author: Laura Cowen

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medwireNews: A trial among women with gestational diabetes has failed to show that treatment with sequential oral metformin and glyburide is noninferior to insulin with respect to the proportion of infants born large for gestational age.

Between 2016 and 2022, Doortje Rademaker (University of Amsterdam, the Netherlands) and colleagues enrolled 820 individuals (mean age 33 years) with singleton pregnancies between 16 and 34 weeks of gestation who had gestational diabetes that was not controlled by dietary changes. The study participants were randomly assigned to receive a sequential oral glucose-lowering medication protocol (n=409) or insulin (n=411).

Participants in the oral treatment group were given metformin at an initial dose of 500 mg once daily, increasing to 1000 mg twice daily or the highest level tolerated. Glycemic control was defined as a capillary glucose self-test fasting glucose of 95 mg/dL (5.3 mmol/L) or less, a 1-hour postprandial glucose level no higher than 140 mg/dL (7.8 mmol/L), or a 2-hour postprandial glucose of 120 mg/dL (6.7 mmol/L) or less.

If glycemic targets were not met with metformin, participants were also given an oral 2.5 mg dose of glyburide before meals with a dose increase up to 5 mg available. Glyburide was subsequently substituted for insulin if targets were still not met with combination therapy. Overall, 23.5% of women in the oral treatment group received glyburide and 11.5% were given insulin.

The researchers report in JAMA that 23.9% of infants born to women using oral treatments were large for gestational age, defined as greater than the 90th percentile.

By comparison, 19.9% of infants born in the insulin group were large for gestational age, giving an absolute risk difference of 4.0%. Importantly, at 9.8%, the upper limit of the 95% confidence interval for the absolute risk difference between the two groups exceeded the prespecified noninferiority margin of 8.0%, meaning that the sequential oral medication strategy was not noninferior to insulin.

Rademaker and team also found that the secondary outcome of maternal hypoglycemia (glucose <70 mg/dL or <3.9 mmol/L) was significantly more common with oral glucose-lowering agents than with insulin, occurring at rates of 20.9% and 10.9%, respectively.

However, there were no differences between the two groups in the rates of all other secondary outcomes, namely cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission.

More women allocated to oral agents reported adverse effects than did those given insulin (78 vs 56%). The most common adverse effects were nausea (39 vs 13%) and diarrhea (39 vs 5%), followed by headaches (20 vs 13%) and vomiting (15 vs 2%). Despite the differences in adverse effects, both groups reported a median patient satisfaction score of 5 points on a 0- to 6-point scale, although oral agent-treated patients were more likely to recommend their protocol and wish to continue their treatment than their insulin-treated counterparts.

In an accompanying editorial, Camille Powe, from Massachusetts General Hospital in Boston, USA, writes: “Given the cost, complexity, and burden associated with insulin therapy, Rademaker et al have contributed a valiant, yet ultimately unsuccessful, attempt to establish an alternative oral pharmacotherapeutic strategy for the thousands of pregnant individuals diagnosed with gestational diabetes each year.”

She therefore concludes that the “findings support the continued primacy of insulin as the preferred pharmacotherapy for gestational diabetes compared with a sequential oral medication strategy that includes glyburide.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA 2025; doi:10.1001/jama.2024.23410
JAMA 2025; doi:10.1001/jama.2024.27148

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