Sequential oral meds fall short, insulin remains best for gestational diabetes

In the management of gestational diabetes, a sequential oral glucose-lowering medication strategy of metformin and additional glyburide, if needed, failed to demonstrate noninferiority to insulin, according to a study.

Specifically, the primary outcome of the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex) was 23.9 percent with oral medications as opposed to 19.9 percent with insulin (absolute risk difference, 4.0 percent, 95 percent confidence interval [CI], −1.7 to 9.8; p=0.09 for noninferiority). [JAMA 2025;doi:10.1001/jama.2024.23410]

No significant between-group differences were seen in secondary outcomes except for maternal hypoglycaemia, which was reported in 20.9 percent of women who received oral medications and in 10.9 percent of those treated with insulin (absolute risk difference, 10.0 percent, 95 percent CI, 3.7–21.2).

In terms of safety, questionnaire data indicated that more women in the oral medications arm than in the insulin arm reported adverse effects (78 percent vs 56 percent, respectively). The most common adverse effects were nausea (39 percent vs 13 percent) and diarrhoea (39 percent vs 5 percent), followed by headaches (20 percent vs 13 percent) and vomiting (15 percent vs 1.7 percent).

Exploratory analysis showed that neonatal intravenous glucose therapy was administered more frequently to women who received oral medications than to those treated with insulin (6.4 percent vs 3.2 percent). The investigators noted that this result may be explained by glyburide’s mechanism of interrupting the negative feedback of decreasing glucose on pancreatic insulin secretion.

Meanwhile, patient satisfaction scores were similar between the two arms (median, 5 vs 5 on a 0–6-point scale). However, those in the oral medications arm would recommend their treatment to others with the same condition more often (median score, 5 vs 4) and would be more satisfied to continue their current treatment (median score, 5 vs 4). 

“These findings support the continued primacy of insulin as the preferred pharmacotherapy for gestational diabetes compared with a sequential oral medication strategy that includes glyburide,” wrote Dr Camille Powe from the Massachusetts General Hospital, Harvard Medical School, in Boston, Massachusetts, US, in an accompanying editorial. [JAMA 2025;doi:10.1001/jama.2024.27148]

“Given the cost, complexity, and burden associated with insulin therapy, [the trial has] 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. For now, insulin reigns supreme,” Powe said.

The trial included 820 women with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation, as well as suboptimal glycaemic control after 2 weeks of dietary changes. These women were randomly assigned to receive metformin (initiated at 500 mg once daily and increased every 3 days to 1,000 mg twice daily or highest level tolerated; n=409) or insulin (prescribed according to local practice; n=411). Glyburide was added to metformin, and then glyburide switched to insulin, if needed, to achieve glucose targets.

Eleven women withdrew their consent and five were lost to follow up, leaving 406 in the oral medications arm and 398 in the insulin arm. The mean age of the entire cohort was 33.2 years, 58 percent were White, mean prepregnancy BMI was 30.4 kg/m², and 35 percent were nulliparous. In the oral medications arm, 320 women (79 percent) maintained glycaemic control without insulin.

The trial was limited by its open-label nature, which introduces the possibility of bias in treatment allocation and outcome assessment. Additionally, the trial was conducted in the Netherlands and included women with a gestational diabetes diagnosis as early as 16 weeks of gestation, limiting the generalizability of the findings to other populations.