A large randomized clinical trial found that treating gestational diabetes with oral glucose-lowering medications may not match insulin's effectiveness in preventing large-for-gestational-age infants. 

In the trial, published in JAMA, researchers enrolled 820 patients with gestational diabetes across 25 Dutch centers between June 2016 and November 2022. They noted that 23.9% of the infants born to those treated with oral medications were large for gestational age compared with 19.9% of those in the insulin group. The absolute risk difference of 4.0% (95% confidence interval [CI] = –1.7% to 9.8%) exceeded the prespecified noninferiority margin of 8%.

The study tested a sequential treatment strategy starting with metformin (500 mg initially, increased to 1,000 mg twice daily), adding glyburide if needed (2.5 mg before meals, maximum 5 mg three times daily), and then substituting insulin for glyburide if glycemic targets weren't met.

Among the participants receiving oral agents, 55% (n = 224) maintained glycemic control with metformin alone, while 23.6% (n = 96) required additional glyburide. Just 7.7% (n = 31) ultimately required insulin, with 3.7% (n = 15) switching to insulin or combined therapy because of side effects.

The study population had a mean age of 33.2 years and included diverse demographics: 58.8% White, 14.9% Middle Eastern/North African, and 9.7% Indian/Pakistani/Bangladeshi/Hindu. Prepregnancy body mass index (BMI) distribution showed 49.8% of the oral medication group and 52.8% of the insulin group had BMI > 30.

Maternal hypoglycemia occurred more frequently in the oral medication group (20.9%) compared with the insulin group (10.9%), with an absolute risk difference of 10.0% (95% CI = 3.7%–21.2%).

Neonatal outcomes showed similar patterns across groups:

• Mean birth weight: 3358.3 g vs 3343.1 g
• Birth weight > 95th percentile: 15.0% vs 13.1%
• Birth weight > 97th percentile: 9.8% vs 9.3%
• Neonatal hypoglycemia (< 47 mg/dL): 54.1% vs 50.4%
• NICU admission: 4.4% vs 4.8%.

Adverse effects were more common with oral medications (78%) vs insulin (56%). Specific side effects included:

• Nausea: 39.4% vs 13.0%
• Diarrhea: 38.6% vs 5.0%
• Fatigue: 28.7% vs 21.3%
• Headache: 20.1% vs 13.0%
• Vomiting: 14.6% vs 1.7%.

Patient satisfaction scores were similar between groups (median = 5, interquartile range [IQR] = 4–6 for both), though participants receiving oral medications reported higher likelihood to recommend their treatment (median = 5, IQR = 5–6 vs median = 4, IQR = 3–6).

The trial had several limitations, including its open-label design and potential limited generalizability outside the Netherlands. The study population included those diagnosed with gestational diabetes as early as 16 weeks gestation, which may not apply to individuals diagnosed after 20 weeks as recommended by the U.S. Preventive Services Task Force.

Conflict of interest disclosures can be found in the study.