RCT: Sequential Oral Agents Not Noninferior to Insulin for Gestational Diabetes

Background: Gestational diabetes mellitus (GDM) affects a growing number of pregnant individuals worldwide. While insulin has long been the standard pharmacological treatment, oral glucose-lowering agents (metformin and glyburide) have gained traction.

Objective: This trial investigated whether a sequential oral glucose-lowering regimen—beginning with metformin and adding glyburide as needed—was noninferior to an insulin-based strategy in reducing the risk of infants born large for gestational age (LGA).

Methods: This open-label, randomized, noninferiority trial enrolled 820 participants with singleton pregnancies at 16 to 34 weeks of gestation across 25 Dutch centers. Participants were randomized 1:1 to either (1) metformin initiated at 500 mg once daily and increased every three days up to 1000 mg twice daily or the highest tolerated dose with glyburide at 2.5 mg 30-60 minutes before each meal (with a dose increase up to a maximum of 5 mg three times per day) added if needed, and insulin added only if both failed, discontinuing glyburide, or (2) standard insulin therapy. The primary outcome was LGA (>90th percentile for gestational age and sex).

Results: Among those allocated to oral therapy (n=409), 79% achieved glycemic control without insulin. However, 23.9% of infants in the oral-therapy group were LGA vs 19.9% in the insulin group (absolute risk difference 4.0%; 95% CI, −1.7% to 9.8%). This exceeded the predefined 8% absolute risk difference noninferiority margin (P = .09 for noninferiority). Maternal hypoglycemia occurred more often with oral agents (20.9% vs 10.9%; absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%), and neonatal intravenous glucose therapy was administered more frequently to those randomized to oral agents (6.4% vs 3.2%). Exploratory analysis not powered for definitive conclusions of participants requiring only metformin (no glyburide) showed a somewhat lower LGA rate (19.7%).

Conclusions: A sequential oral pharmacotherapy strategy—beginning with metformin and adding glyburide if needed—did not meet noninferiority criteria compared to insulin for preventing LGA births in GDM. While oral agents can reduce the overall need for insulin, the higher rate of maternal hypoglycemia, the higher rate of neonatal hypoglycemia requiring intravenous glucose therapy, and the borderline higher LGA incidence underscore the continued importance of insulin-based strategies, especially considering that the results support a larger body of evidence that glyburide is a suboptimal treatment for gestational diabetes. These results reinforce that insulin remains the preferred first-line pharmacological treatment for GDM, in line with current guidelines. Although patient satisfaction can be higher with oral agents, clinicians should carefully weigh the risks. Further research is needed to clarify the role of metformin-only approaches in GDM management.

Strengths and Limitations: Strengths include a large multicenter design and a clear noninferiority framework. Limitations include the open-label design, which introduces the possibility of bias in treatment allocation and outcome assessment, the reliance on local clinical protocols for insulin adjustments, and variations in diagnostic criteria.

Future Research: Ongoing trials are examining whether metformin alone might match insulin’s efficacy for GDM. Further studies should address long-term offspring outcomes.

Reference:
Rademaker D, de Wit L, Duijnhoven RG, et al. Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial. JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.23410
Powe CE. For Gestational Diabetes Pharmacotherapy, Insulin Reigns Supreme (Editorial). JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.27148