A randomized clinical trial has challenged the use of oral glucose-lowering medications as a replacement for insulin in managing gestational diabetes. The study, conducted across 25 centers in the Netherlands, found that a sequential regimen of metformin and glyburide did not achieve non-inferior outcomes compared to insulin in preventing infants from being born large for gestational age (LGA).
The open-label trial, known as SUGAR-DIP, enrolled 820 pregnant individuals between 16 and 34 weeks of gestation who had not achieved adequate glycemic control through dietary intervention. Participants were randomized to receive either the oral regimen or insulin. The primary outcome was the percentage of infants born LGA, defined as birth weight above the 90th percentile based on gestational age and sex.
The results, published in JAMA, indicated that 23.9% of infants in the oral medication group were LGA, compared to 19.9% in the insulin group. This absolute risk difference of 4% (95% CI -1.7% to 9.8%) did not meet the criteria for non-inferiority, as the confidence interval exceeded the pre-defined non-inferiority margin of 8%.
Increased Hypoglycemia with Oral Agents
One notable finding was the higher incidence of maternal hypoglycemia in the oral medication group. 20.9% of pregnant individuals treated with metformin and glyburide experienced hypoglycemia, compared to only 10.9% in the insulin group (absolute risk difference 10%, 95% CI 3.7%-21.2%).
Insulin Still Reigns Supreme
According to Camille Powe, MD, of Massachusetts General Hospital, "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."
While oral agents like metformin and glyburide have been considered due to their ease of administration and lower cost, concerns about their long-term safety and placental transfer have persisted. The American Diabetes Association has already cautioned against using these oral agents as first-line treatments, recommending insulin instead.
Trial Details and Outcomes
In the SUGAR-DIP trial, metformin was initiated at 500 mg once daily and increased to 1,000 mg twice daily, or the highest tolerated dose. Glyburide was added if glycemic control was not achieved, with a maximum dose of 5 mg three times per day. If glycemic targets were still unmet, insulin was initiated, and glyburide was discontinued.
Interestingly, 21% of participants in the oral medication group eventually required insulin, a figure lower than the 46% reported in a previous trial (MiG: TOFU) that compared metformin alone with insulin. This suggests that adding glyburide to metformin may reduce the number of patients requiring insulin, although this may vary depending on population characteristics.
Adverse Effects
The study also revealed a higher incidence of adverse effects in the oral medication group. 77.9% of those on oral medications experienced adverse events, compared to 55.9% on insulin. Common events included nausea, diarrhea, fatigue, headache, hypoglycemia, and vomiting.
Study Limitations
The researchers noted that the study population included individuals diagnosed with gestational diabetes as early as 16 weeks of gestation, and the findings may not be applicable to those diagnosed after 20 weeks, as recommended by the U.S. Preventive Services Task Force.
