Trial supports insulin as first-line treatment for gestational diabetes

Treating gestational diabetes with metformin, adding glyburide as needed, led to a slightly higher proportion of infants born large for gestational age compared to using insulin, according to results of a randomized clinical trial.

Researchers randomized 820 patients (mean age, 33.2 years) at 25 Dutch medical centers to oral glucose-lowering medications or insulin between June 2016 and November 2022. All participants had gestational diabetes, were singleton pregnancies between 16 and 34 weeks of gestation, and had insufficient glycemic control after two weeks of dietary changes. A total of 409 patients were randomized to receive metformin (initiated at a dose of 500 mg once daily and increased every three days to 1,000 mg twice daily or highest level tolerated) and 411 to insulin. If glucose targets were not achieved, glyburide was added to metformin, and then insulin was substituted for glyburide if needed. The primary outcome was the percentage of infants born large for gestational age; secondary outcomes included hypoglycemia, cesarean delivery, and pregnancy-induced hypertension, among other complications. Findings were published by JAMA on Jan. 6.

Seventy-nine percent (n=320) of patients randomized to oral agents maintained glycemic control without insulin. Insulin was required per protocol in 11% of participants assigned to the oral medication group. Ten percent of those assigned to oral therapy were treated with insulin off protocol due to lack of glyburide availability or without a known reason. Among patients taking oral agents, 23.9% of infants (n=97) were large for gestational age compared with 19.9% (n=79) among those taking insulin (absolute risk difference, 4.0% [95% CI, −1.7% to 9.8%]; P=0.09 for noninferiority). The confidence interval of the risk difference exceeded the absolute noninferiority margin of 8%.

One-fifth of patients (20.9%) taking oral glucose-lowering agents experienced maternal hypoglycemia compared with 10.9% of patients taking insulin (absolute risk difference, 10.0%; 95% CI, 3.7% to 21.2%). There were no differences in other secondary outcomes between groups. More patients taking oral agents reported adverse effects compared with those taking insulin (78% vs. 56%, respectively), with nausea, diarrhea, and headaches reported most frequently.

The trial was conducted in the Netherlands and findings may not be generalizable to other populations, the study authors cautioned. Results may also not be applicable to individuals diagnosed with gestational diabetes after 20 weeks of gestation.

An accompanying editorial reiterated that the findings support insulin as the preferred pharmacotherapy for gestational diabetes compared with a sequential oral medication strategy, calling the study “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.”