Insulin Beats Oral Alternatives for Gestational Diabetes Outcome

Oral glucose-lowering medications weren’t up to snuff with insulin for gestational diabetes, a randomized clinical trial found.

Among 820 individuals, 23.9% of infants born to mothers treated with a sequential regimen of metformin and the sulfonylurea glyburide were large for gestational age (above the 90th percentile) compared with 19.9% treated with insulin (absolute risk difference 4%, 95% CI -1.7% to 9.8%, P=0.09 for noninferiority), found Doortje Rademaker, MD, of Amsterdam University Medical Centers in the Netherlands, and colleagues.

The confidence interval of the risk difference exceeded the absolute noninferiority margin of 8%, Rademaker’s group said in JAMA.

In addition, only 10.9% of pregnant individuals treated with insulin had maternal hypoglycemia compared with 20.9% of those treated with the oral agents (absolute risk difference 10%, 95% CI 3.7%-21.2%).

“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,” noted accompanying editorial author Camille Powe, MD, of Massachusetts General Hospital in Boston.

Insulin has long been the typical pharmacological go-to agent for gestational diabetes, the researchers pointed out, but oral glucose-lowering agents like metformin and glyburide have been given strong consideration as possible alternatives since they’re easier to administer, less costly, and have better acceptance among patients.

Glyburide was the most commonly prescribed therapy for gestational diabetes in 2011, largely due to a trial that found it achieved blood glucose concentrations similar to insulin, Powe pointed out. But this trial was underpowered to “adequately examine several important individual maternal and neonatal outcomes.”

More recently, glyburide began to fall out of favor after the American Diabetes Association cautioned against use of metformin and glyburide as first-line treatment — instead recommending insulin — citing a lack of long-term safety data and concerns that these oral agents cross the placenta.

“Given the cost, complexity, and burden associated with insulin therapy, Rademaker et al. have 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,” said Powe. “For now, insulin reigns supreme.”

For the SUGAR-DIP open-label trial, individuals from 25 centers in the Netherlands who failed to reach glycemic control — defined as a fasting glucose >95 mg/dL, 1-hour postprandial glucose >140 mg/dL, or 2-hour postprandial glucose >120 mg/ measured by capillary glucose self-testing — following 2 weeks of dietary intervention and were between 16 and 34 weeks of gestation were enrolled. They were randomized in a 1:1 ratio to either the oral regimen or insulin.

Average age was 33.2 years, mean prepregnancy BMI was 30.4, 58% were white, and 35% of participants were nulliparous.

Metformin was started at a dose of 500 mg once daily and increased every 3 days to 1,000 mg twice daily or the highest tolerated dose. If glycemic control was still not achieved, 2.5 mg glyburide was added 30 to 60 minutes before each meal. A dose increase up to a maximum of 5 mg three times per day was possible. If maximum tolerated doses of metformin and glyburide still didn’t achieve glycemic control, then glyburide was discontinued, insulin was initiated, and the maximum dose of metformin was continued.

The researchers found 21% of participants treated with metformin and glyburide eventually needed insulin — either as hyperglycemic treatment, due to adverse effects or lack of glyburide availability, or without a known reason. This was substantially lower than the 46% of participants in the 2008 MiG: TOFU trial that compared metformin alone with insulin. Rademaker’s group said this suggests that “adding glyburide to metformin may reduce the number of patients requiring insulin, although this will also depend on population characteristics.”

Besides maternal hypoglycemia, no other secondary outcomes differed between the two treatment groups. This included primary or secondary cesarean delivery, pregnancy-induced hypertension, preeclampsia/hemolysis, elevated liver enzymes, low platelet count syndrome, and gestational weight gain.

As for adverse effects, 77.9% of those on oral medications and 55.9% of those on insulin experienced any. Events including nausea (39.4% vs 13%), diarrhea (38.6% vs 5%), fatigue (28.7% vs 21.3%), headache (20.1% vs 13%), hypoglycemia (20.9% vs 10.9%), and vomiting (14.6% vs 1.7%) were all more commonly reported with oral treatment.

Rademaker’s group pointed out that the study population included those with a gestational diabetes diagnosis as early as 16 weeks of gestation, and their findings may not be applicable to individuals diagnosed after 20 weeks of gestation, as recommended by the U.S. Preventive Services Task Force.

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