Glyburide Tied to Greater Neonatal Risk Than Insulin in GDM

Marlene Busko

April 01, 2015

In a study of more than 9000 US women with gestational diabetes mellitus (GDM) who were covered by health insurance, infants whose mothers were treated with glyburide were more likely to be admitted to a neonatal intensive care unit (NICU), have hypoglycemia, and have respiratory distress than infants whose mothers received insulin.

The study was published March 30 in JAMA Pediatrics.

The data show that "for every 1000 women treated with glyburide rather than insulin, we would expect 30 additional NICU stays of at least 24 hours, 14 additional newborns large for gestational age, and 11 additional cases of respiratory distress treated in the NICU," first author Wendy Camelo Castillo, PhD, from the University of Maryland, Baltimore, and senior author Michele Jonsson Funk, PhD, from the University of North Carolina at Chapel Hill, North Carolina, explained to Medscape Medical News in an email.

More research is urgently needed, they say.

"Given the widespread use of glyburide, further investigation of these differences in pregnancy outcomes [should be] a public-health priority," they stress.

Writing in an accompanying editorial, Richard IG Holt, PhD, FRCP, from the University of Southampton, United Kingdom, agrees: "This latest study heightens residual concerns about the use of glyburide to treat GDM that need to be resolved [in further studies] before this drug should be recommended for continued use in pregnancy."

In the meantime, however, it is important to remember that "insulin may not be a reasonable treatment approach for all women [with GDM that is not controlled by diet and exercise]... due to the cost and difficulty storing and administering it," Drs Camelo Castillo and Jonsson Funk observe. "In those cases, treatment with oral medication [such as metformin or glyburide] would be preferable to uncontrolled hyperglycemia or elevated blood glucose in pregnancy."

Is Glyburide Safe in Pregnancy?

In 7% to 10% of women with GDM, diet and exercise alone are not sufficient to control glucose levels, and these pregnant women need pharmacotherapy, Dr Camelo Castillo and colleagues write.

Insulin is the only drug approved by the US Food and Drug Administration and endorsed by the American Diabetes Association to treat GDM. In 2000, Langer et al randomized 404 women with GDM to glyburide or insulin and found no overall differences in glycemic control (N Engl J Med. 2000;343: 1134-1138).

Newer guidelines such as those from the American College of Obstetrics and Gynecology and the UK National Institute for Health and Care Excellence endorsed the use of glyburide for GDM and the practice increased in the past decade, but studies to support this were underpowered to detect rare adverse events.

Thus, the researchers conducted a retrospective cohort study using a large insurance-claims database to identify US women who had GDM and received insulin or glyburide in the 150 days prior to delivery, from January 1, 2000 to December 31, 2011. They excluded women with preexisting type 1 or type 2 diabetes and those younger than 15 or older than 45.

Of 110,870 women with GDM, 9173 (8.3%) were treated with glyburide (n = 4982) or insulin (n = 4191). The women had a mean age of 33.5 years, and 7% were taking metformin. The mean duration of glyburide or insulin treatment was about 50 days. Obesity and preeclampsia were more common in women treated with glyburide, and hypothyroidism and infertility treatment were more common in women treated with insulin.

Interestingly, the proportion of the cohort treated with glyburide increased from 8.5% in 2000 to 64.4% in 2011.

Compared with infants whose mothers were treated with insulin, those whose mothers received glyburide were 41% more likely to be admitted to the NICU, 40% more likely to have hypoglycemia, and 63% more likely to have respiratory distress. More mothers taking insulin than taking glyburide had a cesarean delivery (52.5% vs 50.6%).

Adverse Neonatal Outcomes in Infants Whose Mothers Received Glyburide vs Insulin for GDM

Outcome Glyburide (%) Insulin (%) RR (95% CI)*
NICU admission 10.2 7.2 1.41 (1.23–1.62)
Respiratory distress 2.9 1.7 1.63 (1.23–2.15)
Hypoglycemia 1.9 1.3 1.40 (1.00–1.95)
Large for gestational age 4.7 3.2 1.43 (1.16–1.76)
NICU = neonatal intensive care unit
RR = relative risk
*Adjusted for age and relevant covariates

Whether Metformin Is Better Remains to Be Seen

"The major limitation with the current evidence has been the lack of power to demonstrate differences between insulin and glyburide, [so] the article by Camelo Castillo et al…is therefore a welcome addition to the debate," Dr Holt writes.

However, a limitation is that, as it was an observational analysis, there may be confounding by sociodemographic characteristics. Nevertheless, because the findings are consistent with previous smaller studies, "the time has come to reconsider the place of glyburide in pregnancy…[and] to determine which women are most likely to benefit from glyburide or perhaps more importantly not be harmed," he notes.

And whether or not metformin might be a better treatment option in GDM remains to be seen. "A number of observational studies and clinical trials have suggested that metformin hydrochloride may be a better choice," he observes.

But although a recent meta-analysis concluded that metformin is superior to glyburide (BMJ. 2015;350: h102), the data were from less than 350 women, and metformin is known to cross the placenta, so "it is not yet clear that metformin is a better choice," Drs Camelo Castillo and Jonsson Funk conclude.

Dr Jonsson Funk received a grant from the Agency for Healthcare Research and Quality and salary support from the Center for Pharmacoepidemiology, which is funded by unrestricted grants from GlaxoSmithKline, Merck, and UCB Biosciences. Disclosures for the coauthors are listed in the article. Dr Holt was a member of the 2008 National Institute for Health and Care Excellence diabetes and pregnancy guideline development group.

JAMA Pediatrics. Published online March 30, 2015. Abstract, Editorial

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