The State Of Knowledge About Oral Hypoglycemics
The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.
Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.
In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.
In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”
A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.
“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”
Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.
Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.
Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.