The Challenge of Heterogeneity
In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.
Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.
A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.
Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”
Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.
There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)
“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”
Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.
The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity
Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.
She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.
A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”
Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.
“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”
The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.
In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.
Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”