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FAIRFAX, VIRGINIA — , but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.
Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.
The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.
The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.
“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.
The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.
The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.
The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.
The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
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.
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].”
FAIRFAX, VIRGINIA — , but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.
Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.
The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.
The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.
“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.
The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.
The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.
The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.
The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
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.
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].”
FAIRFAX, VIRGINIA — , but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.
Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.
The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.
The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.
“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.
The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.
The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.
The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.
The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
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.
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].”
FROM DPSG-NA 2023