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DOI: 10.1055/a-2407-0905
From Standard of Care to Emerging Innovations: Navigating the Evolution of Pharmacological Treatment of Gestational Diabetes
Funding A.P. is supported in part by R01HD108194. U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Child Health and Human Development.
- Glycemic Thresholds in the Treatment of Gestational Diabetes Mellitus
- Glycemic Targets in the Treatment of Gestational Diabetes Mellitus
- Updates in Established Treatments for Gestational Diabetes Mellitus
- Emerging and Novel Therapies for Gestational Diabetes Mellitus
- Conclusion
- References
Abstract
The incidence of gestational diabetes mellitus (GDM) continues to increase in the United States and globally. While the first-line treatment of GDM remains diet and exercise, 30% of patients with GDM will require pharmacotherapy. However, many controversies remain over the specific glycemic threshold values at which pharmacotherapy should be started, how intensified the therapy should be, and whether oral agents are effective in GDM and remain safe for long-term offspring health. This review will summarize recently completed and ongoing trials focused on GDM pharmacotherapy, including those examining different glycemic thresholds to initiate therapy and treatment intensity.
Key Points
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The incidence of GDM continues to increase in the United States and globally.
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While the first-line treatment of GDM remains diet, 30% of patients require pharmacotherapy.
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Controversies remain over the specific glycemic threshold values at which pharmacotherapy is needed.
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Another controversy is how tightly to control GDM.
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Additional controversies are the safety of metformin and incretins in terms of offspring's long-term health.
The incidence of gestational diabetes mellitus (GDM) continues to increase in the United States and globally, reaching up to 10% in pregnant individuals in North America.[1] [2] [3] [4] [5] This increase reflects higher rates of overweight and obesity in pregnant individuals. Gestational diabetes is associated with significant maternal and neonatal adverse outcomes including preeclampsia, birth injury as well as remote cardiometabolic disease.[6] [7] [8] [9] Treatment of GDM is focused on reducing maternal hyperglycemia to prevent adverse pregnancy outcomes.[10] [11] While the first-line treatment of GDM remains diet and exercise,[12] about 30% of patients with GDM will require pharmacological treatment.[13] However, many controversies remain over the specific threshold values at which pharmacological therapy should be started,[12] [14] [15] how intensified the therapy should be to prevent each of the adverse outcomes of GDM,[16] [17] [18] and what is the most efficacious and safe pharmacologic treatment for GDM.[19] [20] [21] [22] Furthermore, recent studies caution for the need for more data on the safety of oral agents and various novel therapies have emerged as effective treatment agents in type 2 diabetes and obesity, with potential application for GDM.
In this review, we will describe completed and ongoing studies focused on GDM management including those examining different glycemic thresholds to initiate therapy, and studies comparing tight and standard glycemic targets. We will also review data on established pharmacologic treatments and introduce data on emerging and novel therapies. Please see [Table 1] as a summary of the most frequently cited studies in this review.
Glycemic thresholds for intensive treatment |
Glycemic targets for treatment initiation |
Pharmacologic agents for GDM treatment |
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ACOG[12] thresholds for adding pharmacotherapy: FPG is “consistently” at ≥95 mg/dL, or 1- or 2-hour PPGs are “consistently” at ≥140 or ≥120 mg/dL, respectively |
ACOG and ADA recommend a target of <95 mg/dL for FPG, <140 mg/dL for 1-hour PPG, and <120 mg/dL for 2-hour PPG[12] [22] |
In 2018, ACOG and the ADA recommended insulin as a first-line pharmacotherapy, and to consider metformin instead of glyburide as an oral agent for second-line treatment. SMFM continues to support metformin as a first-line pharmacologic alternative to insulin[12] [13] |
• ADA, Royal College of Obstetricians and Gynaecologists, and the Canadian Diabetes Association do not provide criteria for pharmacotherapy initiation[22] [23] [24] |
• Parretti et al,[31] Yogev et al,[30] and Siegmund et al[32] demonstrated in nondiabetic, nonobese pregnant individuals that FPG is approximately 57 to 81 mg/dL, 1-hour PPG is approximately 101 to 103 mg/dL, and 2-hour PPG is approximately 97 to 110 mg/dL |
• Boggess et al[50] showed that adding metformin to insulin in GDM diagnosed prior to 23 weeks did not reduce adverse neonatal outcomes but the group with metformin had less LGA, and lower birth weight but no change in neonatal fat mass |
• Survey of 452 MFM clinicians in the United States: begin pharmacotherapy at ≥50% elevated BGs above targets, with 28 to 75% adding pharmacotherapy between 20 and 50% elevated BGs above target[25] |
• Crowther et al[15] showed that treatment to lower targets of FPG ≤90 mg/dL, 1-hour PPG ≤133 mg/dL, and 2-hour PPG ≤121 mg/dL did not reduce LGA but reduced composite serious health outcomes for the infant |
• Landi et al[51] did find differences in birth weight after in utero metformin exposure versus insulin for GDM |
• Langer et al[26] and Harrison et al[17] demonstrated higher rates of SGA with more intensive treatment |
• Scifres et al[40] demonstrated in obese individuals with GDM lower targets of FPG <90 mg/dL and 2-hour PPG <120 mg/dL no difference in GDM-related outcomes |
• Next generation of incretin-focused therapy is being studied given their glucagon inhibition, slowing gastric emptying, limited risk of hypoglycemia, and minimal transplacental transfer[66] [67] [68] |
Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ADA, American Diabetes Association; MFM, Maternal–Fetal Medicine; SMFM, Society for Maternal–Fetal Medicine; GDM, gestational diabetes mellitus; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; SGA, small for gestational age.
Glycemic Thresholds in the Treatment of Gestational Diabetes Mellitus
While at least 30% of individuals with GDM will require pharmacotherapy, the definition of what constitutes an unsuccessful attempt at medical nutrition therapy (MNT) has not been established. The American College of Obstetricians and Gynecologists (ACOG) recommends adding pharmacotherapy if fasting blood glucose values are “consistently” at ≥95 mg/dL, or if 1- or 2-hour postprandial glucose values are “consistently” at ≥140 or ≥120 mg/dL, respectively.[12] The term “consistently” is not defined. Other professional societies, including the American Diabetes Association (ADA),[22] the Royal College of Obstetricians and Gynaecologists,[23] and the Canadian Diabetes Association,[24] also do not provide details for pharmacotherapy initiation criteria. As a result, initiation of pharmacological therapy is at a provider's discretion with a wide variation in practice. This variation was demonstrated in a 2021 national survey of 452 Maternal–Fetal Medicine (MFM) clinicians from academic and private practices.[25] The survey asked several questions related to GDM diagnosis, surveillance, and management, including at what point MFM clinicians add pharmacological therapy. There was a consensus not to add pharmacological therapy to MNT when <20% of glucose values were above target, with only 4.2% of the respondents indicating that they would add pharmacological therapy. Similarly, when ≥50% of glucose values were above target, 98.0% indicated that they would add pharmacological therapy to MNT. However, in the range between 20 and 50% of elevated glucose values, the practice varied from 28.1 to 75.0% of the clinicians adding pharmacotherapy.[25]
The questions regarding the degree of treatment intensity should be asked in the setting of what adverse pregnancy outcomes could be prevented with strict glycemic control. When looking at abnormal fetal growth, the most common complication of GDM, Langer et al demonstrated that two margins exist for abnormal fetal growth, where at intensive treatment to target blood glucose of ≤86 mg/dL, the incidence of small for gestational age (SGA) increased significantly while the incidence of large for gestational age (LGA) was low and the opposite was seen with the target blood glucose of ≥105 mg/dL.[26] Regarding intensive treatment effect on other GDM-related adverse outcomes, including metabolic complications of macrosomia, hypoglycemia, and respiratory complications, Langer et al reported that with a threshold of mean blood glucose of <100 mg/dL the metabolic complication rate is similar to nondiabetic population, and the rate of respiratory complications is reduced with a mean blood glucose of ≤105 mg/dL.[27]
In terms of using current ACOG- and ADA-recommended glycemic targets, studies are limited in answering the question of how many values above the standard fasting and postprandial thresholds merit initiation of pharmacologic treatment. Harrison et al conducted a retrospective study of 417 patients with GDM and found that patients who received pharmacotherapy at 20 to 39% of elevated glucose values (using ACOG and ADA definition for glycemic targets), compared to those who received pharmacotherapy at ≥40%, had lower odds of composite neonatal outcome that included LGA, preterm birth, and neonatal intensive care unit admission (47.9 vs. 31.4%, adjusted OR 0.48, 95% CI 0.30–0.77).[17] This was primarily driven by a significant reduction in LGA from 21.1 to 9.1% (p = 0.001).[17] In contrast, the incidence of SGA was significantly higher in the intensive treatment group (8.0 vs. 2.9%, adjusted OR 2.91, 95% CI 1.31–11.22).[17] Caissutti et al conducted a systematic review of 17 randomized controlled trials (RCTs) on therapies for GDM that reported criteria for pharmacologic therapy dose adjustment.[28] The authors found that the percentage of elevated blood glucose values necessitating the addition of pharmacologic therapy to MNT was widely ranging from 1 abnormal value over the course of 1 to 2 weeks to more than 50% of abnormal values per week. None of the RCTs reviewed compared maternal or neonatal outcomes based on when the pharmacotherapy was started.[28] Palatnik et al are currently conducting a single-site RCT investigating intensive glycemic control by comparing two thresholds (20 vs. 40%) of percent elevated glucose values prior to insulin initiation and titration.[29]
Glycemic Targets in the Treatment of Gestational Diabetes Mellitus
In addition to the limited number of high-quality trials investigating glycemic thresholds to initiate pharmacologic therapy, few studies have investigated glycemic targets in GDM and most of them were limited by small sample sizes with less than 20 participants or included hospitalized patients with different eating habits given the constraints of inpatient setting.[30] [31] [32] [33] [34] [35] [36] [37] Here we describe the results of a few larger studies done in outpatient settings. A study by Parretti et al included 51 nonobese individuals with normal glucose challenge test (GCT) and term delivery.[31] Using intermittent capillary testing, the study demonstrated mean fasting blood glucose of 57.2 ± 3.9 mg/dL, mean 1-hour postprandial values: 101.2 ± 4.9 mg/dL after breakfast, 101.9 ± 3.4 mg/dL after lunch, and 102.2 ± 3.2 mg/dL after dinner.[31] A study by Yogev et al with 42 nondiabetic individuals with 1-hour GCT value of <130 mg/dL and a body mass index (BMI) of <27.3 kg/m2 using continuous glucose monitoring (CGM) demonstrated the following mean fasting and postprandial glucose values: fasting glucose value of 72.1 ± 13 mg/dL, 1-hour postprandial glucose value of 103.2 ± 13 mg/dL, and 2-hour postprandial glucose value of 96.8 ± 12 mg/dL.[30] Among 15 participants with a BMI of ≥27.3 kg/m2, the fasting glucose value differed significantly from the nonobese group (73.2 ± 9), however, both 1- and 2-hour postprandial values were significantly higher compared with the nonobese group, 112.1 ± 13 mg/dL and 107.4 ± 14 mg/dL, respectively.[30] Another study by Siegmund et al with 32 nonobese individuals using CGM demonstrated mean fasting glucose of 81.1 ± 10.8 mg/dL with a mean 2-hour postprandial value of 110.6 ± 12.6 mg/dL.[32] These studies demonstrate lower glucose values than the currently recommended glycemic targets for GDM management. One systematic review of 34 studies of individuals with GDM and pregestational diabetes found that fasting (<90 mg/dL) among patients with GDM in the third trimester was associated with reduced macrosomia (OR = 0.53, 95% CI: 0.31–0.90), however, this was based on observational studies.[38] An RCT by de Veciana et al compared preprandial and postprandial glucose testing in 66 patients with GDM requiring insulin and found that treating to the postprandial goal of 1 hour <140 mg/dL, compared with a preprandial goal of 60 to 105 mg/dL reduced the outcomes of neonatal hypoglycemia, macrosomia, and cesarean delivery.[39]
Data were lacking on comparing fasting and postprandial targets in a randomized controlled fashion and their effect on GDM-related pregnancy outcomes until a recently published RCT by Crowther et al.[15] This stepped-wedge, cluster-randomized trial included 1,100 individuals diagnosed with GDM between 22 and 34 weeks gestation. All individuals initially were treated to targets of fasting plasma glucose (FPG) <99 mg/dL, 1-hour postprandial glucose <144 mg/dL, and 2-hour postprandial glucose <126 mg/dL. Every 4 months, two hospitals implemented tighter targets of FPG and randomized to tighter glycemic targets, defined as FPG ≤90 mg/dL, 1-hour ≤133 mg/dL, and 2-hour ≤121 mg/dL. The primary outcome of LGA was similar between the two groups, 14.6 vs. 15.1%, p = 0.839.[15] Secondary outcome of composite serious health outcome for the infant of perinatal death, birth trauma, or shoulder dystocia was reduced in the tighter group (1.3 vs. 2.6%, adjusted relative risk [aRR] = 0.23, 95% CI: 0.06–0.88, p = 0.032); however, rates of maternal major hemorrhage, coagulopathy, embolism, and obstetric complications were higher in the tighter group (5.9 vs. 3.0%, adjusted RR = 2.29, 95% CI: 1.14–4.59).[15]
When looking at overweight or obese individuals with GDM, one small RCT of 60 participants by Scifres et al evaluated the feasibility of insensitive glycemic control, defined as fasting <90 mg/dL and 1-hour postprandial <120 mg/dL compared with standard ACOG and ADA thresholds (<95 mg/dL and 1-hour <140 mg/dL).[40] The study found no difference in GDM-related outcomes between the tighter versus standard glycemic target groups; there was a higher utilization of pharmacotherapy in the tighter group, with lower glucose values but no difference in the rates of hypoglycemia between the groups.[40] No additional RCTs were published to date comparing pregnancy outcomes based on glycemic targets in GDM. Scifres et al are currently conducting a multicenter randomized trial to test the impact of lower glycemic target on perinatal outcomes in patients with GDM and BMI ≥25 kg/m2.[41]
Updates in Established Treatments for Gestational Diabetes Mellitus
Results from trials by Langer et al[42] and Rowan et al[43] supported the use of oral agents in individuals with GDM. Both studies noted overall similar maternal and neonatal outcomes in individuals randomized to an oral agent compared to insulin. One significant difference was the higher rate of preterm birth in individuals exposed to metformin, although that was not seen in follow-up studies.[43] Among those treated with metformin, 77% said they would choose metformin in a subsequent pregnancy compared to only 27% in the insulin group (p < 0.001).[43] Following the publication of these findings, the use of oral agents for the treatment of GDM increased significantly and glyburide, followed by metformin became the most prevalent drug used for GDM management.[44] [45]
Subsequently, data from meta-analyses highlighted a significantly higher risk of adverse outcomes including macrosomia and neonatal hypoglycemia with glyburide compared to insulin use.[46] [47] The findings were completed by evidence of transplacental passage of glyburide and higher than previously expected fetal exposure.[48] In 2018, the ACOG and the ADA updated their guidance to prioritize the use of insulin and to consider metformin instead of glyburide as an oral agent for second-line treatment, with the Society for Maternal–Fetal Medicine (SMFM) supporting metformin as a first-line pharmacologic alternative to insulin.[12] [13]
Two recent systematic reviews compared the safety and efficacy of insulin with oral antidiabetic medications[21] [49] with one of the studies examining specifically their effect on neonatal anthropometry.[49] The Cochrane review included 53 RCTs with moderate to very low quality of evidence and concluded that insulin and oral antidiabetic medications had similar effects on preeclampsia, cesarean delivery, risk of developing type 2 diabetes, LGA, neonatal hypoglycemia, perinatal death, neonatal adiposity at birth or childhood adiposity.[21] While long-term maternal and neonatal outcomes were poorly reported, the review suggested that there are minimal harms associated with the effects of treatment with either insulin, glyburide, acarbose, or metformin. The second systematic review and meta-analysis examined the impact of insulin and oral antidiabetic medications on neonatal anthropometry independent of maternal glycemic control.[49] It included 33 studies that used either insulin, glyburide, or metformin. The review found that neonates exposed to glyburide were heavier at birth and had a higher risk of macrosomia and total fat mass compared to neonates exposed to insulin. In contrast, neonates exposed to metformin were born lighter compared to neonates exposed to insulin or glyburide. Furthermore, neonates exposed to metformin had decreased ponderal index, and reduced head and chest circumference, compared with insulin exposure.[49]
The finding of metformin potentially lowering neonatal lean mass was also demonstrated in a recent multisite U.S. RCT by Boggess et al, the Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy (MOMPOD) trial, examining the impact of metformin added to insulin treatment in patients with type 2 diabetes (preexisting diabetes or GDM diagnosed prior to 23 weeks gestation).[50] The primary outcome of the MOMPOD was a composite of adverse neonatal outcomes including perinatal death, neonatal hypoglycemia, umbilical artery pH <7.05, shoulder dystocia, LGA, SGA, and/or low birth weight <2,500 g. Secondary outcomes included maternal hypoglycemia and neonatal fat mass. The study was stopped for futility in achieving the primary outcome. However, the investigators found that the metformin group had lower rates of LGA (adjusted odds ratio 0.63; 95% CI 0.46–0.86), reduced birth weight (mean difference −155 g; 95% CI: −265 to −45), and reduced birth weight z-score (mean difference −0.32; 95% CI: −0.48 to −0.15), while there was no difference in neonatal fat mass (mean difference −0.04; 95% CI: −0.09 to 0.01).[50] Thus, the reduction in birth weight was likely driven by lower neonatal lean mass.
In contrast, a population-based cohort study of patients with GDM in New Zealand examined a child's growth and development at age 4 years exposed in utero to either insulin or metformin.[51] The investigators found no difference in weight for height z-scores between children exposed to metformin compared with insulin (mean difference, −0.10; 95% CI: −0.20 to 0.01). They also did not find a difference in the rates of weight for height z-scores ≥85th percentile between treatment groups (adjusted risk ratio = 0.92; 95% CI: 0.83–1.02).[51]
Another multisite RCT by Dunne et al from Ireland, the EMERGE (Effectiveness of Metformin in Addition to Usual Care in the Reduction of Gestational Diabetes Mellitus Effects) trial, examined whether starting metformin at the time of GDM diagnosis and prior to lifestyle modifications would result in better outcomes, defined as a composite of insulin initiation or a fasting glucose level above 5.1 mmol/L (∼92 mg/dL) at 32 or 38 weeks gestation compared with insulin once lifestyle modifications fail.[52] In both groups, if glucose values were above the target, insulin was added to the treatment. The investigators did not find a difference in the composite outcome; however, insulin initiation rates in the metformin group were lower (38 vs. 51%) with a longer time to insulin initiation compared to the control group. The group that received metformin had less fasting glucose level above 5.1 mmol/L, had lower mean fasting glucose at 32 weeks (mean difference, −3.6 mg/dL; 95% CI: −3.4 to −0.2 mg/dL) and 38 weeks (mean difference, 3.6 mg/dL; 95% CI: −5.1 to −1.6 mg/dL), lower maternal weight gain (mean difference, −1.2 kg; 95% CI: −1.99 to −0.42), and lower rates of LGA (6.5 vs. 14.9%).[52] Both the MOMPOD and the EMERGE trials plan long-term offspring follow-up to further elucidate the risks and benefits of prenatal metformin exposure.
While these RCTs did not show strong evidence for metformin initiation at the time of GDM diagnosis, metformin is still being used frequently as the first-line pharmacologic agent for routine GDM treatment. A national survey of U.S. MFM clinicians from 2019 to 2020 demonstrated that while 66.2% initiate insulin as first-line pharmacotherapy, 26.0% of the MFM clinicians initiate oral antidiabetic agents as the first-line pharmacotherapy with a preference for metformin (82.5%).[25] About 7.8% of the MFM clinicians practice shared decision-making regarding insulin versus oral antidiabetic agents.[25] When comparing insulin to oral antidiabetic medications preference based on the type of clinician managing GDM, endocrinologists were more likely to prescribe insulin compared with MFM clinicians or general OBGYNs.[53] [54] ACOG recommends prescribing metformin as a first-line pharmacotherapy for individuals who decline insulin, are unable to administer insulin safely, or cannot afford insulin while the SMFM supports metformin as a first-line pharmacologic alternative to insulin.[12] [13] Given the overall high prevalence of metformin use, there could be additional reasons and patients' preferences for choosing metformin over insulin. A Patient-Centered Outcomes Research Institute (PCORI)-funded study is underway to compare the effectiveness of metformin insulin for the treatment of GDM.[55] It plans to enroll over 1,500 individuals with GDM and investigate pregnancy outcomes, patient experience, and offspring early childhood growth. The study highlights the need for data on long-term offspring effects following maternal GDM treatment given the known transgenerational effect of the condition itself.[56]
Emerging and Novel Therapies for Gestational Diabetes Mellitus
When investigating novel therapeutics approaches for GDM, it is important to consider individual pathophysiology associated with insulin secretion during pregnancy. Pregnancy is associated with substantial changes in glucose metabolism including a 50 to 60% decrease in insulin sensitivity by late gestation.[57] [58] [59] Gestational diabetes is considered a state of predominant insulin resistance mediated by hormones and adipokines. Defects in postreceptor insulin signaling lead to maternal hyperglycemia.[60] [61] However, data suggest there is an adaptive increase in insulin secretion during pregnancy. Outside of pregnancy, a defect in either insulin secretion or insulin sensitivity can be identified as the primary driver of hyperglycemia.[62] [63] In a large North American cohort of over 800 individuals, Powe et al estimated insulin secretion and insulin sensitivity at the time of GDM testing.[64] The authors noted three subgroups of GDM with almost one-third of individuals with GDM having predominant insulin secretion defects, half having predominant insulin sensitivity defects with hyperinsulinemia, and the remainder having a combination of both defects.[64] Further, individuals with predominant insulin sensitivity defects had altered adipokine profiles, had larger infants, and were at greater risk of GDM-related complications.[64] Heterogeneity of physiological processes underlying hyperglycemia in GDM was also noted by Benhalima et al in a European cohort.[65] In their study, individuals with GDM and high insulin resistance had a higher risk of preterm delivery (OR = 2.41 [95% CI: 1.08, 5.38]) and neonatal hypoglycemia (OR = 4.86 [95% CI: 2.04, 11.53]) compared to individuals with normal glucose tolerance even after adjusting for demographics, BMI, FPG, Hemoglobin A1C (HbA1c), lipid levels, and gestational weight gain.[65] Interestingly, individuals with GDM and predominant insulin deficiency had pregnancy outcomes similar to individuals with normal glucose tolerance.[65] These findings suggest possible subtypes of gestational diabetes with varying risks of maternal and fetal outcomes based on individual pathophysiology. These results were the foundation for a pilot RCT comparing current standard therapy to treatment choice that is aligned with individual GDM pathophysiology: Metabolic Analysis for Treatment Choice in Gestational Diabetes Mellitus (identifier: NCT03029702).
More recently, advances in diabetes care have focused on the incretin response and insulin metabolism. Incretin hormones are gut peptides that are secreted after oral intake and that stimulate insulin secretion together with hyperglycemia. The glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP-1) are the known incretin hormones from the upper and lower gut.[66] [67] [68] Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretion response to oral as compared to intravenous glucose administration, inhibiting glucagon release, and slowing gastric emptying.[66] [67] [68] The incretin effect is diminished or absent from individuals with type 2 diabetes.[69] The role of incretins in pregnancy and their impact on GDM pathophysiology are still unclear. There is evidence of a marked increase in insulin secretion in early pregnancy (12–14 weeks gestation).[70] This effect seems to precede and appears to be independent of changes in insulin resistance.[70] A few studies have investigated incretin hormones during oral glucose tolerance testing. A study by Jones et al noted an association between fasting and 2-hour GLP-1 levels but not GIP, and plasma insulin levels during an oral glucose tolerance test (OGTT).[71] Fritsche et al described similar fasting GLP-1 and GIP levels but higher levels at 30 minutes after 75-g OGTT in individuals with GDM compared to those with normal glucose tolerance.[72] In individuals with normal glucose tolerance, insulin secretion was driven by glucose levels.[72] In contrast, individuals with GDM exhibited a positive association between GLP-1 and insulin secretion, even after adjusting for glucose and basal insulin.[72] Importantly, these studies enrolled participants between 24 and 28 weeks gestation and might not provide insight into the interplay between incretins and insulin secretion in early pregnancy. Given the expanding use of treatments focused on incretins outside of pregnancy, more work is needed to investigate their use in GDM. The impact of incretin-focused therapy on insulin secretion, its limited risk for hypoglycemia, and the evidence of minimal transplacental transfer support its potential benefit in individuals with GDM. Currently, there is a single study investigating the pharmacokinetics and pharmacodynamics of exenatide, an early-generation incretin-mimetic, in individuals with GDM (identifier: NCT05482789).
Conclusion
There is widespread acceptance of the maternal and fetal risks associated with GDM leading to recommendations for screening and treatment. However, there is limited evidence to guide practice including specific thresholds to initiate pharmacotherapy and glycemic goals of care. Further, treatment variety and data on long-term offspring effects are needed to match differences in individual pathophysiology and treatment requirements. Current treatment strategies are unable to offset the impact of increasing GDM incidence and novel care advances are critical to positively influence the health of a mother with GDM and the health and development of her child across the life cycle.
Conflict of Interest
None declared.
Each author has indicated that they have met the journal's requirements for authorship.
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- 30 Yogev Y, Ben-Haroush A, Chen R, Rosenn B, Hod M, Langer O. Diurnal glycemic profile in obese and normal weight nondiabetic pregnant women. Am J Obstet Gynecol 2004; 191 (03) 949-953
- 31 Parretti E, Mecacci F, Papini M. et al. Third-trimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: correlation with sonographic parameters of fetal growth. Diabetes Care 2001; 24 (08) 1319-1323
- 32 Siegmund T, Rad NT, Ritterath C, Siebert G, Henrich W, Buhling KJ. Longitudinal changes in the continuous glucose profile measured by the CGMS in healthy pregnant women and determination of cut-off values. Eur J Obstet Gynecol Reprod Biol 2008; 139 (01) 46-52
- 33 Cousins L, Rigg L, Hollingsworth D, Brink G, Aurand J, Yen SS. The 24-hour excursion and diurnal rhythm of glucose, insulin, and C-peptide in normal pregnancy. Am J Obstet Gynecol 1980; 136 (04) 483-488
- 34 Porter H, Lookinland S, Belfort MA. Evaluation of a new real-time blood continuous glucose monitoring system in pregnant women without gestational diabetes. A pilot study. J Perinat Neonatal Nurs 2004; 18 (02) 93-102
- 35 Metzger BE, Phelps RL, Freinkel N, Navickas IA. Effects of gestational diabetes on diurnal profiles of plasma glucose, lipids, and individual amino acids. Diabetes Care 1980; 3 (03) 402-409
- 36 Hernandez TL, Friedman JE, Van Pelt RE, Barbour LA. Patterns of glycemia in normal pregnancy: should the current therapeutic targets be challenged?. Diabetes Care 2011; 34 (07) 1660-1668
- 37 Lewis SB, Wallin JD, Kuzuya H. et al. Circadian variation of serum glucose, C-peptide immunoreactivity and free insulin normal and insulin-treated diabetic pregnant subjects. Diabetologia 1976; 12 (04) 343-350
- 38 Prutsky GJ, Domecq JP, Wang Z. et al. Glucose targets in pregnant women with diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2013; 98 (11) 4319-4324
- 39 de Veciana M, Major CA, Morgan MA. et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995; 333 (19) 1237-1241
- 40 Scifres CM, Mead-Harvey C, Nadeau H. et al. Intensive glycemic control in gestational diabetes mellitus: a randomized controlled clinical feasibility trial. Am J Obstet Gynecol MFM 2019; 1 (04) 100050
- 41 Scifres CM, Battarbee AN, Feghali MN. et al. Intensive glycaemic targets in overweight and obese individuals with gestational diabetes mellitus: clinical trial protocol for the iGDM study. BMJ Open 2024; 14 (02) e082126
- 42 Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343 (16) 1134-1138
- 43 Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358 (19) 2003-2015
- 44 Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin Jr DK, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000-2011. Obstet Gynecol 2014; 123 (06) 1177-1184
- 45 Cesta CE, Cohen JM, Pazzagli L. et al. Antidiabetic medication use during pregnancy: an international utilization study. BMJ Open Diabetes Res Care 2019; 7 (01) e000759
- 46 Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015; 350: h102
- 47 Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin Jr DK, Jonsson Funk M. Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes. JAMA Pediatr 2015; 169 (05) 452-458
- 48 Hebert MF, Ma X, Naraharisetti SB. et al; Obstetric-Fetal Pharmacology Research Unit Network. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009; 85 (06) 607-614
- 49 Tarry-Adkins JL, Aiken CE, Ozanne SE. Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: a systematic review and meta-analysis. PLoS Med 2020; 17 (05) e1003126
- 50 Boggess KA, Valint A, Refuerzo JS. et al. Metformin plus insulin for preexisting diabetes or gestational diabetes in early pregnancy: The MOMPOD randomized clinical trial. JAMA 2023; 330 (22) 2182-2190
- 51 Landi SN, Radke S, Engel SM. et al. Association of long-term child growth and developmental outcomes with metformin vs insulin treatment for gestational diabetes. JAMA Pediatr 2019; 173 (02) 160-168
- 52 Dunne F, Newman C, Alvarez-Iglesias A. et al. Early metformin in gestational diabetes: a randomized clinical trial. JAMA 2023; 330 (16) 1547-1556
- 53 Harrison RK, Johnson C, Cruz M, Wong A, Davitt C, Palatnik A. Provider-based initiation and management of pharmacologic therapy for gestational diabetes mellitus. J Matern Fetal Neonatal Med 2022; 35 (23) 4478-4484
- 54 Palatnik A, Harrison RK, Thakkar MY, Walker RJ, Egede LE. Correlates of insulin selection as a first-line pharmacological treatment for gestational diabetes. Am J Perinatol 2022; 39 (01) 8-15
- 55 Venkatesh KK, Wu J, Trinh A. et al. Patient priorities, decisional comfort, and satisfaction with metformin versus insulin for the treatment of gestational diabetes mellitus. Am J Perinatol 2024; 41 (S 01): e3170-e3182
- 56 Patient-Centered Outcomes Research Institute. . Accessed on March 28, 2024 at: https://www.pcori.org/research-results/2023/decide-comparative-effectiveness-trial-oral-metformin-versus-injectable-insulin-treatment-gestational-diabetes#project_information
- 57 Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol 1999; 180 (04) 903-916
- 58 Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 1991; 165 (6 Pt 1): 1667-1672
- 59 Catalano PM, Tyzbir ED, Wolfe RR. et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol 1993; 264 (1 Pt 1): E60-E67
- 60 Friedman JE, Ishizuka T, Shao J, Huston L, Highman T, Catalano P. Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes 1999; 48 (09) 1807-1814
- 61 Friedman JE, Kirwan JP, Jing M, Presley L, Catalano PM. Increased skeletal muscle tumor necrosis factor-alpha and impaired insulin signaling persist in obese women with gestational diabetes mellitus 1 year postpartum. Diabetes 2008; 57 (03) 606-613
- 62 Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 1981; 68 (06) 1456-1467
- 63 Kahn SE, Prigeon RL, McCulloch DK. et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993; 42 (11) 1663-1672
- 64 Powe CE, Allard C, Battista M-C. et al. Heterogeneous contribution of insulin sensitivity and secretion defects to gestational diabetes mellitus. Diabetes Care 2016; 39 (06) 1052-1055
- 65 Benhalima K, Van Crombrugge P, Moyson C. et al. Characteristics and pregnancy outcomes across gestational diabetes mellitus subtypes based on insulin resistance. Diabetologia 2019; 62 (11) 2118-2128
- 66 Drucker DJ. The biology of incretin hormones. Cell Metab 2006; 3 (03) 153-165
- 67 Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87 (04) 1409-1439
- 68 Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Investig 2010; 1 (1-2): 8-23
- 69 Gautier JF, Choukem SP, Girard J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab 2008; 34 (Suppl. 02) S65-S72
- 70 Powe CE, Huston Presley LP, Locascio JJ, Catalano PM. Augmented insulin secretory response in early pregnancy. Diabetologia 2019; 62 (08) 1445-1452
- 71 Jones DL, Petry CJ, Burling K. et al. Pregnancy glucagon-like peptide 1 predicts insulin but not glucose concentrations. Acta Diabetol 2023; 60 (12) 1635-1642
- 72 Fritsche L, Heni M, Eckstein SS. et al. Incretin hypersecretion in gestational diabetes mellitus. J Clin Endocrinol Metab 2022; 107 (06) e2425-e2430
Address for correspondence
Publication History
Received: 15 April 2024
Accepted: 27 August 2024
Article published online:
27 September 2024
© 2024. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
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- 30 Yogev Y, Ben-Haroush A, Chen R, Rosenn B, Hod M, Langer O. Diurnal glycemic profile in obese and normal weight nondiabetic pregnant women. Am J Obstet Gynecol 2004; 191 (03) 949-953
- 31 Parretti E, Mecacci F, Papini M. et al. Third-trimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: correlation with sonographic parameters of fetal growth. Diabetes Care 2001; 24 (08) 1319-1323
- 32 Siegmund T, Rad NT, Ritterath C, Siebert G, Henrich W, Buhling KJ. Longitudinal changes in the continuous glucose profile measured by the CGMS in healthy pregnant women and determination of cut-off values. Eur J Obstet Gynecol Reprod Biol 2008; 139 (01) 46-52
- 33 Cousins L, Rigg L, Hollingsworth D, Brink G, Aurand J, Yen SS. The 24-hour excursion and diurnal rhythm of glucose, insulin, and C-peptide in normal pregnancy. Am J Obstet Gynecol 1980; 136 (04) 483-488
- 34 Porter H, Lookinland S, Belfort MA. Evaluation of a new real-time blood continuous glucose monitoring system in pregnant women without gestational diabetes. A pilot study. J Perinat Neonatal Nurs 2004; 18 (02) 93-102
- 35 Metzger BE, Phelps RL, Freinkel N, Navickas IA. Effects of gestational diabetes on diurnal profiles of plasma glucose, lipids, and individual amino acids. Diabetes Care 1980; 3 (03) 402-409
- 36 Hernandez TL, Friedman JE, Van Pelt RE, Barbour LA. Patterns of glycemia in normal pregnancy: should the current therapeutic targets be challenged?. Diabetes Care 2011; 34 (07) 1660-1668
- 37 Lewis SB, Wallin JD, Kuzuya H. et al. Circadian variation of serum glucose, C-peptide immunoreactivity and free insulin normal and insulin-treated diabetic pregnant subjects. Diabetologia 1976; 12 (04) 343-350
- 38 Prutsky GJ, Domecq JP, Wang Z. et al. Glucose targets in pregnant women with diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2013; 98 (11) 4319-4324
- 39 de Veciana M, Major CA, Morgan MA. et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995; 333 (19) 1237-1241
- 40 Scifres CM, Mead-Harvey C, Nadeau H. et al. Intensive glycemic control in gestational diabetes mellitus: a randomized controlled clinical feasibility trial. Am J Obstet Gynecol MFM 2019; 1 (04) 100050
- 41 Scifres CM, Battarbee AN, Feghali MN. et al. Intensive glycaemic targets in overweight and obese individuals with gestational diabetes mellitus: clinical trial protocol for the iGDM study. BMJ Open 2024; 14 (02) e082126
- 42 Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343 (16) 1134-1138
- 43 Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358 (19) 2003-2015
- 44 Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin Jr DK, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000-2011. Obstet Gynecol 2014; 123 (06) 1177-1184
- 45 Cesta CE, Cohen JM, Pazzagli L. et al. Antidiabetic medication use during pregnancy: an international utilization study. BMJ Open Diabetes Res Care 2019; 7 (01) e000759
- 46 Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015; 350: h102
- 47 Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin Jr DK, Jonsson Funk M. Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes. JAMA Pediatr 2015; 169 (05) 452-458
- 48 Hebert MF, Ma X, Naraharisetti SB. et al; Obstetric-Fetal Pharmacology Research Unit Network. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009; 85 (06) 607-614
- 49 Tarry-Adkins JL, Aiken CE, Ozanne SE. Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: a systematic review and meta-analysis. PLoS Med 2020; 17 (05) e1003126
- 50 Boggess KA, Valint A, Refuerzo JS. et al. Metformin plus insulin for preexisting diabetes or gestational diabetes in early pregnancy: The MOMPOD randomized clinical trial. JAMA 2023; 330 (22) 2182-2190
- 51 Landi SN, Radke S, Engel SM. et al. Association of long-term child growth and developmental outcomes with metformin vs insulin treatment for gestational diabetes. JAMA Pediatr 2019; 173 (02) 160-168
- 52 Dunne F, Newman C, Alvarez-Iglesias A. et al. Early metformin in gestational diabetes: a randomized clinical trial. JAMA 2023; 330 (16) 1547-1556
- 53 Harrison RK, Johnson C, Cruz M, Wong A, Davitt C, Palatnik A. Provider-based initiation and management of pharmacologic therapy for gestational diabetes mellitus. J Matern Fetal Neonatal Med 2022; 35 (23) 4478-4484
- 54 Palatnik A, Harrison RK, Thakkar MY, Walker RJ, Egede LE. Correlates of insulin selection as a first-line pharmacological treatment for gestational diabetes. Am J Perinatol 2022; 39 (01) 8-15
- 55 Venkatesh KK, Wu J, Trinh A. et al. Patient priorities, decisional comfort, and satisfaction with metformin versus insulin for the treatment of gestational diabetes mellitus. Am J Perinatol 2024; 41 (S 01): e3170-e3182
- 56 Patient-Centered Outcomes Research Institute. . Accessed on March 28, 2024 at: https://www.pcori.org/research-results/2023/decide-comparative-effectiveness-trial-oral-metformin-versus-injectable-insulin-treatment-gestational-diabetes#project_information
- 57 Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol 1999; 180 (04) 903-916
- 58 Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 1991; 165 (6 Pt 1): 1667-1672
- 59 Catalano PM, Tyzbir ED, Wolfe RR. et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol 1993; 264 (1 Pt 1): E60-E67
- 60 Friedman JE, Ishizuka T, Shao J, Huston L, Highman T, Catalano P. Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes 1999; 48 (09) 1807-1814
- 61 Friedman JE, Kirwan JP, Jing M, Presley L, Catalano PM. Increased skeletal muscle tumor necrosis factor-alpha and impaired insulin signaling persist in obese women with gestational diabetes mellitus 1 year postpartum. Diabetes 2008; 57 (03) 606-613
- 62 Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 1981; 68 (06) 1456-1467
- 63 Kahn SE, Prigeon RL, McCulloch DK. et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993; 42 (11) 1663-1672
- 64 Powe CE, Allard C, Battista M-C. et al. Heterogeneous contribution of insulin sensitivity and secretion defects to gestational diabetes mellitus. Diabetes Care 2016; 39 (06) 1052-1055
- 65 Benhalima K, Van Crombrugge P, Moyson C. et al. Characteristics and pregnancy outcomes across gestational diabetes mellitus subtypes based on insulin resistance. Diabetologia 2019; 62 (11) 2118-2128
- 66 Drucker DJ. The biology of incretin hormones. Cell Metab 2006; 3 (03) 153-165
- 67 Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87 (04) 1409-1439
- 68 Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Investig 2010; 1 (1-2): 8-23
- 69 Gautier JF, Choukem SP, Girard J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab 2008; 34 (Suppl. 02) S65-S72
- 70 Powe CE, Huston Presley LP, Locascio JJ, Catalano PM. Augmented insulin secretory response in early pregnancy. Diabetologia 2019; 62 (08) 1445-1452
- 71 Jones DL, Petry CJ, Burling K. et al. Pregnancy glucagon-like peptide 1 predicts insulin but not glucose concentrations. Acta Diabetol 2023; 60 (12) 1635-1642
- 72 Fritsche L, Heni M, Eckstein SS. et al. Incretin hypersecretion in gestational diabetes mellitus. J Clin Endocrinol Metab 2022; 107 (06) e2425-e2430