Continuous Glucose Monitoring (CGM) Substudy of the DECIDE RCT

Ohio State University

Overview

This is a nested multicenter prospective cohort conducted concurrently and in conjunction with the DECIDE two-arm, pragmatic non-inferiority comparative effectiveness Randomized Controlled Trial (RCT) (NCT06445946) of metformin versus insulin among individuals with Gestational diabetes mellitus (GDM) requiring pharmacotherapy for glycemic control. Continuous Glucose Monitoring (CGM)-derived glycemic metric in pregnancy and postpartum will be compared between individuals randomized to metformin versus insulin. In addition, the association between CGM metrics and adverse pregnancy outcomes will be examined. Finally, whether CGM metrics can accurately identify diabetes postpartum compared with an oral glucose tolerance test and hemoglobin A1c will be determined. A total of 300 (150 metformin, 150 insulin) pregnant individuals will be recruited with GDM who require pharmacotherapy to use a blinded CGM device (Dexcom, Inc, San Diego, CA) at two pregnancy (medication randomization, late third trimester) and three postpartum timepoints (delivery, \~6 weeks, and \~2 years).

Gestational diabetes mellitus (GDM) is the most frequent metabolic complication of pregnancy, and affects nearly 1 in 10 pregnant individuals in the U.S. annually. GDM increases the risks of both adverse pregnancy and postpartum outcomes for the affected individual and exposed offspring. Following a diagnosis of GDM, individuals are instructed to achieve glycemic control to decrease the risk of adverse pregnancy outcomes through monitoring of blood glucose, dietary modifications, and increased physical activity. However, \>1 in 4 individuals with GDM will not achieve targeted glycemic control with diet and behavior changes alone, and require pharmacotherapy. This is a multicenter prospective observational cohort nested in the DECIDE randomized controlled trial (NCT06445946). DECIDE is a two-arm, pragmatic non-inferiority comparative effectiveness RCT of metformin versus insulin to prevent adverse pregnancy outcomes and to confirm postpartum safety among individuals with GDM who require pharmacotherapy to achieve glycemic control. This trial will determine whether metformin is not inferior to insulin in reducing adverse pregnancy outcomes and is comparably safe for exposed pregnant individuals and their children. This substudy will be conducted concurrently and in conjunction with the parent study. A subset of 300 individuals (150 metformin, 150 insulin) will be enrolled in this substudy from the 1,572 individuals from the parent trial. Primary aim: To compare CGM-derived glycemic profiles (primary outcome: time in range of 63 to 140 mg/dL; secondary outcomes (mean glucose, coefficient of variation, and percentage of time below the target glucose range or above the target glucose range) in pregnancy between individuals with GDM randomized to metformin versus insulin. Secondary aims: To examine the association between CGM metrics and adverse pregnancy outcomes (large-for-gestational-age at birth, neonatal hypoglycemia, and hyperbilirubinemia, hypertensive disorder of pregnancy, preterm birth \<37 weeks, NICU admission, neonatal mechanical ventilation, neonatal oxygen support, neonatal respiratory distress syndrome). To examine whether CGM metrics can identify diabetes and postpartum cardiometabolic outcomes (prediabetes, type 2 diabetes, impaired glucose tolerance, impaired fasting glucose, hypertension, obesity, and cholesterol abnormalities) compared with an oral glucose tolerance test or hemoglobin A1c.

Interventions

CGM device - Metformin groupDEVICE

Individuals randomized to metformin will be provided with a CGM device (Dexcom, Inc, San Diego, CA) to be worn for up to 10 days (minimum \>5 days) at two pregnancy (randomization to metformin or insulin, late third trimester \> 340/7 weeks) and three postpartum timepoints (immediately after delivery, \~6 weeks, and \~2 years).

CGM device - Insulin groupDEVICE

Individuals randomized to insulin will be provided with a CGM device (Dexcom, Inc, San Diego, CA) to be worn for up to 10 days (minimum \>5 days) at two pregnancy (randomization to metformin or insulin, late third trimester \> 340/7 weeks) and three postpartum timepoints (immediately after delivery, \~6 weeks, and \~2 years).

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Singleton gestation. Twin reduction to singleton, either spontaneously or therapeutically, is eligible if it occurred before 14 weeks gestational age. * Age \>18 years * Gestational age at randomization between 200/7 - 316/7 weeks based on project gestational age. * GDM diagnosis between 200/7 - 316/7 weeks based on project gestational age. * Requires medication for glucose control defined as ≥30% elevated glucose values (either fasting or postprandial or both) in the week prior to randomization per determination of the provider or documented in the medical record. * Patient willingness and ability to attend 2-year follow-up visit. * Patient willingness to wear and return a blinded CGM device. It is possible that some enrolled individuals may choose to use a separate CGM device for glucose monitoring as part of clinical care. Exclusion Criteria: * Renal disease (serum creatinine \>1.3 mg/dL) due to the potential impact of metformin on renal function. * Major structural malformation of the fetus. * Known fetal aneuploidy based on invasive testing or positive for aneuploidy on cell-free fetal DNA screening. * Contraindication to metformin or insulin, including: history of lactic acidosis, intractable nausea and vomiting, prior documented allergy and/or anaphylaxis. * Pregestational diabetes documented in the medical record, GDM diagnosis \<20 weeks, or prior A1c\>6.5% * Fasting hyperglycemia \>115 mg/dl for ≥50% of fasting glucose values in the past week (due to the high risk of metformin failure with fasting hyperglycemia). * Enrolled in a trial that influences primary study outcomes of the parent DECIDE trial (composite neonatal outcome at delivery or childhood body mass index at 2 years). * Prenatal care or delivery planned at a location where access to the complete electronic medical record will not be available to research staff. * Language barrier (appropriate translation resources unavailable at the site). * Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, may be included. * In addition, individuals who report a prior allergy or sensitivity to CGM will also be excluded.

Outcomes

Primary Outcomes

Time in range (TIR)

Percent of time CGM readings are within the pregnancy target glucose range of 63 to 140 mg/dL. This outcome will be assessed as a continuous measure in increments of 1%.

Time frame: From medication randomization till late third trimester, up to 14 weeks

Secondary Outcomes

Coefficient of variation (CV)

Percent of glycemic variability calculated as the standard deviation (SD) of glucose values divided by the mean glucose in the same observation period, continuous measure

Time frame: From medication randomization till 2 years postpartum, up to 40 months.

Time below range (TBR)

Percent of CGM readings and time below the target glucose range of \<63 mg/dL, continuous measure

Time frame: From medication randomization till 2 years postpartum, up to 40 months.

Time above range (TAR)

Percent of CGM readings and time above the target glucose range of \>140 mg/dL, continuous measure

Time frame: From medication randomization till 2 years postpartum, up to 40 months.

Large-for-gestational-age at birth

LGA will be defined as a birthweight ≥90th%tile for gestational age based on a US birth certificate reference adjusted for parity and/or fetal sex.

Time frame: At delivery

Hypoglycemia

Neonatal hypoglycemia will be defined as a blood glucose \<35 mg/dL or treatment \<24 hours after birth with either IV, PO, or gel glucose therapy.

Time frame: <24 hours after birth

Hyperbilirubinemia

Neonatal hyperbilirubinemia will be defined as treated with phototherapy or exchange transfusion in the first postnatal week and either treatment in the first postnatal week or kernicterus.

Time frame: Within one week after birth

Hypertensive disorder of pregnancy

HDP will include either gestational hypertension or preeclampsia. Gestational hypertension will be defined as: systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure. Preeclampsia will be defined as: above blood pressure criteria AND proteinuria (300 mg or more per 24 hour urine collection, protein/creatinine ratio of 0.3 mg/dL or more, or dipstick reading of 2+) OR thrombocytopenia (platelet count less than 100 109/L), renal insufficiency (serum creatinine greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease), impaired liver function (elevated blood concentrations of liver transaminases to twice normal concentration), pulmonary edema, new-onset headache or visual symptoms not attributed to other diagnoses.

Time frame: Randomization to delivery

Preterm birth

Preterm birth \<37 weeks and \<34 weeks based on project gestational age.

Time frame: At birth

Requiring mechanical ventilation

Intubation, continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) for ventilation or cardiopulmonary resuscitation within first 72 hours of birth.

Time frame: <72 hours after birth

NICU admission

Admitted to NICU or intermediate nursery ≥72 hours, any indication.

Time frame: Birth to infant date of delivery discharge (length of NICU admission will vary for each infant )

Oxygen support

Requiring oxygen support.

Time frame: <72 hours after birth

Respiratory distress syndrome

Signs of respiratory distress with oxygen requirement and confirmed by chest x-ray.

Time frame: Anytime during the first 72 hours after birth

Treatment supplementation

Insulin use among individuals randomized to metformin between randomization and delivery.

Time frame: From randomization to delivery

Type 2 diabetes (T2D)

A1c \> 6.5% OR fasting plasma glucose \> 126 mg/dL OR OGTT \> 200 mg/dL OR prior diagnosis per patient report.

Time frame: From delivery to 2 years postpartum

Prediabetes

A1c 5.7% to 6.4% OR fasting plasma glucose 100 mg/dl to 125 mg/dL OR OGTT 140 to 199 mg/dL.

Time frame: From delivery to 2 years postpartum

Impaired glucose tolerance (IGT)

OGTT 2-hour value of 140 to 199 mg/dL32

Time frame: From delivery to 2 years postpartum

Impaired fasting glucose (IFG)

OGTT value of 100 to 125 mg/dL.

Time frame: From delivery to 2 years postpartum.

Obesity overall and by class

Weight and height will be combined to report BMI in kg/m\^2. BMI per the following classifications will be assessed: Normal or underweight: \< 25 kg/m2; Overweight: 25 to \< 30 kg/m2; Class 1: 30 to \< 35 kg/m2; Class 2: 35 to \< 40 kg/m2; and Class 3: 40 kg/m2 or greater.

Time frame: 2 years postpartum

Hypertension

Per American Heart Association criteria as below and/or antihypertensive medication or prior diagnosis per patient report, and defined as: Elevated: Systolic between 120-129 and diastolic less than 80 mm Hg; Stage 1: Systolic between 130-139 or diastolic between 80-89 mm Hg; and Stage 2: Systolic at least 140 or diastolic at least 90 mm Hg.

Time frame: 2 years postpartum

Cholesterol

Fasting state, defined as a continuous measure and dichotomous at the following thresholds for each component: Total cholesterol: \> 200 mg/dL; LDL cholesterol: \> mg/dL; HDL cholesterol: \< 40 mg/dL; Triglycerides: \> 200 mg/dL.

Time frame: 2 years postpartum

Mean glucose

Mean glucose in mg/dL per CGM readings, continuous measure

Time frame: From medication randomization till 2 years postpartum, up to 40 months.

Continuous Glucose Monitoring (CGM) Substudy of the DECIDE RCT

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes