Comparison of Insulin Alone to Insulin With Metformin to Treat Gestational Diabetes Mellitus

Study Overview
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Brief Summary
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This study is a prospective, unmasked randomized clinical trial comparing the use of insulin vs combination insulin and metformin for treatment in women diagnosed with gestational diabetes mellitus (GDM). The investigator's hypothesis is that the combination of metformin and insulin will be superior to insulin alone to achieve tight glucose control during pregnancy.

Detailed Description
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The objective of this study is to compare the effectiveness of insulin alone vs the combination of insulin and metformin in treating patients with gestational diabetes (GDM). Currently, outside of pregnancy, the treatment of type 2 diabetes mellitus (T2DM) with both metformin and insulin is superior to using insulin alone. In pregnancy, insulin alone has traditionally been used, though some advocate the use of metformin alone as primary therapy. There have been no trials published to date specifically comparing combination therapy to insulin alone. Our hypothesis is that the combination of metformin and insulin will improve overall control of blood glucose, the improvement of which has been demonstrated to improve maternal and neonatal outcomes. Control of blood glucose will be determined by hemoglobin A1c at the time of delivery.

Official Title
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Comparison of Insulin Alone to Insulin With Metformin to Treat Gestational Diabetes Mellitus

Conditions
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Gestational Diabetes

Intervention / Treatment
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* Drug: Insulin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to read and write English and/or Spanish and give written consent Diagnosis of GDM, defined as an abnormal glucose tolerance test performed after 12 weeks gestation using 1 of the 2 criteria below: 50 gram 1 hour oral diabetes screening testing yielding a result of > 200 mg/dL A 100 gram 3 hour oral glucose tolerance testing yielding >2 abnormal values (normal values defined as fasting blood glucose < 95, 1 hour < 180, 2 hour < 155 and 3 hour < 140) Singleton gestation Gestational age between 12 and 34 weeks and 6 days determined by last menstrual period (LMP) confirmed by ultrasound using criteria set forth by the ACOG (Committee on Obstetric Practice). If LMP is unknown then gestational age must be set by ultrasound prior to 20 weeks gestation. Exclusion Criteria: Pre-existing DM either by diagnosis preceding pregnancy or hemoglobin A1c >6.5 collected during the current pregnancy Uncontrolled chronic hypertension, as this may alter maternal and perinatal outcomes measured. Multiple gestations Major fetal anomalies anticipated to require NICU admission Contraindication to metformin (allergy, history of lactic acidosis, pre-existing renal disease (Cr >1.5 mg/dL), active liver disease, current alcohol abuse). Vitamin B12 deficiency, as metformin reduces intestinal absorption of vitamin B12 Medications known to effect glucose metabolism other than insulin and metformin as this may mask any effect between the two treatments. Known inability to tolerate metformin.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: insulin<br> | Drug: Insulin<br>* Weight based insulin will be calculated using 0.7 units/kg/day in the first trimester, 0.8 units/kg/day in the second trimester and 1 units/kg/day in the third trimester. This total insulin will then be divided into short acting insulin and intermediate acting insulin per provider discretion.<br>|
| Active Comparator: insulin and metformin<br> | Drug: Insulin<br>* Weight based insulin will be calculated using 0.7 units/kg/day in the first trimester, 0.8 units/kg/day in the second trimester and 1 units/kg/day in the third trimester. This total insulin will then be divided into short acting insulin and intermediate acting insulin per provider discretion.<br>Drug: Metformin<br>* Will be initiated at dose of 500 mg twice daily. If glycemic control is suboptimal, the dose of metformin will be increased to 1000 mg twice a day. Metformin will be titrated prior to increases in insulin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hgb A1c | Hgb A1c test | collected at the time of delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total daily dose of insulin | Total daily dose of insulin at the end of pregnancy | Will be recorded on hospital admission for delivery | 
| Glucose control | Average of fasting and 2 hour postprandial glucose values | patients will collect glucose values fasting and 2 hrs postprandial every day from enrollment until delivery. | 
| Incidence of maternal hypoglycemia | episodes of maternal hypoglycemia defined as glucose ≤70 mg/dL | patients will be screened weekly for episodes of hypoglycemia until delivery | 
| Change in hemoglobin A1c over the course of the pregnancy | If baseline hemoglobin A1c was collected as part of routine care prior to enrollment, this value will be compared to the hemoglobin A1c collected at delivery | hemoglobin A1c will be collected at delivery (per above) and comparison performed after collection | 
| Incidence of maternal side effects | maternal reported medication side effects (i.e. nausea, vomiting, diarrhea) | Will be assessed weekly until delivery | 
| Treatment acceptability | determined using Diabetes Treatment Satisfaction Questionnaire. Survey includes 8 questions that are answered on a scale of 0-6; 0 indicating the least and 6 the highest level of satisfaction. The individual questions will be compared. Total satisfaction will also be compared by summing the responses to all 8 questions on a composite scale of 0-48 | Will be collected postpartum after delivery | 
| Maternal weight gain | weight gain through pregnancy | This will be calculated as the difference from the weight measured at the inital prenatal visit (the specific timing of which is patient dependant) and at the time of admission for delivery | 
| Incidence of hypertensive disorder of pregnancy | gestational HTN, superimposed pre-eclampsia, pre-eclampsia-eclampsia | from enrollment through study completion (30 days after delivery) | 
| Incidence of composite of adverse maternal outcomes | death, ICU admission, postpartum hemorrhage, blood transfusion, organ failure, chorioamnionitis/endometritis | from enrollment through study completion (30 days after delivery) | 
| Breast feeding status | Whether patient is breast feeding or bottle feeding upon discharge from the hospital after delivery | Will be recorded at the time of hospital discharge after delivery (typically 2-4 days after delivery) | 
| Mode of delivery | Mode of delivery | recorded at time of delivery | 
| Gestational age at delivery | Gestational age at delivery | recorded at time of delivery | 
| Infant birthweight (using age/sex matched percentiles) | Infant birthweight (using age/sex matched percentiles) | measured at time of birth | 
| Incidence of composite neonatal morbidity | Presence of any of the following: NICU admission, hypoglycemia, hyperbilirubinemia, birth trauma, stillbirth, respiratory distress syndrome, sepsis, neonatal death prior to discharge, 5 minute Apgar score < 7, umbilical artery cord pH <7.10 | from delivery through study completion (30 days after delivery) | 
| Incidence neonatal hypoglycemia | hypoglycemia requiring intravenous treatment | from delivery through study completion (30 days after delivery) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin