Effectiveness of Metformin Compared to Insulin in Pregnant Women With Mild Preexisting or Early Gestational Diabetes

Study Overview
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Brief Summary
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Many women come into pregnancy with diabetes that is controlled with either Metformin or diet control; however, the current standard of care for the treatment of preexisting diabetes in pregnancy is insulin. Metformin is widely used in the non-pregnant population for glycemic control, and has been used in pregnancy for other indications without adverse maternal or fetal outcomes. What remains unproven is the ability of Metformin to adequately control glucose in women during pregnancy. Our goal is to randomize 100 women who enter pregnancy with diabetes that is controlled by either diet or an oral agent and women who are found to have an abnormal glucose challenge test at less than 20 weeks to either standard treatment with weight based Regular and neutral protamine Hagedorn (NPH) insulin or Metformin. Our hypothesis is that Metformin will provide glycemic control that is equivalent to insulin in these women.

Official Title
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Pilot Study of Metformin vs. Insulin in Pregnant Overt Diabetics (MIPOD)

Conditions
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Non Insulin Dependent Diabetes, Pregnancy

Intervention / Treatment
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* Drug: Metformin
* Drug: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Receiving prenatal care at University of North Carolina (UNC), Chapel Hill Obstetric clinics and planning delivery at UNC Women's Hospital Diagnosis of Diabetes prior to pregnancy with use of an oral hypoglycemic agent or dietary control Diagnosis of early gestational diabetes prior to 20 weeks gestation via abnormal 3 hour glucose challenge testing using the national diabetes data group (NDDG)criteria Less than 24 weeks at study enrollment Singleton or twin pregnancy English or Spanish speaking Able to give informed consent Exclusion Criteria: End organ complications of diabetes (retinopathy, renal insufficiency, etc.) Prior need for insulin for glycemic control History of diabetic ketoacidosis (DKA) or hyperosmolar state Prior adverse reaction (ie. lactic acidosis) or allergy to Metformin Kidney or liver disease Significant medical co-morbidities (lupus, cystic fibrosis, etc.) Hypertension controlled on one medication, well controlled asthma, and well controlled thyroid disease are not excluded.

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 |
| --- | --- |
| Experimental: Metformin<br>Women who enter pregnancy with a diagnosis of non insulin dependent/Type 2 Diabetes that is controlled with diet or an oral hypoglycemic agent, and women who demonstrate abnormal glucose tolerance prior to 20 weeks of gestation by abnormal 3 hour glucose challenge testing will be offered study participation. After informed consent, they will be randomized 1:1 to either the Metformin or Insulin group. | Drug: Metformin<br>* Women randomized to the Experimental arm will receive standard diet and glucose self-monitoring education. They will be initiated on Metformin 500 BID if they were medication naïve, or will be continued on their current dosage of Metformin if they were taking it prior to pregnancy. At each clinic visit fasting and one hour post prandial glucose values will be reviewed, and dosage will be titrated to a maximum of 2250mg/day to achieve target glycemic control. If glycemic control can not be achieved with Metformin as a single agent insulin will be added.<br>* Other names: Glucophage;|
| Active Comparator: Insulin<br>Women who enter pregnancy with a diagnosis of non insulin dependent/Type 2 Diabetes that is controlled with diet or an oral hypoglycemic agent, and women who demonstrate abnormal glucose tolerance prior to 20 weeks of gestation by abnormal 3 hour glucose challenge testing will be offered study participation. After informed consent, they will be randomized 1:1 to either the Metformin or Insulin group. | Drug: Insulin<br>* Women randomized to the Insulin group will receive standard diet and glycemic monitoring education. They will be initiated on weight based Regular and NPH insulin at a total dosage of 0.7units/kg in the first trimester or 0.8units/kg in the second trimester divided as 2/3 of the total dosage (with 2/3 given as NPH and 1/3 given as Regular) administered before breakfast and 1/3 of the total dosage (with 1/2 given as NPH and 1/2 given as Regular)administered with dinner. At each clinic visit fasting and one hour post prandial glucose values will be reviewed, and dosage will be titrated to achieve optimal glycemic control with fasting values <90 and one hour post prandial values <130.<br>* Other names: Humulin N;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Glucose Measurements | Patients self monitored glucose measures throughout pregnancy to aid glycemic control. Fasting morning measures and postprandial measures were taken at 1 hour after breakfast, lunch, and dinner. | Daily fasting and 1-hr post prandial measures were taken from time of enrollment until delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Obstetric Complications | Maternal complications were stillbirths, major malformations, shoulder dystocia, or postpartum hemorrhage requiring transfusion. | Throughout pregnancy until hospital discharge following delivery. | 
| Maternal Weight Gain |  | Baseline throughout pregnancy until last prenatal visit. | 
| Number of Babies With Neonatal Hypoglycemia | Initial neonatal glucose < 40 mg/dL | Time of delivery through hospital discharge | 
| Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester |  | 1st, 2nd, and 3rd trimester | 
| Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | NUMBER OF ASSESSMENTS OF FASTING GLUCOSE VALUES <95 | Baseline throughout pregnancy until time of delivery | 
| Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | NUMBER OF ASSESSMENTS OF POSTPRANDIAL GLUCOSE VALUES <130 | Baseline throughout pregnancy until time of delivery | 
| Number of Episodes Maternal Hypoglycemia | Maternal glucose < 60 mg/dL | Baseline throughout pregnancy until time of delivery | 
| Number of Babies With Adverse Neonatal Outcomes | Resuscitation in the delivery room, preterm birth < 37 weeks, neonatal intensive care unit care, birth injury or diagnosis of neonatal complication, glucose infusion, antibiotics, or phototherapy. | Delivery until hospital discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Insulin Dependent Diabetes, Pregnancy