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

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

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.

Study Overview

• Status: Completed
• Conditions: Pregnancy; Non Insulin Dependent Diabetes
• Intervention / Treatment: Drug: Metformin; Drug: Insulin

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospitals Obstetric Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; 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; 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.; Other Names: Glucophage
Active Comparator: Insulin; 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; 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.; Other Names: Novolin R; Regular Insulin; Humulin R; Humulin N; Novolin N; NPH Insulin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: WakeMed Health and Hospitals
• Investigators: Principal Investigator: Ashley Hickman, MD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Hickman MA, McBride R, Boggess KA, Strauss R. Metformin compared with insulin in the treatment of pregnant women with overt diabetes: a randomized controlled trial. Am J Perinatol. 2013 Jun;30(6):483-90. doi: 10.1055/s-0032-1326994. Epub 2012 Oct 24.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: February 2, 2009
• First Submitted That Met QC Criteria: February 2, 2009
• First Posted (Estimate): February 4, 2009

Study Record Updates

• Last Update Posted (Actual): April 25, 2017
• Last Update Submitted That Met QC Criteria: April 21, 2017
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Pregnancy; Non Insulin Dependent Diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Metformin; Insulin, Isophane; Isophane Insulin, Human
• Other Study ID Numbers: UNC08-0898