Metformin Versus Insulin in Gestational Diabetes

Metformin Versus Insulin in Gestational Diabetes. A Randomized Controlled Single Center Trial.

Gestational diabetes is traditionally treated with insulin. Metformin is a peroral drug used worldwide in the treatment of type 2 diabetes and also in a few studies on patients with gestational diabetes. The investigators aim is to compare insulin and metformin in the treatment of gestational diabetes. The investigators hypothesis is that there is no difference between insulin and metformin treated mothers in the main outcome criteria (birth weight, neonatal complications).

Study Overview

• Status: Completed
• Conditions: Gestational Diabetes
• Intervention / Treatment: Drug: metformin; Drug: insulin

Detailed Description

Gestational diabetes is traditionally treated with insulin. Metformin is a peroral drug used worldwide in the treatment of type 2 diabetes and also in a few studies on patients with gestational diabetes. The investigators aim is to compare insulin and metformin in the treatment of gestational diabetes. The investigators hypothesis is that there is no difference between insulin and metformin treated mothers in the main outcome criteria (birth weight, neonatal complications). The study was performed as a randomized controlled trial in one center, Turku University hospital using the non-inferiority design in June 2006 - December 2010. The final study population consisted of altogether 217 women, of whom 110 received metformin and 107 insulin.

• Study Type: Interventional
• Enrollment (Actual): 221
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Mothers with gestational diabetes who had at least twice plasma glucose at fasting > 5.4 mmol/L and/or 1 hour postprandial value > 7.7 mmol/L at 24 to 32 gestational weeks

Exclusion Criteria:

1. Fasting glucose > 7.0 mmol/L or 1 hour postprandial plasma glucose > 11.0 mmol/L or Glycosylated hemoglobin A1c (HbA1c) > 7.0%
2. Renal, hepatic or cardiac failure
3. Pregestational use of metformin
4. Pregnancy with multiple fetuses

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
Active Comparator: Metformin; Metformin 500 mg 1-2 tablets twice daily according to plasma glucose values	Drug: metformin; metformin 1 g twice daily or maximum tolerated dose less than 2 g daily; Other Names: Diformin retard 500 mg
Active Comparator: insulin; NPH insulin once or twice daily and/or insulin lispro or aspart according to preprandial and postprandial glucose values	Drug: insulin; subcutaneous Neutral Protamine Hagedorn (NPH) insulin and/or rapid acting insulin analog adjusted according to plasma glucose values until delivery; Other Names: Humalog; Protaphane

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birth Weight Per Arm	birth weight adjusted for gestational weeks expressed as standard deviation units using data from Finnish fetal growth charts in normal pregnancies	delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnancy Induced Hypertension Per Arm	Participants with pregnancy induced hypertension defined as blood pressure over 140/90 mmHg or increase in systolic blood pressure > 30 mmHg or diastolic blood pressure > 15 mmHg	up to on the average 40 weeks of gestation
Maternal Weight Gain Per Arm		up to on the average 40 weeks of gestation
Pre-eclampsia Per Arm		up to on the average 40 weeks of gestation
Mode of Delivery Per Arm		delivery
Gestational Weeks at Delivery Per Arm		delivery
Induction of Delivery Per Arm		delivery
Shoulder Dystocia Per Arm		delivery
Neonatal Hypoglycemia Per Arm		0-24 h after delivery
Neonatal Hyperbilirubinemia Per Arm		0-3 days after delivery
Apgar Score at 5 Min After Delivery Per Arm	Apgar score 0-10. 0-2 points from heart rate; 0-2 points for respiratory effort; 0-2 points for skin colour; 0-2 points for muscle tone; 0-2 points for reflex response. For all items the higher the value, the better the outcome	5 minutes after delivery
Neonate Transfer to Intensive Care Unit Per Arm		0-5 days after delivery
Child Outcome at 2 Years Per Arm	neuropsychological and motor skills testing	2 years after birth

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Investigators: Principal Investigator: Tapani Rönnemaa, MD, PhD, Professor, Chief Physician

Publications and helpful links

General Publications

• Huhtala MS, Ronnemaa T, Pellonpera O, Tertti K. Cord serum metabolome and birth weight in patients with gestational diabetes treated with metformin, insulin, or diet alone. BMJ Open Diabetes Res Care. 2021 May;9(1):e002022. doi: 10.1136/bmjdrc-2020-002022.
• Huhtala MS, Tertti K, Juhila J, Sorsa T, Ronnemaa T. Metformin and insulin treatment of gestational diabetes: effects on inflammatory markers and IGF-binding protein-1 - secondary analysis of a randomized controlled trial. BMC Pregnancy Childbirth. 2020 Jul 11;20(1):401. doi: 10.1186/s12884-020-03077-6.
• Huhtala MS, Tertti K, Pellonpera O, Ronnemaa T. Amino acid profile in women with gestational diabetes mellitus treated with metformin or insulin. Diabetes Res Clin Pract. 2018 Dec;146:8-17. doi: 10.1016/j.diabres.2018.09.014. Epub 2018 Sep 15.
• Pellonpera O, Ronnemaa T, Ekblad U, Vahlberg T, Tertti K. The effects of metformin treatment of gestational diabetes on maternal weight and glucose tolerance postpartum--a prospective follow-up study. Acta Obstet Gynecol Scand. 2016 Jan;95(1):79-87. doi: 10.1111/aogs.12788. Epub 2015 Nov 8.
• Tertti K, Laine K, Ekblad U, Rinne V, Ronnemaa T. The degree of fetal metformin exposure does not influence fetal outcome in gestational diabetes mellitus. Acta Diabetol. 2014 Oct;51(5):731-8. doi: 10.1007/s00592-014-0570-6. Epub 2014 Mar 16.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: November 3, 2010
• First Submitted That Met QC Criteria: November 11, 2010
• First Posted (Estimate): November 15, 2010

Study Record Updates

• Last Update Posted (Estimate): November 24, 2014
• Last Update Submitted That Met QC Criteria: November 21, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: insulin; metformin; gestational diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes, Gestational; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 246/2005