Metformin for the Treatment of Microvascular Dysfunction After Gestational Diabetes

The purpose of this investigation is to examine the mechanisms mediating vascular dysfunction in women who have had gestational diabetes and how metformin may be a valuable treatment tool to improve microvascular function in these women before the onset of disease.

Study Overview

• Status: Recruiting
• Conditions: Gestational Diabetes
• Intervention / Treatment: Drug: Metformin Hydrochloride; Other: placebo

Detailed Description

Women with a history of gestational diabetes mellitus (GDM) are at a 2-fold greater risk for the development of overt cardiovascular disease (CVD) following the effected pregnancy. While subsequent development of type II diabetes elevates this risk, prior GDM is an independent risk factor for CVD morbidity, particularly within the first decade postpartum. GDM is associated with impaired endothelial function during pregnancy and decrements in macro- and microvascular function persist postpartum, despite the remission of insulin resistance following delivery. Collectively, while the association between GDM and elevated lifetime CVD risk is clear, and available evidence demonstrates a link between GDM and vascular dysfunction in the decade following pregnancy, the mechanisms mediating this persistent dysfunction remain unexamined.

The purpose of this investigation is to examine the mechanisms mediating vascular dysfunction in women who have had gestational diabetes and how metformin may be a valuable treatment tool to improve microvascular function in these women before the onset of disease. This study will give rise to a new line of research that will center around the goal of improving lifetime cardiovascular outcomes in women with a history of GDM.

In this study, the investigators use the blood vessels in the skin as a representative vascular bed for examining mechanisms of microvascular dysfunction in humans. Using a minimally invasive technique (intradermal microdialysis for the local delivery of pharmaceutical agents) they examine the blood vessels in a dime-sized area of the skin in women who have had GDM. Local heating of the skin at the microdialysis sites is used to explore differences in mechanisms governing microvascular control. As a compliment to these measurements, the investigators also draw blood from the subjects and isolate the inflammatory cells.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Anna Stanhewicz, PhD; Phone Number: 3194671732; Email: anna-stanhewicz@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa
      • Contact: Anna Stanhewicz, PhD; Phone Number: 319-467-1732; Email: anna-stanhewicz@uiowa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• ≥12 weeks and ≤5 years postpartum
• history of GDM or healthy pregnancy

Exclusion Criteria:

• prediabetes or diabetes (HbA1c ≥5.7%)
• current tobacco use
• cardiovascular or metabolic disease
• cardiovascular or metabolic medication
• history of hypertension during pregnancy
• current pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Other: placebo; 12 weeks: placebo tablet once daily for the first 7 days then twice daily for the remaining 11 weeks.
Active Comparator: metformin	Drug: Metformin Hydrochloride; 12 weeks: 850mg metformin once daily for first 7 days then twice daily for the remaining 11 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
blood flow response to acetylcholine	cutaneous microvascular dilation (cutaneous conductance ; %max) response to acetylcholine	baseline
blood flow response to acetylcholine	cutaneous microvascular dilation (cutaneous conductance ; %max) response to acetylcholine	1 week of treatment
blood flow response to acetylcholine	cutaneous microvascular dilation (cutaneous conductance ; %max) response to acetylcholine	6 weeks of treatment
blood flow response to acetylcholine	cutaneous microvascular dilation (cutaneous conductance ; %max) response to acetylcholine	12 weeks of treatment
blood flow response to insulin	cutaneous microvascular dilation (cutaneous conductance ; %max) response to insulin	baseline
blood flow response to insulin	cutaneous microvascular dilation (cutaneous conductance ; %max) response to insulin	1 week of treatment
blood flow response to insulin	cutaneous microvascular dilation (cutaneous conductance ; %max) response to insulin	6 weeks of treatment
blood flow response to insulin	cutaneous microvascular dilation (cutaneous conductance ; %max) response to insulin	12 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of nitric oxide-dependent dilation	NO-dependent (%) cutaneous microvascular dilation response to acetylcholine	baseline
Percentage nitric oxide-dependent dilation	NO-dependent (%) cutaneous microvascular dilation response to acetylcholine	1 week of treatment
Percentage of nitric oxide-dependent dilation	NO-dependent (%) cutaneous microvascular dilation response to acetylcholine	6 weeks of treatment
Percentage of nitric oxide-dependent dilation	NO-dependent (%) cutaneous microvascular dilation response to acetylcholine	12 weeks of treatment

Collaborators and Investigators

• Sponsor: Anna Stanhewicz, PhD
• Investigators: Principal Investigator: Anna Stanhewicz, PhD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: June 14, 2023
• First Posted (Actual): June 26, 2023

Study Record Updates

• Last Update Posted (Actual): May 13, 2025
• Last Update Submitted That Met QC Criteria: May 7, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: postpartum; gestational diabetes; vascular
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Pregnancy Complications; Glucose Metabolism Disorders; Diabetes, Gestational; Diabetes Mellitus; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: 202303345; 1R01HL169201-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Findings from the primary studies will be published and submitted to PubMed Central in compliance with the NIH public access policy. These findings will also be made public through the clinicaltrial.gov record. The final data set will be stripped of any identifying data prior to release for sharing. We will make the data and any associated documentation available to users only under a data-sharing agreement that provides for: 1) a commitment to using the data only for research purposes and not to identify any one individual participant; 2) a commitment to securing the data using appropriate computer technology; and 3) a commitment to destroying or returning the data after all analyses are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No