Exercise Dose and Metformin for Vascular Health in Metabolic Syndrome

September 18, 2025 updated by: Steven K Malin, PhD, Rutgers University

Exercise Dose and Metformin for Vascular Health in Adults With Metabolic Syndrome

Health organizations recommend exercise in an intensity based manner to promote cardiovascular adaptation and prevent disease. Metformin is a common anti-diabetes medication that reduces future type 2 diabetes and cardiovascular disease (CVD) risk. However, the optimal dose of exercise to be combined with metformin for vascular health remains unknown. The purpose of this study is to evaluate whether combining high or low intensity exercise with metformin has the potential to outperform either exercise intensity alone on blood flow across the arterial tree as well as impact insulin action in individuals with metabolic syndrome. Identification of such outcomes will indicate 1) whether and how metformin should be combined with physical activity for CVD prevention, 2) provide the first indication of whether exercise intensity reduces CVD risk via multi-level vasculature function vs. metabolic insulin action, and 3) provide a rational early treatment for people with metabolic syndrome to prevent/treat type 2 diabetes and CVD.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

91

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New Jersey
      • New Brunswick, New Jersey, United States, 08901
        • Rutgers University Loree Gymnasium

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

36 years to 66 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Male or female ≥40 and ≤80 years old.
  • Has a body mass index ≥25 and ≤47 kg/m2.
  • Not diagnosed with Type 2 or Type 1 diabetes
  • Not currently engaged in > 150 min/wk of exercise
  • Weight stable (<2kg weight change in past 3 months)
  • Non-smoking >5 years

At minimum, subject will have abdominal obesity (increased waist circumference as defined below) and may have any additional National Cholesterol Education Adult Treatment Panel III Metabolic Syndrome criteria:

  • Increased waist circumference (≥102 cm in men; ≥88 cm in women)
  • Elevated triglycerides (≥150 mg/dl), or on medication for treating the condition
  • Reduced HDL-cholesterol (<40mg/dl in men, <50 mg/dl in women), or on medication for treating the condition
  • High blood pressure (≥130 mmHg systolic or ≥85mmHg diastolic), or on medication for treating the condition
  • Elevated fasting glucose (≥100 mg/dl), or on medication for treating the condition
  • Other major risk factors to be noted based on the Framingham Risk Score
  • HbA1c 5.7-6.4%
  • LDL > 130 mg/dL
  • Family history of type 2 diabetes (immediate family, i.e. parent/sibling)
  • History of gestational diabetes
  • History of Polycystic Ovarian Syndrome
  • Family history of pre-mature cardiovascular disease (immediate family i.e. parent/sibling) before 55 for males or 65 for females that can include heart attack, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease or clinical coronary heart disease)
  • Age ( > 45 years old for men; > 55 years old for women)
  • Black/African American, Mexican, Asian, and/or Hispanic
  • Subjects currently taking medications that affect heart rate and rhythm (i.e. Ca++ channel blockers, nitrates, alpha- or beta-blockers)

Exclusion Criteria:

  • Subjects prescribed metformin or have taken metformin within 1 year.
  • Subjects with abnormal estimated glomerular filtration rate (eGFR).
  • Hypertriglyceridemic (>400 mg/dl) and hypercholesterolemic (>260 mg/dl) subjects
  • Hypertensive (>160/100 mmHg)
  • Subjects with a history of significant metabolic, cardiac, congestive heart failure, cerebrovascular, hematological, pulmonary, gastrointestinal, liver, renal, or endocrine disease or cancer that in the investigator's opinion would interfere with or alter the outcome measures, or impact subject safety.
  • Pregnant (as evidenced by positive pregnancy test) or nursing women
  • Subjects with contraindications to participation in an exercise training program
  • Currently taking active weight suppression medication (e.g. phentermine,orlistat, lorcaserin, naltrexone-bupropion in combination, liraglutide, benzphetamine, diethylpropion, phendimetrazine)
  • Known hypersensitivity to perflutren (contained in Definity)
  • Subjects who are considered non-English speaking individuals

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: LoEx with Placebo
Low intensity exercise with placebo.
Drug: Placebo
Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets.
Behavioral: Low Intensity Exercise
Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions.
Other Names:
  • LoEx
Placebo Comparator: HiEx with Placebo
High intensity exercise with placebo.
Drug: Placebo
Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets.
Behavioral: High Intensity Exercise
High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions.
Other Names:
  • HiEx
Active Comparator: LoEx with Metformin
Low intensity exercise with metformin.
Behavioral: Low Intensity Exercise
Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions.
Other Names:
  • LoEx
Drug: Metformin
Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d.
Active Comparator: HiEx with Metformin
High intensity exercise with metformin.
Behavioral: High Intensity Exercise
High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions.
Other Names:
  • HiEx
Drug: Metformin
Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery
Time Frame: 0 and 16 weeks
Endothelial function assessed as a percentage change in brachial artery diameter from baseline to deflation (5 minutes after artery occlusion by blood pressure cuff inflation). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
0 and 16 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR).
Time Frame: 0 and 16 weeks
The glucose infusion rate (mg/kg/min) divided by steady-state insulin (uU/mL) during a 120 minute euglycemic-hyperinsulinemic clamp provides an index of metabolic insulin sensitivity. Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
0 and 16 weeks
Change in Fasting Augmentation Index
Time Frame: 0 and 16 weeks
Measure of Arterial Stiffness calculated by dividing the augmentation pressure by the pulse pressure, then multiplying by 100 and normalizing to a heart rate of 75 bpm (AIx75). Delta = Week 16 - Week 0. Lower values and negative change scores following the intervention indicate a better outcome.
0 and 16 weeks
Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm.
Time Frame: 0 and 16 weeks
Product of microvascular blood volume (VI; video intensity units) and microvascular flow velocity (sec^-1). Insulin-stimulated microvascular blood flow is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
0 and 16 weeks
Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm.
Time Frame: 0 and 16 weeks
Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular flow velocity is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
0 and 16 weeks
Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm.
Time Frame: 0 and 16 weeks
Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular blood volume is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
0 and 16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rutgers University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Steven K Malin, PhD, Rutgers University - New Brunswick

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 7, 2017

Primary Completion (Actual)

March 11, 2024

Study Completion (Actual)

May 23, 2024

Study Registration Dates

First Submitted

November 7, 2017

First Submitted That Met QC Criteria

November 20, 2017

First Posted (Actual)

November 28, 2017

Study Record Updates

Last Update Posted (Estimated)

September 22, 2025

Last Update Submitted That Met QC Criteria

September 18, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 19364
  • 1R01HL130296-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Metabolic Syndrome

Clinical Trials on Placebo

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Slovenia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe