Exercise Dose and Metformin for Vascular Health in Metabolic Syndrome

NCT03355469 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 193641R01HL130296-01A1
• Study Type: interventional
• Target: 91
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metabolic Syndrome

Outcome Measures

Primary Outcomes (1)

• Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery

  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 Outcomes (5)

• Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR).

  0 and 16 weeks

• Change in Fasting Augmentation Index

  0 and 16 weeks

• Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm.

  0 and 16 weeks

• Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm.

  0 and 16 weeks

• Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm.

  0 and 16 weeks

Study Arms (4)

LoEx with Placebo

PLACEBO COMPARATOR

Low intensity exercise with placebo.

Drug: Placebo; Behavioral: Low Intensity Exercise

HiEx with Placebo

PLACEBO COMPARATOR

High intensity exercise with placebo.

Drug: Placebo; Behavioral: High Intensity Exercise

LoEx with Metformin

ACTIVE COMPARATOR

Low intensity exercise with metformin.

Drug: Metformin; Behavioral: Low Intensity Exercise

HiEx with Metformin

ACTIVE COMPARATOR

High intensity exercise with metformin.

Drug: Metformin; Behavioral: High Intensity Exercise

Interventions

Metformin DRUG

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.

HiEx with Metformin; LoEx with Metformin

Placebo DRUG

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.

HiEx with Placebo; LoEx with Placebo

Low Intensity Exercise BEHAVIORAL

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.

Also known as: LoEx

LoEx with Metformin; LoEx with Placebo

High Intensity Exercise BEHAVIORAL

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.

Also known as: HiEx

HiEx with Metformin; HiEx with Placebo

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Rutgers University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Rutgers University Loree Gymnasium

New Brunswick, New Jersey, 08901, United States

Location

Related Publications (33)

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• Malin SK, Remchak ME, Heiston EM, Fabris C, Shah AM. Pancreatic beta-cell Function is Higher in Morning Versus Intermediate Chronotypes With Obesity. Obes Sci Pract. 2025 Feb 26;11(2):e70064. doi: 10.1002/osp4.70064. eCollection 2025 Apr.

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  PMID: 35429387 DERIVED

MeSH Terms

Conditions

Metabolic Syndrome

Interventions

Metformin; High-Intensity Interval Training

Condition Hierarchy (Ancestors)

Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Physical Conditioning, Human; Exercise; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Limitations and Caveats

Due to unforeseen technical issues with the vascular imaging files, we were regrettably unable to analyze the endothelial function data (FMD) for a majority of participants who had been randomized to HiEx with Metformin group, as well as others in the remaining 3 treatment groups.

Results Point of Contact

• Title: Dr. Steven Malin
• Organization: Rutgers University

steven.malin@rutgers.edu

848-932-705

Study Officials

• Steven K Malin, PhD

  Rutgers University - New Brunswick

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Each subject will be randomly assigned to receive low intensity exercise training + placebo, high intensity exercise training + placebo, or these exercise programs with metformin.

Study Record Dates

• First Submitted: November 7, 2017
• First Posted: November 28, 2017
• Study Start: August 7, 2017
• Primary Completion: March 11, 2024
• Study Completion: May 23, 2024
• Last Updated: September 22, 2025
• Results First Posted: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)