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

December 23, 2022 updated by: Steven K Malin, PhD, Rutgers, The State University of New Jersey
Arterial disease is the leading cause of morbidity/mortality in Metabolic syndrome (MetS). This occurs early as evidenced by arterial dysfunction that, in turn, raises blood pressure and glucose. 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 risk. However, the optimal exercise dose to be combined with metformin for additive effects on vascular function is unknown. Based on the investigator's preliminary work, the overall hypothesis is that metformin blunts adaptation following high intensity exercise training (HiEx) by lowering mitochondrial derived oxidative stress signaling. The investigators further hypothesize that low intensity exercise (LoEx) training combined with metformin will promote additive effects on vascular function compared to LoEx or HiEx+metformin, and maintain/improve non-exercise physical activity patterns. In this double-blind trial, obese 30-60y MetS participants will be randomized to: 1) LoEx+placebo; 2) LoEx+metformin, 3) HiEx+placebo; or 4) HiEx+metformin for 16 weeks.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The purpose of this study is to evaluate whether combining different intensities of exercise (specifically low and high-intensity) with the drug metformin has the potential to outperform either exercise intensity alone and improve blood flow in individuals with metabolic syndrome. Metformin is a commonly used drug to help manage blood sugar. This study is being done because of the high prevalence of both type 2 diabetes and metabolic syndrome in the United States. Metabolic syndrome refers to a group of risk factors that raises an individual's risk for heart disease, strokes, type 2 diabetes, and other health problems. These risk factors include a large waistline, high levels of fat in the blood, high blood pressure and high fasting blood sugars. By adding manageable amounts of physical activity and taking the drug metformin, it is conceivable that individuals could greatly reduce their risk of developing type 2 diabetes and/or cardiovascular disease. Therefore, the objective of the investigator's research is to understand how metformin effects both vascular (related to blood flow) and metabolic (related to the body's normal biochemical processes)insulin sensitivity in adults with metabolic syndrome and the role of training intensity on these factors. The term insulin sensitivity refers to how the body's cells react to glucose, also known as blood sugar. In individuals that are insulin sensitive, their cells are better able to process the glucose to use for energy and other metabolic processes. In individuals that are insulin resistant, or who have a lower sensitivity, their cells are not able to efficiently use the available blood glucose, which results in higher blood glucose levels that can lead to negative health outcomes, including the development of type 2 diabetes. The overarching hypothesis is that metformin may blunt the adaptation following high intensity exercise by lowering the amount of oxidative stress. Oxidative stress refers to an imbalance of the body's reactive oxygen species and the body's ability to detoxify these chemical molecules to reduce inflammation and damage. Thus, compared with high intensity exercise plus metformin, low intensity exercise plus metformin will produce greater vascular and metabolic insulin sensitivity changes following 16 weeks of treatment.

In addition, the investigators anticipate that high intensity exercise based training alone will produce greater effects than low intensity exercise. Lastly, the investigators hypothesize that these changes in metabolic and insulin sensitivity will correlate with glycemic control (the ability to control blood sugar) and blood pressure changes.

Study Type

Interventional

Enrollment (Anticipated)

80

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 Contact

Study Contact Backup

Study Locations

  • United States
    • New Jersey
      • New Brunswick, New Jersey, United States, 08901
        • Recruiting
        • Loree Gymnasium
        • Contact:
      • New Brunswick, New Jersey, United States, 08901
        • Recruiting
        • New Jersey Institute for Food, Nutrition & Health
        • Contact:
      • New Brunswick, New Jersey, United States, 08901
        • Recruiting
        • Rutgers Clinical Research Center
        • Contact:

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

40 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male or female ≥ 40 and ≤ 80 years old
  • Has a body mass index ≥ 25 and ≤ 47 kg/m^2
  • Not diagnosed with Type 2 diabetes
  • Not currently engaged in > 150 min/wk of exercise
  • At minimum, subjects 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 (< 40 mg/dl in men, < 50 mg/dl in women), or on medication for treating the condition
  • High blood pressure (≥ 130 mmHg systolic or ≥ 85 mmHg diastolic), or on medication for treating the condition
  • Elevated fasting glucose (≥ 100 mg/dl), or on medication for treating the condition
  • Subjects currently taking medications that affect heart rate and rhythm (i.e. calcium-channel blockers, nitrates, alpha- or beta-blockers)
  • 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

Exclusion Criteria:

  • Morbidly obese patients (BMI > 47 kg/m^2) and overweight/lean patients (BMI < 27 kg/m^2)
  • Evidence of type 1 diabetes and diabetics requiring insulin therapy
  • Subjects who have not been weight stable (> 2 kg weight change in past 3 months)
  • Subjects who have not been recently active (> 30 min of moderate/high intensity exercise, 2 times/week)
  • Subjects who are smokers or who have quit smoking < 5 years ago
  • 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 microbubbles)
  • 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+Placebo

Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions while receiving placebo.

Drug: Low Intensity Exercise + Placebo

Low Intensity Exercise (LoEx) measured by a percentage of maximal heart rate in combination with placebo.
Behavioral: Exercise
Either low intensity or high intensity exercise
Drug: Placebo
Will be randomized to receive either the placebo or metformin drug
Placebo Comparator: HiEx+Placebo

Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions while receiving placebo.

Drug: High Intensity Exercise + Placebo

High Intensity Exercise (HiEx) measured by a percentage of maximal heart rate in combination with placebo.
Behavioral: Exercise
Either low intensity or high intensity exercise
Drug: Placebo
Will be randomized to receive either the placebo or metformin drug
Active Comparator: LoEx+Metformin

Subjects randomly assigned to this group will participate in the same 3 supervised training sessions and 2 unsupervised training sessions, but they will be provided Metformin. Metformin is a common medication routinely used to treat high blood sugar and has secondary effects on vascular health. Subjects will not find out whether or not they are on Metformin until after the study is complete. If their doctor needs to know, the people doing this study can find out.

Drug: Low Intensity Exercise + Metformin

Low Intensity Exercise (LoEx) measured by a percentage of maximal heart rate in combination with placebo.
Behavioral: Exercise
Either low intensity or high intensity exercise
Drug: Metformin
Taken if randomized to exercise + metformin group (either low or high intensity exercise)
Active Comparator: HiEx+Metformin

Subjects randomly assigned to this group will participate in the same HiEx 3 supervised training sessions and 2 unsupervised training sessions, but they will be provided Metformin.

Drug: High Intensity Exercise + Metformin

High Intensity Exercise (HiEx) measured by a percentage of maximal heart rate in combination with placebo.
Behavioral: Exercise
Either low intensity or high intensity exercise
Drug: Metformin
Taken if randomized to exercise + metformin group (either low or high intensity exercise)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Flow Mediated Dilation of Brachial Artery
Time Frame: At 0 and 16 weeks
Measure of blood flow
At 0 and 16 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Metabolic Insulin Sensitivity by the Euglycemic Clamp
Time Frame: At 0 and 16 weeks
Measure of glucose metabolism
At 0 and 16 weeks
Changes in Post Ischemic Flow Velocity in Brachial Artery
Time Frame: At 0 and 16 weeks
Measure of blood flow
At 0 and 16 weeks
Change in Contrast Enhanced Ultrasound
Time Frame: At 0 and 16 weeks
Measure of microvascular blood flow
At 0 and 16 weeks
Change in Pulse Wave Velocity
Time Frame: At 0 and 16 weeks
Measure of arterial stiffness
At 0 and 16 weeks
Change in Augmentation Index
Time Frame: At 0 and 16 weeks
Measure of arterial stiffness
At 0 and 16 weeks
Change in Ambulatory Blood Pressure
Time Frame: At 0 and 16 weeks
Measure of vascular health
At 0 and 16 weeks

Collaborators and Investigators

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

Sponsor

Rutgers, The State University of New Jersey

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Steven K Malin, PhD, Rutgers, The State University of New Jersey

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)

November 28, 2017

Primary Completion (Anticipated)

March 1, 2024

Study Completion (Anticipated)

May 1, 2025

Study Registration Dates

First Submitted

March 15, 2021

First Submitted That Met QC Criteria

March 23, 2021

First Posted (Actual)

March 26, 2021

Study Record Updates

Last Update Posted (Actual)

December 30, 2022

Last Update Submitted That Met QC Criteria

December 23, 2022

Last Verified

December 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro2020002029
  • 5R01HL130296-04 (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.

Yes

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.

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