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

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ClinicalTrials.gov Identifier: NCT04817787
Recruitment Status : Recruiting
First Posted : March 26, 2021
Last Update Posted : January 13, 2022
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Steven K Malin, PhD, Rutgers, The State University of New Jersey

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metabolic Syndrome Insulin Sensitivity Vascular Stiffness Drug: Metformin Behavioral: Exercise Drug: Placebo Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Exercise Dose and Metformin for Vascular Health in Adults With Metabolic Syndrome
Actual Study Start Date : May 1, 2021
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : May 2025

Resource links provided by the National Library of Medicine


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.

Drug: Metformin
Taken if randomized to exercise + metformin group (either low or high intensity exercise)

Behavioral: Exercise
Either low intensity 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.

Drug: Metformin
Taken if randomized to exercise + metformin group (either low or high intensity exercise)

Behavioral: Exercise
Either low intensity or high intensity exercise




Primary Outcome Measures :
  1. Change in Flow Mediated Dilation of Brachial Artery [ Time Frame: At 0 and 16 weeks ]
    Measure of blood flow


Secondary Outcome Measures :
  1. Change in Metabolic Insulin Sensitivity by the Euglycemic Clamp [ Time Frame: At 0 and 16 weeks ]
    Measure of glucose metabolism

  2. Changes in Post Ischemic Flow Velocity in Brachial Artery [ Time Frame: At 0 and 16 weeks ]
    Measure of blood flow

  3. Change in Contrast Enhanced Ultrasound [ Time Frame: At 0 and 16 weeks ]
    Measure of microvascular blood flow

  4. Change in Pulse Wave Velocity [ Time Frame: At 0 and 16 weeks ]
    Measure of arterial stiffness

  5. Change in Augmentation Index [ Time Frame: At 0 and 16 weeks ]
    Measure of arterial stiffness

  6. Change in Ambulatory Blood Pressure [ Time Frame: At 0 and 16 weeks ]
    Measure of vascular health



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female ≥ 40 and ≤ 80 years old
  • Has a body mass index ≥ 27 and ≤ 47 kg/m^2
  • Not diagnosed with Type 2 diabetes
  • Not currently engaged in > 60 min/wk of exercise
  • Meet at least 3 of 5 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)

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04817787


Contacts
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Contact: Steven K Malin, PhD 848-932-9525 steven.malin@rutgers.edu
Contact: Jaclyn Dosik, MEd 240-676-6789 jaclyn.dosik@rutgers.edu

Locations
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United States, New Jersey
Loree Gymnasium Recruiting
New Brunswick, New Jersey, United States, 08901
Contact: Steven K Malin, PhD    848-932-9525    steve.malin@rutgers.edu   
New Jersey Institute for Food, Nutrition & Health Recruiting
New Brunswick, New Jersey, United States, 08901
Contact: Steven K Malin, PhD    848-932-9525    steven.malin@rutgers.edu   
Rutgers Clinical Research Center Recruiting
New Brunswick, New Jersey, United States, 08901
Contact: Steven K Malin, PhD    848-932-9525    steven.malin@rutgers.edu   
Sponsors and Collaborators
Rutgers, The State University of New Jersey
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Steven K Malin, PhD Rutgers, The State University of New Jersey
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Responsible Party: Steven K Malin, PhD, PhD, FACSM, Associate Professor, Rutgers, The State University of New Jersey
ClinicalTrials.gov Identifier: NCT04817787    
Other Study ID Numbers: Pro2020002029
5R01HL130296-04 ( U.S. NIH Grant/Contract )
First Posted: March 26, 2021    Key Record Dates
Last Update Posted: January 13, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Metabolic Syndrome
Insulin Resistance
Syndrome
Disease
Pathologic Processes
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs