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

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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

Study Description

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.

Study Design

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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

MedlinePlus related topics: Exercise for Older Adults Metabolic Syndrome

Drug Information available for: Metformin Metformin hydrochloride

U.S. FDA Resources

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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

Contacts and Locations

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

More Information

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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

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