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

Primary Purpose

Metabolic Syndrome, Insulin Sensitivity, Vascular Stiffness

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Metformin

Exercise

Placebo

About this trial

This is an interventional prevention trial for Metabolic Syndrome

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Loree GymnasiumRecruiting
New Jersey Institute for Food, Nutrition & HealthRecruiting
Rutgers Clinical Research CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Arm Label

LoEx+Placebo

HiEx+Placebo

LoEx+Metformin

HiEx+Metformin

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Change in Flow Mediated Dilation of Brachial Artery

Measure of blood flow

Secondary Outcome Measures

Change in Metabolic Insulin Sensitivity by the Euglycemic Clamp

Measure of glucose metabolism

Changes in Post Ischemic Flow Velocity in Brachial Artery

Measure of blood flow

Change in Contrast Enhanced Ultrasound

Measure of microvascular blood flow

Change in Pulse Wave Velocity

Measure of arterial stiffness

Change in Augmentation Index

Measure of arterial stiffness

Change in Ambulatory Blood Pressure

Measure of vascular health

Full Information

NCT ID

NCT04817787

First Posted

March 15, 2021

Last Updated

December 23, 2022

Sponsor

Rutgers, The State University of New Jersey

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT04817787

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 28, 2017 (Actual)

Primary Completion Date

March 2024 (Anticipated)

Study Completion Date

May 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Rutgers, The State University of New Jersey

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metabolic Syndrome, Insulin Sensitivity, Vascular Stiffness

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

LoEx+Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

HiEx+Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

LoEx+Metformin

Arm Type

Active Comparator

Arm Description

Arm Title

HiEx+Metformin

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

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

Intervention Type

Behavioral

Intervention Name(s)

Exercise

Intervention Description

Either low intensity or high intensity exercise

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Will be randomized to receive either the placebo or metformin drug

Primary Outcome Measure Information:

Title

Change in Flow Mediated Dilation of Brachial Artery

Description

Measure of blood flow

Time Frame

At 0 and 16 weeks

Secondary Outcome Measure Information:

Title

Change in Metabolic Insulin Sensitivity by the Euglycemic Clamp

Description

Measure of glucose metabolism

Time Frame

At 0 and 16 weeks

Title

Changes in Post Ischemic Flow Velocity in Brachial Artery

Description

Measure of blood flow

Time Frame

At 0 and 16 weeks

Title

Change in Contrast Enhanced Ultrasound

Description

Measure of microvascular blood flow

Time Frame

At 0 and 16 weeks

Title

Change in Pulse Wave Velocity

Description

Measure of arterial stiffness

Time Frame

At 0 and 16 weeks

Title

Change in Augmentation Index

Description

Measure of arterial stiffness

Time Frame

At 0 and 16 weeks

Title

Change in Ambulatory Blood Pressure

Description

Measure of vascular health

Time Frame

At 0 and 16 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Steven K Malin, PhD

Phone

848-932-9525

steven.malin@rutgers.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Jaclyn Dosik, MEd

Phone

240-676-6789

jaclyn.dosik@rutgers.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Steven K Malin, PhD

Organizational Affiliation

Rutgers, The State University of New Jersey

Official's Role

Principal Investigator

Facility Information:

Facility Name

Loree Gymnasium

City

New Brunswick

State/Province

New Jersey

ZIP/Postal Code

08901

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Steven K Malin, PhD

Phone

848-932-9525

steve.malin@rutgers.edu

Facility Name

New Jersey Institute for Food, Nutrition & Health

City

New Brunswick

State/Province

New Jersey

ZIP/Postal Code

08901

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Steven K Malin, PhD

Phone

848-932-9525

steven.malin@rutgers.edu

Facility Name

Rutgers Clinical Research Center

City

New Brunswick

State/Province

New Jersey

ZIP/Postal Code

08901

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Steven K Malin, PhD

Phone

848-932-9525

steven.malin@rutgers.edu

12. IPD Sharing Statement

Plan to Share IPD

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

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