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

Study Overview
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Brief Summary
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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.

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

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Drug: Low Intensity Exercise + Metformin
* Drug: High Intensity Exercise + Metformin
* Drug: Low Intensity Exercise + Placebo
* Drug: High Intensity Exercise + Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female >40 and <70 years old. Has a body mass index >27 and <47 kg/m2. 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 (<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 Exclusion Criteria: Morbidly obese patients (BMI >47 kg/m2) and overweight/lean patients (BMI <27 kg/m2) 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 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 currently taking medications that affect heart rate and rhythm (i.e. Ca++ channel blockers, nitrates, alpha- or beta-blockers). 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, benzephetamine, diethylpropion, phendimetrazine) Known hypersensitivity to perflutren (contained in Definity)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: LoEx+placebo<br>Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions and receive placebo. | Drug: Low Intensity Exercise + Placebo<br>* Low Intensity exercise (LoEx) measured by a percentage of maximal heart rate in combination with placebo.<br>|
| Placebo Comparator: HiEx+placebo<br>Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions and receive placebo. | Drug: High Intensity Exercise + Placebo<br>* High Intensity exercise (HiEx) measured by a percentage of maximal heart rate in combination with placebo.<br>|
| Active Comparator: LoEx+metformin<br>If subjects are assigned to this group they will participate in the same LoEx exercise program as outlined above. But, here 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 be able to find out if you are on metformin until the study is done. If their doctor needs to know, the people doing this study can find out. | Drug: Low Intensity Exercise + Metformin<br>* Low Intensity exercise (LoEx) measured by a percentage of maximal heart rate in combination with metformin.<br>|
| Active Comparator: HiEx+metformin<br>If subjects are assigned to this group you will participate in the same HiEx exercise program and receive metformin as outlined above. | Drug: High Intensity Exercise + Metformin<br>* High Intensity exercise (HiEx) measured by a percentage of maximal heart rate in combination with metformin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Flow Mediated Dilation of brachial artery | 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 | Measure of glucose metabolism | At 0 and 16 weeks | 
| Change in Post Ischemic Flow Velocity in brachial artery | Measure of blood flow | At 0 and 16 weeks | 
| Change in Contrast Enhanced Ultrasound | Measure of Microvascular blood flow | At 0 and 16 weeks | 
| Change in Pulse Wave Velocity | Measure of Arterial Stiffness | At 0 and 16 weeks | 
| Change in Augmentation Index | Measure of Arterial Stiffness | At 0 and 16 weeks | 
| Change in Ambulatory Blood Pressure | Measure of Vascular health | At 0 and 16 weeks |