Exercise Dose and Metformin for Vascular Health in Metabolic Syndrome

Phase 2

Completed

Interventions: Drug: High Intensity Exercise + Placebo
Drug: Low Intensity Exercise + Metformin
Drug: High Intensity Exercise + Metformin
Drug: Low Intensity Exercise + Placebo

Brief Summary: 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.

Recruitment & Eligibility

Inclusion Criteria

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)

Arm && Interventions

Group	Intervention	Description
HiEx+placebo	High Intensity Exercise + Placebo	Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions and receive placebo.
LoEx+metformin	Low Intensity Exercise + Metformin	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.
HiEx+metformin	High Intensity Exercise + Metformin	If subjects are assigned to this group you will participate in the same HiEx exercise program and receive metformin as outlined above.
LoEx+placebo	Low Intensity Exercise + Placebo	Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions and receive placebo.

Primary Outcome Measures

Name	Time	Method
Change in Flow Mediated Dilation of brachial artery	At 0 and 16 weeks	Measure of blood flow

Secondary Outcome Measures

Name	Time	Method
Change in Ambulatory Blood Pressure	At 0 and 16 weeks	Measure of Vascular health
Change in Metabolic Insulin Sensitivity by the Euglycemic Clamp	At 0 and 16 weeks	Measure of glucose metabolism
Change in Post Ischemic Flow Velocity in brachial artery	At 0 and 16 weeks	Measure of blood flow
Change in Contrast Enhanced Ultrasound	At 0 and 16 weeks	Measure of Microvascular blood flow
Change in Augmentation Index	At 0 and 16 weeks	Measure of Arterial Stiffness
Change in Pulse Wave Velocity	At 0 and 16 weeks	Measure of Arterial Stiffness