Exercise Dose and Metformin for Vascular Health in Adults With Metabolic Syndrome
Study Details
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 |
|---|---|---|
|
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
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 [At 0 and 16 weeks]
Measure of blood flow
Secondary Outcome Measures
- Change in Metabolic Insulin Sensitivity by the Euglycemic Clamp [At 0 and 16 weeks]
Measure of glucose metabolism
- Changes 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 Pulse Wave Velocity [At 0 and 16 weeks]
Measure of arterial stiffness
- Change in Augmentation Index [At 0 and 16 weeks]
Measure of arterial stiffness
- Change in Ambulatory Blood Pressure [At 0 and 16 weeks]
Measure of vascular health
Eligibility Criteria
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/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 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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Loree Gymnasium | New Brunswick | New Jersey | United States | 08901 |
| 2 | New Jersey Institute for Food, Nutrition & Health | New Brunswick | New Jersey | United States | 08901 |
| 3 | Rutgers Clinical Research Center | New Brunswick | New Jersey | United States | 08901 |
Sponsors and Collaborators
- Rutgers, The State University of New Jersey
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Steven K Malin, PhD, Rutgers, The State University of New Jersey
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Pro2020002029
- 5R01HL130296-04