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

Metabolic Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04817787
• Other study ID #: Pro2020002029
• Secondary ID: 5R01HL130296-04
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: November 28, 2017
• Est. completion date: May 2025

Study information

• Verified date: December 2022
• Source: Rutgers, The State University of New Jersey
• Contact: Steven K Malin, PhD
• Phone: 848-932-9525
• Email: steven.malin[@]rutgers.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: May 2025
• Est. primary completion date: March 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Insulin Resistance
• Insulin Sensitivity
• Metabolic Syndrome
• Syndrome
• Vascular Stiffness

Intervention

Drug:
• Metformin
Taken if randomized to exercise + metformin group (either low or high intensity exercise)

Behavioral:
• Exercise
Either low intensity or high intensity exercise

Drug:
• Placebo
Will be randomized to receive either the placebo or metformin drug

Locations

Country	Name	City	State
United States	Loree Gymnasium	New Brunswick	New Jersey
United States	New Jersey Institute for Food, Nutrition & Health	New Brunswick	New Jersey
United States	Rutgers Clinical Research Center	New Brunswick	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Rutgers, The State University of New Jersey	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (30)

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Vincent MA, Clerk LH, Lindner JR, Price WJ, Jahn LA, Leong-Poi H, Barrett EJ. Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1191-7. doi: 10.1152/ajpendo.00497.2005. — View Citation

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* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Flow Mediated Dilation of Brachial Artery	Measure of blood flow	At 0 and 16 weeks
Secondary	Change in Metabolic Insulin Sensitivity by the Euglycemic Clamp	Measure of glucose metabolism	At 0 and 16 weeks
Secondary	Changes in Post Ischemic Flow Velocity in Brachial Artery	Measure of blood flow	At 0 and 16 weeks
Secondary	Change in Contrast Enhanced Ultrasound	Measure of microvascular blood flow	At 0 and 16 weeks
Secondary	Change in Pulse Wave Velocity	Measure of arterial stiffness	At 0 and 16 weeks
Secondary	Change in Augmentation Index	Measure of arterial stiffness	At 0 and 16 weeks
Secondary	Change in Ambulatory Blood Pressure	Measure of vascular health	At 0 and 16 weeks