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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
First received
Last updated
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
Health authority
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

Study Design


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)

Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, Hildebrand K, Fung M, Verma S, Lonn EM. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation. 2011 Jan 18;123(2):163-9. doi: 10.1161/CIRCULATIONAHA.110.953653. Epub 2011 Jan 3. — View Citation

Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E252-63. doi: 10.1152/ajpendo.00186.2011. Epub 2011 May 24. — View Citation

Bateman LA, Slentz CA, Willis LH, Shields AT, Piner LW, Bales CW, Houmard JA, Kraus WE. Comparison of aerobic versus resistance exercise training effects on metabolic syndrome (from the Studies of a Targeted Risk Reduction Intervention Through Defined Exercise - STRRIDE-AT/RT). Am J Cardiol. 2011 Sep 15;108(6):838-44. doi: 10.1016/j.amjcard.2011.04.037. Epub 2011 Jul 7. — View Citation

Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006 May;55(5):1436-42. doi: 10.2337/db05-1373. — View Citation

Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation. 2002 Oct 15;106(16):2085-90. doi: 10.1161/01.cir.0000033824.02722.f7. — View Citation

DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol. 2011 Aug 2;108(3 Suppl):3B-24B. doi: 10.1016/j.amjcard.2011.03.013. — View Citation

Donley DA, Fournier SB, Reger BL, DeVallance E, Bonner DE, Olfert IM, Frisbee JC, Chantler PD. Aerobic exercise training reduces arterial stiffness in metabolic syndrome. J Appl Physiol (1985). 2014 Jun 1;116(11):1396-404. doi: 10.1152/japplphysiol.00151.2014. Epub 2014 Apr 17. — View Citation

Eggleston EM, Jahn LA, Barrett EJ. Early microvascular recruitment modulates subsequent insulin-mediated skeletal muscle glucose metabolism during lipid infusion. Diabetes Care. 2013 Jan;36(1):104-10. doi: 10.2337/dc11-2399. Epub 2012 Sep 6. — View Citation

Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol. 2003 May 21;41(10):1769-75. doi: 10.1016/s0735-1097(03)00333-4. — View Citation

Green DJ, Eijsvogels T, Bouts YM, Maiorana AJ, Naylor LH, Scholten RR, Spaanderman ME, Pugh CJ, Sprung VS, Schreuder T, Jones H, Cable T, Hopman MT, Thijssen DH. Exercise training and artery function in humans: nonresponse and its relationship to cardiovascular risk factors. J Appl Physiol (1985). 2014 Aug 15;117(4):345-52. doi: 10.1152/japplphysiol.00354.2014. Epub 2014 Jun 19. — View Citation

Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Fernando Costa. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary. Crit Pathw Cardiol. 2005 Dec;4(4):198-203. doi: 10.1097/00132577-200512000-00018. No abstract available. — View Citation

Keske MA, Clerk LH, Price WJ, Jahn LA, Barrett EJ. Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal. Diabetes Care. 2009 Sep;32(9):1672-7. doi: 10.2337/dc09-0206. Epub 2009 Jun 1. — View Citation

Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, Boutouyrie P. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke. 2003 May;34(5):1203-6. doi: 10.1161/01.STR.0000065428.03209.64. Epub 2003 Apr 3. — View Citation

Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z. Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab. 2011 Feb;96(2):438-46. doi: 10.1210/jc.2010-1174. Epub 2010 Nov 3. — View Citation

Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. 2009 Sep;94(9):3543-9. doi: 10.1210/jc.2009-0027. Epub 2009 Jun 30. — View Citation

Malin SK, Braun B. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk. Exerc Sport Sci Rev. 2016 Jan;44(1):4-11. doi: 10.1249/JES.0000000000000070. — View Citation

Malin SK, Gerber R, Chipkin SR, Braun B. Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care. 2012 Jan;35(1):131-6. doi: 10.2337/dc11-0925. Epub 2011 Oct 31. — View Citation

Malin SK, Niemi N, Solomon TP, Haus JM, Kelly KR, Filion J, Rocco M, Kashyap SR, Barkoukis H, Kirwan JP. Exercise training with weight loss and either a high- or low-glycemic index diet reduces metabolic syndrome severity in older adults. Ann Nutr Metab. 2012;61(2):135-41. doi: 10.1159/000342084. — View Citation

Malin SK, Nightingale J, Choi SE, Chipkin SR, Braun B. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults. Obesity (Silver Spring). 2013 Jan;21(1):93-100. doi: 10.1002/oby.20235. — View Citation

Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001 Apr;37(5):1344-50. doi: 10.1016/s0735-1097(01)01129-9. — View Citation

Mestek ML, Westby CM, Van Guilder GP, Greiner JJ, Stauffer BL, DeSouza CA. Regular aerobic exercise, without weight loss, improves endothelium-dependent vasodilation in overweight and obese adults. Obesity (Silver Spring). 2010 Aug;18(8):1667-9. doi: 10.1038/oby.2009.467. Epub 2010 Jan 7. — View Citation

Patel C, Ghanim H, Ravishankar S, Sia CL, Viswanathan P, Mohanty P, Dandona P. Prolonged reactive oxygen species generation and nuclear factor-kappaB activation after a high-fat, high-carbohydrate meal in the obese. J Clin Endocrinol Metab. 2007 Nov;92(11):4476-9. doi: 10.1210/jc.2007-0778. Epub 2007 Sep 4. — View Citation

Phillips SA, Mahmoud AM, Brown MD, Haus JM. Exercise interventions and peripheral arterial function: implications for cardio-metabolic disease. Prog Cardiovasc Dis. 2015 Mar-Apr;57(5):521-34. doi: 10.1016/j.pcad.2014.12.005. Epub 2014 Dec 18. — View Citation

Potteiger JA, Claytor RP, Hulver MW, Hughes MR, Carper MJ, Richmond S, Thyfault JP. Resistance exercise and aerobic exercise when paired with dietary energy restriction both reduce the clinical components of metabolic syndrome in previously physically inactive males. Eur J Appl Physiol. 2012 Jun;112(6):2035-44. doi: 10.1007/s00421-011-2174-y. Epub 2011 Sep 23. — View Citation

Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, Brancati FL. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008 Oct 27;168(19):2070-80. doi: 10.1001/archinte.168.19.2070. — View Citation

Swift DL, Weltman JY, Patrie JT, Saliba SA, Gaesser GA, Barrett EJ, Weltman A. Predictors of improvement in endothelial function after exercise training in a diverse sample of postmenopausal women. J Womens Health (Larchmt). 2014 Mar;23(3):260-6. doi: 10.1089/jwh.2013.4420. Epub 2013 Dec 3. — View Citation

Tjonna AE, Lee SJ, Rognmo O, Stolen TO, Bye A, Haram PM, Loennechen JP, Al-Share QY, Skogvoll E, Slordahl SA, Kemi OJ, Najjar SM, Wisloff U. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation. 2008 Jul 22;118(4):346-54. doi: 10.1161/CIRCULATIONAHA.108.772822. Epub 2008 Jul 7. — View Citation

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

Vitale C, Mercuro G, Cornoldi A, Fini M, Volterrani M, Rosano GM. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med. 2005 Sep;258(3):250-6. doi: 10.1111/j.1365-2796.2005.01531.x. — View Citation

Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010 Mar 30;55(13):1318-27. doi: 10.1016/j.jacc.2009.10.061. — View Citation

* Note: There are 30 references in allClick 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
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