Metformin in the Diastolic Dysfunction of Metabolic Syndrome (MET-DIME)
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|ClinicalTrials.gov Identifier: NCT02017561|
Recruitment Status : Active, not recruiting
First Posted : December 20, 2013
Last Update Posted : April 20, 2017
Metabolic syndrome (MS) is a cluster of risk factors for cardiovascular disease with increasing prevalence worldwide and insulin resistance is central to its pathophysiology and multi-organ deleterious effects. One of the most affected organs, the heart, undergoes a remodeling process with an increase in fibrous tissue that impairs global cardiac function. Considering that myocardial fibrosis increases myocardial stiffness, one important determinant of diastolic function, it probably contributes decisively to subclinical left ventricular diastolic dysfunction (DD) and heart failure with preserved ejection fraction in patients with MS.
Since insulin resistance is a dominant player in the pathophysiology of MS, improvement of the metabolic profile of these patients with metformin might be associated with favorable remodeling of myocardial structure and an improvement in myocardial function. Metformin is a widely used drug to treat type 2 diabetes mellitus and is considered an option in the treatment of high-risk non-diabetic patients with MS, in addition to lifestyle counseling including a healthy diet and physical activity.
In this way, we aim to: i) assess if treating non-diabetic patients with MS and DD with metformin in addition to lifestyle counseling decreases cardiac fibrosis and improves diastolic function and assess its impact in functional capacity and health-related quality of life (HRQoL); ii) evaluate if biomarkers of cardiac remodeling and inflammation are predictive factors of response to metformin treatment in these patients.
This is a prospective, randomized, open-label, blinded-endpoint (PROBE) trial (scheduled follow-up of 24 months) with 2 arms: lifestyle counseling only and lifestyle counseling plus metformin (maximum dose of 1000mg twice daily).
The primary endpoint will be change in change in mean of septal and lateral early diastolic mitral annular velocities (E') (at the end of the 24 months of follow-up).
The secondary endpoints will include a composite of major cardiovascular events; diastolic function parameters at rest; plasma levels of insulin, glucose, insulin resistance index, NTproBNP, high-sensitivity C-reactive protein, tumor necrosis factor-α (TNFα), tissue inhibitor of matrix metalloproteinase type 1 (TIMP1) and growth differentiation factor-15 (GDF-15); functional capacity; epicardial, pericardial and abdominal adipose tissue volumes, and coronary calcium score; HRQoL.
|Condition or disease||Intervention/treatment||Phase|
|Metabolic Syndrome X Diastolic Dysfunction Insulin Resistance||Behavioral: Lifestyle Counseling Drug: Metformin||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||54 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Single (Outcomes Assessor)|
|Official Title:||Metformin in the Diastolic Dysfunction of Metabolic Syndrome: MET-DIME Trial|
|Study Start Date :||January 2014|
|Estimated Primary Completion Date :||November 2017|
|Estimated Study Completion Date :||November 2017|
Active Comparator: Lifestyle Counseling
Written and individualized information during the interview in all clinic visits, emphasizing the importance of regular moderate-intensity physical activity and healthy diet.
Behavioral: Lifestyle Counseling
Written and individualized information during the interview in all clinic visits, emphasizing the importance of a healthy lifestyle, engaging on regular moderate-intensity physical activity and eating an healthy diet.
Experimental: Metformin + Lifestyle Counseling
Metformin: maximum dose of 1000mg twice daily. Lifestyle counseling: Written and individualized information during the interview in all clinic visits, emphasizing the importance of regular moderate-intensity physical activity and healthy diet.
Behavioral: Lifestyle Counseling
Written and individualized information during the interview in all clinic visits, emphasizing the importance of a healthy lifestyle, engaging on regular moderate-intensity physical activity and eating an healthy diet.Drug: Metformin
Metformin treatment titrated to a maximum dose of 1000mg twice a day. Metformin treatment will start with 500mg at breakfast during the first week and, if well tolerated, increased to 500mg twice a day (breakfast and dinner) in the second week, 1000mg at breakfast and 500mg at dinner in the third week and finally for the target dose of 1000mg twice a day.
- Change in mean early diastolic mitral annular velocity (cm/s) [ Time Frame: Baseline, 6,12 and 24 months ]Change in mean of septal and lateral early diastolic mitral annular velocities (E'), assessed by tissue doppler echocardiography
- Major adverse cardiovascular events [ Time Frame: 12 and 24 months ]Composite outcome of major cardiovascular events: nonfatal myocardial infarction, nonfatal stroke, death judged to be due to cardiovascular causes, hospitalization for heart failure, angina confirmed by ischemic changes on exercise tolerance testing or by clinically significant obstruction on coronary angiography or need for revascularization with angioplasty or coronary-artery bypass grafting.
- Diastolic echocardiographic parameters [ Time Frame: Baseline, 6, 12, 24 months ]E/E´ ratio, isovolumetric relaxation time (IVRT), E/A ratio, mitral deceleration time, grade of diastolic dysfunction according to the consensus document of the American Society of Echocardiography and European Society of Echocardiography, strain rate during isovolumetric relaxation (SR-IVR) and E/SR-IVR ratio.
- Plasma levels of inflammatory and metabolic biomarkers [ Time Frame: Baseline, 6, 12, 24 months ]Plasma levels of insulin, glucose, insulin resistance index, NTproBNP, high-sensitivity C-reactive protein, TNFα, TIMP1 e GDF-15 (growth differentiation factor 15).
- Functional capacity during cardiopulmonary exercise test [ Time Frame: Baseline, 12, 24 months ]Functional capacity during cardiopulmonary exercise test: all patients will perform a symptom-limited treadmill exercise testing according to modified Bruce protocol, with simultaneous respiratory gas analysis. Peak oxygen uptake, anaerobic threshold and ventilatory efficiency will be determined.
- Epicardial, pericardial and abdominal adipose tissue volumes [ Time Frame: Baseline, 24 months ]Cardiac multidetector CT without contrast administration to measure epicardial, pericardial and abdominal adipose tissue volumes
- Coronary artery calcium quantification [ Time Frame: Baseline, 24 months ]Cardiac multidetector CT without contrast administration to assess coronary artery calcification (calcium score)
- Healthcare related quality of life [ Time Frame: Baseline, 12, 24 months ]The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) will be used to assess general health status and HRQoL.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02017561
|Gaia/Espinho Hospital Centre|
|Vila Nova de Gaia, Portugal, 4434-502|
|Principal Investigator:||Ricardo Ladeiras-Lopes, MD||Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto|
|Study Chair:||Adelino F Leite-Moreira, MD,PhD,FETCS||Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto|
|Study Chair:||Vasco Gama, MD||Department of Cardiology, Gaia/Espinho Hospital Centre|