Metformin in the Diastolic Dysfunction of Metabolic Syndrome (MET-DIME)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Universidade do Porto
Sponsor:
Collaborators:
Centro Hospitalar de Vila Nova de Gaia/Espinho
Merck Serono International SA
Information provided by (Responsible Party):
Ricardo Ladeiras-Lopes, Universidade do Porto
ClinicalTrials.gov Identifier:
NCT02017561
First received: December 16, 2013
Last updated: February 17, 2014
Last verified: February 2014
  Purpose

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 Intervention Phase
Metabolic Syndrome X
Diastolic Dysfunction
Insulin Resistance
Behavioral: Lifestyle Counseling
Drug: Metformin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Metformin in the Diastolic Dysfunction of Metabolic Syndrome: MET-DIME Trial

Resource links provided by NLM:


Further study details as provided by Universidade do Porto:

Primary Outcome Measures:
  • Change in mean early diastolic mitral annular velocity (cm/s) [ Time Frame: Baseline, 6,12 and 24 months ] [ Designated as safety issue: No ]
    Change in mean of septal and lateral early diastolic mitral annular velocities (E'), assessed by tissue doppler echocardiography


Secondary Outcome Measures:
  • Major adverse cardiovascular events [ Time Frame: 12 and 24 months ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Cardiac multidetector CT without contrast administration to measure epicardial, pericardial and abdominal adipose tissue volumes

  • Coronary artery calcium quantification [ Time Frame: Baseline, 24 months ] [ Designated as safety issue: No ]
    Cardiac multidetector CT without contrast administration to assess coronary artery calcification (calcium score)

  • Healthcare related quality of life [ Time Frame: Baseline, 12, 24 months ] [ Designated as safety issue: No ]
    The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) will be used to assess general health status and HRQoL.


Estimated Enrollment: 54
Study Start Date: January 2014
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Other Names:
  • Risidon
  • Glucophage

  Eligibility

Ages Eligible for Study:   40 Years to 64 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Non-diabetic adults aged between 40 and 64 years fulfilling the American Heart Association/National Heart, Lung and Blood Institute diagnostic criteria of metabolic syndrome (at least 3 of the following: waist circumference ≥102 cm (males) or ≥88 cm (females); fasting triglycerides≥150 mg/dL or on drug therapy for decreasing triglycerides; fasting HDL-cholesterol ˂40 mg/dL (males) or ˂50 mg/dL (females) or on drug therapy for increase HDL-c; systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or on antihypertensive drug therapy; fasting glycemia≥100 mg/dL
  • Echocardiographic evidence of left ventricle diastolic dysfunction at rest (mean E'˂10,2 cm/s if 40-59 years and ˂7,2 cm/s if 60-64 years).

Exclusion Criteria:

  • diagnosis of diabetes mellitus according to the American Diabetes Association criteria;
  • previous diagnosis of ischemic heart disease;
  • moderate or severe cardiac valvular disease;
  • left ventricle ejection fraction lower than 50%
  • pericardial disease;
  • uncontrolled atrial or ventricular tachyarrhythmias;
  • chronic kidney disease (estimated creatinine clearance lower than 60 mL/min);
  • significant liver disease (aspartate aminotransferase or alanine aminotransferase equal or above 2.5 times the upper limit of normal);
  • females who are pregnant, planning to become pregnant or who admit sexual activity without appropriate contraception;
  • lactation;
  • unable to perform cardiopulmonary exercise test;
  • recent (less than 1 month) change in drug therapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02017561

Contacts
Contact: Ricardo Ladeiras-Lopes, MD 00351966897374 ricardoladeiraslopes@gmail.com

Locations
Portugal
Gaia/Espinho Hospital Centre Recruiting
Vila Nova de Gaia, Portugal, 4434-502
Contact: Ricardo Ladeiras-Lopes, MD    00351966897374    ricardoladeiraslopes@gmail.com   
Principal Investigator: Ricardo Ladeiras-Lopes, MD         
Sub-Investigator: Ricardo Fontes-Carvalho, MD         
Sub-Investigator: Nuno Bettencourt, MD         
Sub-Investigator: Francisco Sampaio, MD         
Sponsors and Collaborators
Universidade do Porto
Centro Hospitalar de Vila Nova de Gaia/Espinho
Merck Serono International SA
Investigators
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
  More Information

No publications provided

Responsible Party: Ricardo Ladeiras-Lopes, Dr. Ricardo Ladeiras-Lopes, Universidade do Porto
ClinicalTrials.gov Identifier: NCT02017561     History of Changes
Other Study ID Numbers: 01.00240
Study First Received: December 16, 2013
Last Updated: February 17, 2014
Health Authority: Portugal: Data Protection Agency
Portugal: National Pharmacy and Medicines Institute
Portugal: Ethics Committee for Clinical Research

Keywords provided by Universidade do Porto:
Diastolic dysfunction
Metabolic syndrome
Metformin

Additional relevant MeSH terms:
Insulin Resistance
Syndrome
Metabolic Syndrome X
Disease
Pathologic Processes
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014