Clinical trial NCT02017561: Metformin in the Diastolic Dysfunction of Metabolic Syndrome
Official title: Metformin in the Diastolic Dysfunction of Metabolic Syndrome: MET-DIME Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metabolic Syndrome X
Diastolic Dysfunction
Insulin Resistance
Keywords: Diastolic dysfunction
Metabolic syndrome
Metformin
Lead sponsor: Universidade do Porto
Sponsor class: OTHER
Collaborators: name: Centro Hospitalar de Vila Nova de Gaia/Espinho
name: Merck Serono International SA
First posted: 2013-12-20
Enrollment: 54
Sex: ALL
Minimum age (years): 40
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Change in mean early diastolic mitral annular velocity (cm/s)
timeFrame: Baseline, 6,12 and 24 months
Secondary outcomes:
measure: Major adverse cardiovascular events
timeFrame: 12 and 24 months
measure: Diastolic echocardiographic parameters
timeFrame: Baseline, 6, 12, 24 months
measure: Plasma levels of inflammatory and metabolic biomarkers
timeFrame: Baseline, 6, 12, 24 months
measure: Functional capacity during cardiopulmonary exercise test
timeFrame: Baseline, 12, 24 months
measure: Epicardial, pericardial and abdominal adipose tissue volumes
timeFrame: Baseline, 24 months
measure: Coronary artery calcium quantification
timeFrame: Baseline, 24 months
measure: Healthcare related quality of life
timeFrame: Baseline, 12, 24 months
Other outcomes:
Locations:
city: Vila Nova de Gaia
country: Portugal
facility: Gaia/Espinho Hospital Centre
Study officials:
affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto
name: Ricardo Ladeiras-Lopes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto
name: Adelino F Leite-Moreira, MD,PhD,FETCS
role: STUDY_CHAIR
affiliation: Department of Cardiology, Gaia/Espinho Hospital Centre
name: Vasco Gama, MD
role: STUDY_CHAIR
References: