Metformin in the Diastolic Dysfunction of Metabolic Syndrome

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.

Conditions

• Metabolic Syndrome X
• Diastolic Dysfunction
• Insulin Resistance

Interventions

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.

Sponsors & Collaborators

• Centro Hospitalar de Vila Nova de Gaia/Espinho

  collaborator OTHER

• Merck Serono International SA

  collaborator INDUSTRY

• Universidade do Porto

  lead OTHER

Principal Investigators

• Ricardo Ladeiras-Lopes, MD · Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto

• Adelino F Leite-Moreira, MD,PhD,FETCS · Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto

• Vasco Gama, MD · Department of Cardiology, Gaia/Espinho Hospital Centre

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

PARALLEL

Eligibility

Min Age

40 Years

Max Age

64 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-01-31

Primary Completion

2019-12-31

Completion

2019-12-31

Countries

• Portugal

Study Locations