Metformin in the Diastolic Dysfunction of Metabolic Syndrome

NCT ID: NCT02017561

Last Updated: 2020-03-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-01-31
• Study Completion Date: 2019-12-31

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.

Conditions

Metabolic Syndrome X; Diastolic Dysfunction; Insulin Resistance

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Lifestyle Counseling

Intervention Type: BEHAVIORAL

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.

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.

Group Type: EXPERIMENTAL

Lifestyle Counseling

Intervention Type: BEHAVIORAL

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.

Metformin

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: BEHAVIORAL

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.

Intervention Type: DRUG

Other Intervention Names

Risidon; Glucophage

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.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centro Hospitalar de Vila Nova de Gaia/Espinho

OTHER

Sponsor Role: collaborator

Merck Serono International SA

INDUSTRY

Sponsor Role: collaborator

Universidade do Porto

OTHER

Sponsor Role: lead

Responsible Party

Ricardo Ladeiras-Lopes

Dr. Ricardo Ladeiras-Lopes

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ricardo Ladeiras-Lopes, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto

Adelino F Leite-Moreira, MD,PhD,FETCS

Role: STUDY_CHAIR

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto

Vasco Gama, MD

Role: STUDY_CHAIR

Department of Cardiology, Gaia/Espinho Hospital Centre

Locations

Gaia/Espinho Hospital Centre

Vila Nova de Gaia, , Portugal

Countries

Portugal

Other Identifiers

01.00240

Identifier Type: -

Identifier Source: org_study_id