Metformin in the Diastolic Dysfunction of Metabolic Syndrome

Overview[ - collapse ][ - ]

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.
ConditionMetabolic Syndrome X
Diastolic Dysfunction
Insulin Resistance
InterventionBehavioral: Lifestyle Counseling
Drug: Metformin
PhasePhase 2
SponsorUniversidade do Porto
Responsible PartyUniversidade do Porto
ClinicalTrials.gov IdentifierNCT02017561
First ReceivedDecember 16, 2013
Last UpdatedFebruary 17, 2014
Last verifiedFebruary 2014

Tracking Information[ + expand ][ + ]

First Received DateDecember 16, 2013
Last Updated DateFebruary 17, 2014
Start DateJanuary 2014
Estimated Primary Completion DateOctober 2016
Current Primary Outcome MeasuresChange 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
Current 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.

Descriptive Information[ + expand ][ + ]

Brief TitleMetformin in the Diastolic Dysfunction of Metabolic Syndrome
Official TitleMetformin in the Diastolic Dysfunction of Metabolic Syndrome: MET-DIME Trial
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.
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment
Condition
  • Metabolic Syndrome X
  • Diastolic Dysfunction
  • Insulin Resistance
InterventionBehavioral: 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
Study Arm (s)
  • 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.
  • 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.

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment54
Estimated Completion DateOctober 2016
Estimated Primary Completion DateOctober 2016
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.
GenderBoth
Ages40 Years
Accepts Healthy VolunteersNo
ContactsContact: Ricardo Ladeiras-Lopes, MD
00351966897374
ricardoladeiraslopes@gmail.com
Location CountriesPortugal

Administrative Information[ + expand ][ + ]

NCT Number NCT02017561
Other Study ID Numbers01.00240
Has Data Monitoring CommitteeYes
Information Provided ByUniversidade do Porto
Study SponsorUniversidade do Porto
CollaboratorsCentro 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 PortoStudy Chair: Adelino F Leite-Moreira, MD,PhD,FETCS Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of PortoStudy Chair: Vasco Gama, MD Department of Cardiology, Gaia/Espinho Hospital Centre
Verification DateFebruary 2014

Locations[ + expand ][ + ]

Gaia/Espinho Hospital Centre
Vila Nova de Gaia, Portugal, 4434-502
Contact: Ricardo Ladeiras-Lopes, MD | 00351966897374 | ricardoladeiraslopes@gmail.com
Principal Investigator: Ricardo Ladeiras-Lopes, MD
Recruiting