Metformin in the Diastolic Dysfunction of Metabolic Syndrome
Condition: Metabolic Syndrome X; Diastolic Dysfunction; Insulin Resistance
MeSH terms: Metabolic Syndrome; Insulin Resistance; Syndrome
Study type: Interventional
Phase: Phase 2

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.
    


Intervention name(s): Lifestyle Counseling; Metformin
Intervention type(s): Behavioral; Drug
Intervention description(s): 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 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 intervention name(s): Risidon; Glucophage
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diastolic dysfunction; Metabolic syndrome; Metformin