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Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

This study has been completed.
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Gail Kurr Adler, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT00865124
First received: March 17, 2009
Last updated: May 19, 2017
Last verified: May 2017
  Purpose

Aldosterone is a significant mediator of cardiovascular injury associated with heart failure and the cardiovascular benefits of mineralocorticoid receptor blockade are additive to those of angiotensin converting enzyme inhibitors or angiotensin II (ANGII) receptor blockers. This study will test the hypothesis that mineralocorticoid receptor (MR) antagonists exert beneficial cardiovascular effects, specifically by decreasing vascular injury and improving vascular function. A randomized, double-blind study will be conducted, in which participants with Type 2 Diabetes Mellitus will undergo a series of assessments to test heart, blood vessel, and kidney function at baseline, and after 2 and 6 months of treatment with one of the following drugs:

  1. spironolactone
  2. hydrochlorothiazide (HCTZ) plus potassium
  3. placebo

In the event of insufficient funds, randomization to the placebo arm will be stopped and primary assessment of outcomes will occur at baseline and after 6 months of treatment.


Condition Intervention
Type 2 Diabetes Mellitus Vascular Disease Drug: Spironolactone Drug: Hydrochlorothiazide + potassium Other: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

Resource links provided by NLM:


Further study details as provided by Gail Kurr Adler, Brigham and Women's Hospital:

Primary Outcome Measures:
  • Change in Coronary Flow Reserve From Baseline to 6 Months [ Time Frame: Baseline and six months ]
    Coronary flow reserve (CFR), or myocardial perfusion reserve, was assessed via cardiac positron emission tomography (PET). CFR is the ratio of adenosine-stimulated blood flow through myocardium to resting blood flow through myocardium. An improvement in coronary flow reserve is beneficial.


Secondary Outcome Measures:
  • Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function [ Time Frame: Baseline and six months ]
    Diastolic function was assessed via tissue doppler imaging (TDI) by echocardiography to determine left ventricular diastolic function before and after 6 months of treatment.

  • Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) [ Time Frame: Baseline and six months ]
    Diastolic function was assessed via tissue doppler imaging (TDI) by echocardiography to determine left ventricular diastolic function before and after 6 months of treatment; and in response to acute administration (3 nanograms/kg/min for 60 min) of the vasoactive agent, Angiotensin II.

  • Change in Renal Plasma Flow [ Time Frame: Baseline and six months ]
    Renal vasculature was assessed by examining renal plasma flow, or para-aminohippurate (PAH) clearance, basally and in response to acute administration (3 nanograms/kg/min for 60 min) of the vasoactive agent, Angiotensin II.


Enrollment: 69
Study Start Date: September 2008
Study Completion Date: May 2014
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Spironolactone (mineralocorticoid receptor [MR] blockade) Drug: Spironolactone
25 mg capsule daily for 6 months
Active Comparator: Hydrochlorothiazide + potassium Drug: Hydrochlorothiazide + potassium
hydrochlorothiazide (HCTZ) + potassium, 12.5 mg/10 milliequivalents (mEq) capsule daily
Placebo Comparator: Placebo capsule Other: Placebo
Placebo capsule daily

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age 18-70 years
  • type 2 diabetes mellitus
  • with or without hypertension

Exclusion Criteria:

  • ischemic changes on resting electrocardiogram,
  • clinical evidence of heart disease (angina, heart failure, unstable angina),cerebrovascular or peripheral vascular disease,
  • significant cardiac arrhythmias,
  • aortic stenosis,
  • 2nd or 3rd degree atrio-ventricular block, sinus node disease, or symptomatic bradycardia,
  • bronchospastic lung disease with active wheezing,
  • known hypersensitivity to adenosine,
  • hemoglobin A1C (HbA1c) > 8.5%, *
  • gout (If not already taking HCTZ),
  • the use of Rosiglitazone,**
  • estimated glomerular filtration rate (eGFR) < 60 ml/min,
  • serum potassium > 5.0 mmol/L,
  • use of potassium-sparing diuretics,**
  • current smoker,*
  • pregnancy,
  • renal disease not related to diabetes mellitus,
  • uncontrolled hypertension, systolic blood pressure (BP) >160 mm Hg and diastolic BP >100 mm Hg,*
  • use of cyclic hormone replacement therapy
  • past intolerance of angiotensin-converting enzyme (ACE) inhibitor therapy
  • other major medical illnesses. Participants with evidence of a previous myocardial infarction on the first adenosine-stimulated positron emission tomography (PET) study will be withdrawn from the study.
  • Screening systolic blood pressure < 105 mm Hg off of anti-hypertensive medications

    • Participants can enroll in study and proceed with in-patient evaluations if during the run-in period adjustments of medications, diet and habits lead to improved glucose control [equivalent to HbA1c <8.5%, controlled hypertension and cessation of smoking.

      • Participants who are currently taking these medications will not qualify for a screening visit. If medications were recently stopped by the participant's physician, he or she may be screened but the baseline assessment protocol must occur 3 months after stopping.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00865124

Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Gail K Adler, MD, PhD Brigham and Women's Hospital
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Gail Kurr Adler, Associate Professor of Medicine, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00865124     History of Changes
Other Study ID Numbers: 2007-P-000564
1R01HL087060-01A2 ( U.S. NIH Grant/Contract )
Study First Received: March 17, 2009
Results First Received: April 12, 2017
Last Updated: May 19, 2017

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Cardiovascular Diseases
Vascular Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hydrochlorothiazide
Spironolactone
Mineralocorticoids
Antihypertensive Agents
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Diuretics, Potassium Sparing
Hormones

ClinicalTrials.gov processed this record on August 22, 2017