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Aldosterone and Vascular Disease in Diabetes Mellitus

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00214825
First Posted: September 22, 2005
Last Update Posted: January 3, 2008
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Institutes of Health (NIH)
Information provided by:
Brigham and Women's Hospital
  Purpose

Specific aims for this proposal are to determine in patients with diabetes mellitus the effects of an aldosterone receptor antagonist on:

  1. Coronary microvascular function assessed by MRI perfusion reserve,
  2. Endothelial dysfunction assessed by brachial artery reactivity studies, and
  3. Inflammation assessed by blood measurements of c-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1).

Condition Intervention
Diabetes Mellitus Endothelial Dysfunction Albuminuria Drug: eplerenone Drug: Hydrochlorothiazide

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double
Primary Purpose: Treatment
Official Title: Aldosterone and Vascular Disease in Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • Coronary microvascular function assessed by myocardial perfusion reserve measured by MRI [ Time Frame: 20 weeks ]

Secondary Outcome Measures:
  • Endothelial dysfunction assessed by brachial artery reactivity [ Time Frame: 20 weeks ]
  • Inflammation and cellular oxidative stress and injury, assessed by CRP, MCP-1, PAI-1, nephrin, cystanin C, F2 isoprostanes, and urinary 12-HETE [ Time Frame: 20 weeks ]
  • Proteinuria [ Time Frame: 20 weeks ]

Enrollment: 46
Study Start Date: August 2003
Study Completion Date: March 2006
Primary Completion Date: March 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
MR antagonist (Eplerenone) + placebo
Drug: eplerenone
50 mg daily for 6 weeks with placebo
Placebo Comparator: 2
Hydrochlorothiazide plus potassium
Drug: Hydrochlorothiazide
HCTZ 12.5 mg with potassium (10 mEq) daily for 6 weeks

Detailed Description:

Recent human and animal studies suggest that activation of the mineralocorticoid receptor (MR) by aldosterone, the final product of the renin-angiotensin-aldosterone system, causes microvascular damage, vascular inflammation, and endothelial dysfunction. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are unable to provide long-term aldosterone suppression. Therefore, we hypothesize that activation of the MR contributes to progression of vascular disease in patients with diabetes already using ACE inhibitor therapy.

Specific aims for this proposal are to determine in patients with type 1 or type 2 diabetes mellitus and proteinuria, already receiving ACE inhibitor or ARB therapy, the effects of an aldosterone receptor antagonist vs. hydrochlorothiazide on:

  1. Coronary microvascular function assessed by MRI perfusion reserve,
  2. Endothelial dysfunction assessed by brachial artery reactivity studies,
  3. Inflammation and cellular oxidative stress and injury, assessed by c-reactive protein (CRP), MCP-1, plasminogen activator inhibitor-1 (PAI-1).
  4. Proteinuria and whether there is a differential effect when a MR antagonist or HCTZ is added to the ACE inhibitor therapy.

This is a double-blind, randomized, cross-over study of men and women (21-64 years old) with type 1 or type 2 diabetes mellitus and albuminuria (³30 mg/g creatinine). Participants will be randomized to a MR antagonist + placebo or HCTZ + potassium supplementation for 6 weeks. The MR antagonist arm will receive eplerenone 50 mg daily. The HCTZ arm will receive HCTZ 12.5 mg with potassium 10 Meq daily. Amlodipine 5 to 10 mg daily will be added during run phase to control blood pressure. Blood pressure goal is less than 130/80 mm Hg. There will be a 4-week washout period before the patients are crossed-over to the other study arm. MRI perfusion reserve, brachial artery reactivity, and blood samples will be obtained at the beginning and end of each treatment arm.

  Eligibility

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Ages Eligible for Study:   21 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Men and women (21-64 years old) with type 1 or type 2 diabetes mellitus and albuminuria (over 30 mg/g creatinine).

Exclusion Criteria:

Exclusion criteria include: (1) subjects without hypertension who have baseline systolic blood pressure <100 mmHg, (2) severe hypertension (blood pressure must be well-controlled on 3 antihypertensive agents or <150/100 mmHg on £2 antihypertensive agents), (3) ischemic changes on resting electrocardiogram, (4) clinical evidence of heart disease, cerebrovascular or peripheral vascular disease, (5) significant cardiac arrhythmias, (6) aortic stenosis, (7) 2nd or 3rd degree atrio-ventricular block, sinus node disease, or symptomatic bradycardia, (8) bronchospastic lung disease with active wheezing, (9) known hypersensitivity to any of the study drugs, (10) any contraindication to MRI, (11) serum creatinine ³ 1.5 mg/dL, (12) serum potassium ³ 5.0 mmol/L, (13) current smoker, (14) Serum transaminases greater than twice the upper limit of normal, (15) a history of gout, (16) pregnancy, and (17) other active medical problems detected by examination or laboratory testing.

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00214825


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)
Investigators
Principal Investigator: Gail K Adler, MD, PhD Brigham and Women's Hospital Boston, MA
  More Information

Publications:
Responsible Party: Gail K. Adler, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00214825     History of Changes
Other Study ID Numbers: 2003-P-001273 BWH
First Submitted: September 20, 2005
First Posted: September 22, 2005
Last Update Posted: January 3, 2008
Last Verified: December 2007

Additional relevant MeSH terms:
Diabetes Mellitus
Vascular Diseases
Albuminuria
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Cardiovascular Diseases
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Hydrochlorothiazide
Eplerenone
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