Aldosterone and Vascular Disease in Diabetes Mellitus

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT00214825
First received: September 20, 2005
Last updated: December 28, 2007
Last verified: December 2007
  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-Blind
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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Endothelial dysfunction assessed by brachial artery reactivity [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Proteinuria [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]

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

Ages Eligible for Study:   21 Years to 64 Years
Genders Eligible for Study:   Both
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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00214825

Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
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
Study First Received: September 20, 2005
Last Updated: December 28, 2007
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Albuminuria
Diabetes Mellitus
Vascular Diseases
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Cardiovascular Diseases
Hydrochlorothiazide
Eplerenone
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Aldosterone Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on July 28, 2014