Aldosterone and Vascular Disease in Diabetes Mellitus
Condition: Diabetes Mellitus; Endothelial Dysfunction; Albuminuria
MeSH terms: Albuminuria; Vascular Diseases; Diabetes Mellitus
Study type: Interventional

Summary: 
      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).
    

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.
    

Intervention name(s): eplerenone; Hydrochlorothiazide
Intervention type(s): Drug; Drug
Intervention description(s): 50 mg daily for 6 weeks with placebo; HCTZ 12.5 mg with potassium (10 mEq) daily for 6 weeks
Intervention MeSH terms: Hydrochlorothiazide; Eplerenone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment