Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

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 receptor blockers. This study will test the hypothesis that 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 subjects 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 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.

• Type 2 Diabetes Mellitus
• Vascular Disease

• Drug: Spironolactone
  25 mg daily
• Drug: hydrochlorothiazide + potassium
  12.5 mg hydrochlorothiazide daily plus 10mEq potassium
• Other: placebo
  placebo capsule

• Experimental: 1
  MR blockade (Spironolactone)
  Intervention: Drug: Spironolactone
• Active Comparator: 2
  hydrochlorothiazide + potassium
  Intervention: Drug: hydrochlorothiazide + potassium
• Placebo Comparator: 3
  placebo capsule
  Intervention: Other: placebo

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 > 8.5%, *
• gout (If not already taking HCTZ),
• the use of Rosiglitazone,**
• 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 BP >160 mm Hg and diastolic BP >100 mm Hg,*
• use of cyclic hormone replacement therapy
• past intolerance of ACE inhibitor therapy
• other major medical illnesses. Subjects with evidence of a previous myocardial infarction on the first adenosine-stimulated PET study will be withdrawn from the study.

• Screening systolic blood pressure < 105 mm Hg off of anti-hypertensive medications

  • Subjects 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.

    • Subjects who are currently taking these medications will not qualify for a screening visit. If medications were recently stopped by the subject's physician, he or she may be screened but the baseline assessment protocol must occur 3 months after stopping.