Context. Impaired coronary circulatory function predicts cardiovascular events, the leading cause of death in patients with diabetes mellitus. Aldosterone causes cardiovascular injury and is not suppressed by chronic angiotensin converting enzyme (ACE) inhibitor therapy.

Objective. To assess whether mineralocorticoid receptor activation contributes to coronary circulatory dysfunction in patients with diabetes who are already receiving ACE inhibitor therapy.

Design. A randomized, double-blind, cross-over study with an intervening 4-week washout period.

Setting. Ambulatory patients from the community.

Patients. 16 subjects (11 men, eight Caucasians, mean age 53 years, mean body mass index 38.0 kg/m²) with diabetes and albuminuria but without clinical cardiovascular disease.

Interventions. ACE inhibitors were switched to enalapril 20 mg daily and other anti-hypertensives were discontinued. Amlodipine 5-10 mg daily was added to achieve blood pressures <130/80 mmHg. Subjects then received, in random order, six weeks of the mineralocorticoid receptor antagonist, eplerenone 50 mg (with placebo pill) daily and six weeks of another diuretic, hydrochlorothiazide 12.5 mg (with potassium 10 mEq) daily.

Main outcome measures. Before and after each six-week treatment period, we measured coronary circulatory function (adenosine-stimulated myocardial perfusion reserve) and endothelial function (brachial artery reactivity, peripheral arterial tonometry).

Results. The eplerenone and hydrochlorothiazide groups had similar blood pressures, serum potassiums, glycemia, and endothelial function. Although pre-treatment myocardial perfusion reserve did not differ between groups, myocardial perfusion reserve was significantly higher post-eplerenone than post-hydrochlorothiazide (median 1.57 vs. 1.30; p=0.03).

Conclusions. Mineralocorticoid receptor blockade improves coronary circulatory function compared to hydrochlorothiazide in patients with diabetes already receiving ACE inhibitor therapy.