Beneficial Effects of EplerenoneVersusHydrochlorothiazide on Coronary Circulatory Function in Patients with Diabetes Mellitus

Abstract

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. Our objective was to assess whether mineralocorticoid receptor activation contributes to coronary circulatory dysfunction in patients with diabetes who are already receiving ACE inhibitor therapy. A randomized, double-blind, crossover study with an intervening washout period of at least 4 wk was conducted with ambulatory patients from the community. Patients included 16 subjects (11 men, eight Caucasians; mean age, 53 yr; mean body mass index, 38.0 kg/m2) with diabetes and albuminuria but without clinical cardiovascular disease. ACE inhibitors were switched to enalapril 20 mg daily, and other antihypertensives were discontinued. Amlodipine 5-10 mg daily was added to achieve blood pressures less than 130/80 mm Hg. Subjects then received, in random order, 6 wk of the mineralocorticoid receptor antagonist eplerenone 50 mg (with placebo pill) daily and 6 wk of another diuretic, hydrochlorothiazide 12.5 mg (with potassium 10 mEq) daily. Before and after each 6-wk treatment period, we measured coronary circulatory function (adenosine-stimulated myocardial perfusion reserve) and endothelial function (brachial artery reactivity and peripheral arterial tonometry). The eplerenone and hydrochlorothiazide groups had similar blood pressures, serum potassium, glycemia, and endothelial function. Although pretreatment myocardial perfusion reserve did not differ between groups, myocardial perfusion reserve was significantly higher after eplerenone than after hydrochlorothiazide (median 1.57 vs. 1.30; P = 0.03). Mineralocorticoid receptor blockade improves coronary circulatory function compared with hydrochlorothiazide in patients with diabetes already receiving ACE inhibitor therapy.