Aldosterone Antagonist

A class of antihypertensive (blood-pressure-lowering) drugs that may offer unique advantages for people with heart failure and people with diabetic nephropathy (kidney disease). The two aldosterone antagonists currently on the market are spironolactone (brand name Aldactone) and eplerenone (Inspra).

Aldosterone is a corticosteroid hormone produced by the adrenal glands. Scientists have long known that aldosterone promotes the retention of sodium, which increases blood volume and thus raises blood pressure. More recently, they have discovered that high levels of aldosterone may cause cardiac fibrosis (scarring), cardiovascular injury, and damage to the blood vessels and glomeruli (tiny filters) of the kidney.

Two relatively new types of blood pressure drugs, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) are thought to have beneficial effects on hypertension, heart failure, and diabetic kidney disease at least in part by suppressing aldosterone levels in the blood. However, during treatment with these drugs, aldosterone levels may eventually return to where they were before treatment or rise even higher, a phenomenon dubbed “aldosterone escape.” Aldosterone escape is estimated to occur in about 20% of people with chronic heart failure and approximately 40% of people with diabetic kidney disease, compromising the drugs’ benefits.

Researchers are now exploring the best role for aldosterone antagonists in treating these related conditions. A study called the Randomized Aldactone Evaluation Study (RALES) evaluated the effects of adding the aldosterone antagonist spironolactone to standard therapy with an ACE inhibitor and other drugs in people with severe heart failure. Compared with the control group not treated with spironolactone, people treated with spironolactone had a 30% reduction in the risk of death, attributed to the lower risk of death from progressive heart failure and sudden death from cardiac causes, as well as a 35% lower frequency of hospitalization for worsening heart failure.

A study called the Eplerenone Post-Acute Myo-cardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) tested the aldosterone blocker eplerenone in people with acute myocardial infarction (heart attack) complicated by left ventricular dysfunction and signs of heart failure who were receiving standard medical therapy. During an average follow-up of 16 months, there were 15% fewer deaths in the eplerenone group than in the placebo group. The rate of death from cardiovascular causes or hospitalizations from cardiovascular events was reduced by 13% with eplerenone.

ACE inhibitors and ARBs have been shown to be beneficial in treating diabetic nephropathy, independent of their effects on blood pressure. Aldosterone antagonists may offer unique advantages in the treatment of this condition as well. In a study reported in the September 2005 issue of Diabetes Care, spironolactone was added to an antihypertensive therapy that included diuretics (“water pills”) and the maximum recommended dose of an ACE inhibitor or ARB in people with Type 2 diabetes who had diabetic nephropathy. Study subjects had reduced albuminuria (a measure of kidney disease) and blood pressure while taking the spironolactone.

The aldosterone antagonists carry a high risk of hyperkalemia (excessive levels of potassium in the blood), especially in people with impaired kidney function who are also treated with an ACE inhibitor or ARB. For this reason, individuals taking these combinations of drugs must follow low-potassium diets and have their plasma potassium levels regularly monitored. No one knows exactly what role aldosterone antagonists will eventually play in treating hypertension, heart failure, and diabetic nephropathy, but they appear to be a useful addition to the arsenal of drugs.