Spironolactone

Spironolactone is a mineralocorticoid receptor antagonist (MRA) and potassium-sparing diuretic used in the management of hypertension, primary hyperaldosteronism, heart failure and ascites. It has anti-androgenic properties and is used off label for acne vulgaris, hirsutism and female pattern hair loss. Figure 1 outlines the pharmacological actions of spironolactone. It is a non- selective antagonist at mineralocorticoid nuclear receptors in the cells of the distal tubule of the nephron. This reduces the production of aldosterone-induced proteins that through several mechanisms, including blocking potassium exchange transporters, promotes excretion of sodium and water with potassium retention. Spironolactone also has a weak antagonist effect at androgen and progesterone receptors, with unwanted side effects of gynaecomastia and sexual dysfunction limiting its use. Spironolactone has good bioavailability reaching peak plasma concentration at 2–3 hours. It is rapidly metabolised in the liver and its metabolites are excreted in urine and bile. Hyperkalaemia is a common and important adverse effect requiring careful monitoring of potassium, particularly in elderly patients and those with renal impairment. The RALES trial (Randomized Aldactone Evaluation Study) was a double-blind, placebo-controlled, randomised trial in 1663 patients with moderate to severe heart failure with reduced ejection fraction (HFrEF) terminated early at 24 months. Compared to placebo, treatment with 25mg spironolactone was associated with a 35% reduction in the risk of hospitalisation (relative risk [RR] 0.65; 95% CI 0.54–0.77; p<0.001) and 30% reduction in risk of death from cardiac causes, a combination of heart failure and sudden cardiac death (RR 0.70; 95% CI 0.60–0.82; p<0.001).1 There was a low incidence of serious hyperkalaemia (2% in the spironolactone group compared to 1% in the placebo group). Ten percent of participants reported gynaecomastia and breast pain. Its effects are thought to be mediated by a reduction in fibrosis and improvement in left ventricular function. The TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) was a randomised, double-blind trial comparing 15–45mg spironolactone with placebo in 3445 patients with heart failure with preserved ejection fraction (HFpEF).2 With a mean follow up of 3.3 years, there was no difference in the primary outcome, a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalisation for the management of heart failure (hazard ratio [HR] 0.89; 95% CI 0.77–1.04; p=0.14). Hospitalisation for heart failure was less in the treatment group (206 patients [12.0%] vs 245 patients [14.2%]; HR 0.83; 95% CI 0.69–0.99; p=0.04). Subsequent analysis of the TOPCAT data has been done to try and identify patients within a heterogenous group who may respond.3 The PATHWAY-2 study (Prevention And Treatment of Hypertension With Algorithm-based therapy) was a double-blind, crossover, placebo-controlled trial which compared the effectiveness of spironolactone in resistant hypertension testing the hypothesis that it is often caused by excessive sodium retention.4 Patients rotated through 12 weeks of once-daily treatment with each of spironolactone (25–50mg), bisoprolol (5–10mg), doxazosin modified release (4–8mg), and placebo, in addition to their baseline blood pressure drugs. Spironolactone was better at lowering blood pressure compared to doxazosin (-4.03mmHg [-5.04 to -3.02]; p<0.0001) and bisoprolol (-4.48mmHg [-5.50 to -3.46]; p<0.0001). These positive results support previous non-placebo-controlled evidence in the ASCOT-BPLA study where spironolactone was added as a fourth-line agent.5 In PATHWAY-2 spironolactone was well tolerated and only 2% of patients experienced hyperkalaemia. There was no significant renal impairment or gynaecomastia when compared to placebo. For the studies with positive primary outcomes, people with diabetes were included (25% of RALES study population and 14% in PATHWAY-2) and the use of spironolactone in HFrEF and resistant hypertension should be considered. Patients with hypertension and diabetes have higher aldosterone concentrations than those with hypertension alone, and the deleterious effect of aldosterone on the vascular endothelium and cardiac function suggests a role for spironolactone in the management of hypertension in this group. This is being investigated in the ESCAM trial (Effect of spironolactone on cardiovascular morbidity and mortality in patients with hypertension and glucose metabolism disorders).6 At the time of writing, this large trial is due to finish at the end of 2023. There has also been interest in the use of spironolactone in diabetic kidney disease (DKD). A meta-analysis of 16 studies in patients with DKD found that the addition of spironolactone resulted in significant reductions in urinary albumin excretion.7 However, the emergence of finerenone, a more selective MRA, may limit the use of spironolactone for this indication. Spironolactone has proven efficacy in reducing morbidity and mortality in moderate to severe heart failure with reduced ejection fraction, including people with diabetes. Its role in patients with HFpEF with or without diabetes is less clear. It should be considered for the management of anyone with resistant hypertension. While an ongoing study is investigating whether spironolactone has cardiovascular benefit in those with diabetes and hypertension, it is unlikely to be used widely in slowing the progression of DKD given the emergence of the more selective and novel MRA finerenone, which has recently been approved for this indication and has fewer side effects.