Aldosterone, a steroidal hormone, is a key component of the renin–angiotensin–aldosterone system (RAAS) axis and plays a critical role in maintaining homeostasis in water and electrolyte balance. It is synthesised in the zona glomerulosa of the adrenal cortex.
Its effects are mediated through its action on aldosterone receptors located in nephrons, cardiomyocytes, the brain, the colon, vascular endothelial and smooth muscle cells, immune cells and fibroblasts.
Aldosterone has both genomic and non-genomic effects. Through its action on epithelial sodium channels in nephrons, it facilitates sodium reabsorption and water retention while increasing potassium excretion through various potassium channels. It also regulates hydrogen ion excretion during acidosis.
Mineralocorticoid receptors (MRs) play an important part in the regulation of physiological functions. In several conditions, such as heart failure (HF), decreased renal perfusion, chronic kidney disease, diabetes, insulin resistance and obesity, there is inappropriate MR overactivation through several pathways.
The consequent increase in aldosterone levels leads to inappropriate salt and water retention, stimulation of various proinflammatory pathways involving interleukins, plasminogen activator inhibitor-1, transforming growth factor-B and other cytokines. This results in hypertension, oxidative stress, reduced availability of nitric oxide, extracellular collagen deposition and endothelial dysfunction, glomerular and interstitial fibrosis, increased myocardial stiffness, hypokalaemia and hypomagnesaemia.
Therefore, aldosterone antagonism is an attractive target in the management of renal dysfunction and HF. Indeed, several clinical trials in the past three decades have demonstrated the beneficial effects of this strategy for both renal and cardiovascular endpoints.
However, the use of agents to reduce MR overactivation remains suboptimal globally, owing to an actual or perceived fear of hyperkalaemia and worsening renal function.
This becomes even more significant with the concomitant use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and angiotensin receptor/neprilysin inhibitors, especially in patients with diabetes or reduced renal function. Paradoxically, these are the patients most likely to benefit from aldosterone inhibition.
Recent years have seen the emergence of several strategies to retain the benefit of aldosterone inhibition while reducing the risk of hyperkalaemia and other side effects.
Probably the biggest restriction on the use of MR antagonists (MRAs) is hyperkalaemia. This can result from certain conditions, such as chronic kidney disease (CKD), diabetes and hypoaldosteronism, or because of the use of MRAs, RAAS inhibitors (RAASis) or potassium-sparing diuretics.
In HF, hyperkalaemia is usually due to the use of RAASis and is more likely to occur in patients who are elderly or have diabetes or CKD. This results in a reduction or cessation of RAASis so the beneficial effect of these important agents can be lost.
Often, despite the correction of other confounding factors such as a high-potassium diet and the cessation of non-steroidal anti-inflammatory drugs, they are never restarted.
Various cation exchange resins are widely available and have been used for the removal of potassium through the gastrointestinal (GI) tract. Their action is inconsistent, and many patients do not tolerate them. In addition, they have not been tested in clinical trials.
Two new agents, patiromer and sodium zirconium cyclosilicate (SZC), also remove potassium from the GI tract by exchanging cations. In well-designed, large clinical trials, they have shown efficacy and safety.
The DIAMOND trial for the use of patiromer showed robust benefits while adverse events were almost identical to those of the placebo.1 The HARMONIZE trial demonstrated the efficacy of SZC, although it had slightly more adverse effects than the placebo.2 These trials showed that these potassium binders can be used in hyperkalaemia and will allow the continued use of RAASis to preserve their beneficial effects.
Finerenone is a non-steroidal MRA, different from steroidal MRAs such as spironolactone and finerenone. It is more selective, less likely to cause hyperkalaemia and, in pre-clinical studies, has been shown to have greater effects on cardiac and renal inflammation and a better impact on remodelling.
In large phase III trials (FIDELIO-CKD and FIGARO-DKD), finerenone reduced HF hospitalisations significantly in patients with type 2 diabetes and chronic kidney disease.3,4 The FINEARTS-HF trial tested finerenone in patients with mildly reduced or preserved ejection fraction (EF) and demonstrated a significant benefit in the combined endpoint of reduction in HF hospitalisations and death.5
Three new trials are a part of the MOONRAKER programme, which will test finerenone in other HF phenotypes. REDEFINE-HF (NCT06008197) is testing hospitalised patients with HF with mid-range ejection fraction, CONFIRMATION (NCT06024746) is enrolling patients recently hospitalised with HF and will test a combination of finerenone plus empagliflozin versus empagliflozin alone, and FINALITY-HF (NCT06033950) will test finerenone in HF with reduced EF (HFrEF) in patients who are intolerant to or unsuitable for steroidal MRAs. Together, they will teach us more about the use and efficacy of finerenone.
Two other novel classes of drugs are being tested for aldosterone inhibition.
Balcinrenone is a non-steroidal MR modulator, and is being tested in the BALANCED-HF trial (NCT06307652) for the treatment of HF with impaired kidney function or CKD in combination with dapagliflozin. It has cardio/renal benefits while reducing the incidence of hyperkalaemia. The results are expected in 2027.
Finally, a class of drugs called aldosterone synthase inhibitors (ASIs) is undergoing various trials. Two of them are baxdrostat and vicadrostat.
Aldosterone synthase is the rate-limiting enzyme in the pathway to produce aldosterone. ASIs bind to the active site of the enzyme, preventing the enzyme from catalysing the conversion of corticosterone to aldosterone.
Selective inhibition of aldosterone synthase has been difficult as it has 93% similarity with the enzyme that synthesises cortisol. These two agents have been shown to inhibit aldosterone levels without affecting cortisol levels in previous trials.
Baxdrostat is being tested in uncontrolled and resistant hypertension (BaxHTN) and the results will be available later this year.6 Another trial, BaxDuo-Prevent (NCT06268873), will evaluate the effect of baxdrostat in combination with dapagliflozin compared with dapagliflozin alone on the risk of incident HF and cardiovascular death in participants with increased risk of developing heart failure.
Vicadrostat is being evaluated in two trials (EASI-HF preserved [NCT06424288] and EASI-HF reduced [NCT06935370]) to test the effect of vicadrostat in patients of HF with mildly reduced or preserved EF and HFrEF, respectively. ASIs in combination with sodium-glucose cotransporter 2 inhibitors are also being tested in several CKD trials. Together, these trials will provide significant information on this new class of drugs.
While there is universal agreement that in pathophysiological conditions such as HF, hypertension or CKD, overactivation of aldosterone is harmful and its suppression yields significant long-term benefits, this class of drugs has been underused.
The availability of novel potassium binders, non-steroidal MRAs, aldosterone receptor modifiers and aldosterone synthase inhibitors is likely to result in a greater benefit for a large number of patients with HF and CKD who are unable to use aldosterone inhibitors. The next 2–3 years are likely to focus on aldosterone, given the large number of ongoing and upcoming trials.