Mechanisms for Mineralocorticoid-driven Age-related Hypertension: Potential Therapeutic Role of Mineralocorticoid Receptor Antagonists and Aldosterone Synthase Inhibitors

Abstract

Hypertension prevalence rises dramatically with advancing age, is not well controlled with current therapy, and contributes substantially to cardiovascular, renal and neurologic disorders that are common in the elderly. The renin-angiotensin-aldosterone system is a hormonal pathway with multiorgan involvement critical to controlling blood pressure. The production of the steroid hormone aldosterone and the activation state of its mineralocorticoid receptor (MR) are important clinical targets for hypertension treatment and cardiorenal disease prevention. This review summarizes studies demonstrating that aging is associated with: 1) dysregulation of adrenal aldosterone production by autonomous aldosterone producing adrenal cells and, when co-morbid with obesity, by factors released from adipose tissue that promote adrenal aldosterone production; 2) increased expression of the MR due to oxidative stress- and inflammation-activated transcription factors; and 3) aldosterone-independent MR activation by oxidative stress-activated Rac1, angiotensin-II signaling, and declining expression of the cortisol-inactivating enzyme 11bHSD2. Together, these data support the concept that elderly individuals are at high risk for mineralocorticoid-driven hypertension and associated cardiovascular, renal, and neurologic disease. The review further describes the different classes of agents that inhibit this pathway, including traditional steroidal MR antagonists (sMRAs), newer nonsteroidal (nsMRAs) and aldosterone synthase inhibitors (ASIs), comparing their modes of action. The sMRAs and nsMRAs have different degrees of MR selectivity and potency, yet they all block MR activation by aldosterone, cortisol, and ligand-independent mechanisms. The ASIs block aldosterone production in the adrenal gland and attenuate aldosterone-mediated MR effects. All three drug classes raise potassium proportional to the degree of renal MR inhibition. Trials are summarized showing efficacy of the new agents in reducing MR activation, aldosterone production, blood pressure and adverse cardiorenal outcomes. Head-to-head studies in older individuals are needed to determine the relative efficacy of aldosterone synthase versus MR inhibition for blood pressure control to improve outcomes in the elderly and very old.

Overview

The prevalence of hypertension rises dramatically with advancing age, with 70% of individuals over 60 years of age having high blood pressure.^1,2 Hypertension is a known risk factor for the development of myocardial infarction, stroke, dementia, heart failure and renal failure, all common conditions in the elderly. Treatment of hypertension is inadequate, with only about half of hypertensives over 60 years of age achieving optimal blood pressure control.³ Clinical data reveal that optimal blood pressure control, even in the elderly and very old, reduces the risk of cardiovascular, renal and neurologic disease.^4,5 This review summarizes research supporting the concept that dysregulation of the hormone aldosterone and its mineralocorticoid receptor (MR) is a common contributor to hypertension, even in the absence of frank primary hyperaldosteronism. Data is also presented indicating that aldosterone-MR dysregulation is exacerbated with advancing age, and hence may be a critical mechanism driving hypertension in the elderly.^6,7 The review is divided into two parts; Part 1 summarizes data supporting dysregulated aldosterone production, MR expression, and MR activation mechanisms with advanced age. This section first reviews the normal regulation of aldosterone and MR and fundamental research discoveries advancing our understanding of the molecular mechanisms driving dysregulated aldosterone production and inappropriate activation of the mineralocorticoid receptor (MR) with aging and how this may be further exacerbated by aging-associated comorbidities such as obesity. Part 2 summarizes the similarities and differences between the steroidal (sMRAs) and new classes of non-steroidal MR antagonists (nsMRAs) and highly selective aldosterone synthase inhibitors (ASIs) along with clinical trials testing these new classes of drugs targeting the aldosterone-MR pathway. The summarized findings provide a rationale for future clinical studies comparing the utility of MRAs and ASIs in the elderly and very old to improve hypertension treatment as a means to achieve better blood pressure control and prevent the adverse cardiovascular, renal and neurologic effects of chronic hypertension that are so common in the rapidly growing aging population.

Part I: Aldosterone and the Mineralocorticoid Receptor in Normal Blood Pressure Regulation and Dysregulation with Aging

The renin-angiotensin-aldosterone system: normal activation and feedback inhibition

The renin-angiotensin-aldosterone (RAAS) system is an endocrinologic signaling cascade that regulates blood pressure to mitigate hypotension (Figure 1).⁸ In the healthy state, the RAAS is activated in response to intravascular volume depletion. Cells of the renal juxtaglomerular apparatus sense hypoperfusion through several mechanisms, including reduction of the perfusion pressure in the afferent arteriole, ß1-adrenergic receptor stimulation, and decreased tubular sodium composition sensed by the macula densa in the kidney.⁹ These signals cause the juxtaglomerular apparatus to release renin, a protease which activates an enzymatic cascade leading to the production of the peptide hormone angiotensin II.¹⁰ Angiotensin II has systemic effects including activating angiotensin type-1 (AT1) receptors in the vasculature to promote vasoconstriction and in the zona glomerulosa within the adrenal cortex to induce the production and release the mineralocorticoid hormone aldosterone.¹⁰ Aldosterone is synthesized in the adrenal cortex by the aldosterone synthase protein CYP11b2, a cytochrome p450 enzyme that catalyzes the final three enzymatic steps in the conversion of cholesterol to aldosterone.¹¹

Figure 1: Normal Aldosterone Production, Impact on Blood Pressure, and Feedback Control Mechanisms:

In response to low intravascular volume, the kidney releases renin which cleaves liver derived angiotensinogen to generate angiotensin II which acts on the adrenal cortex to induce expression of CYP11B2, the aldosterone synthase, resulting in aldosterone production and release. Aldosterone enters cells, binding to and activating the mineralocorticoid receptor (MR). Activated MR regulates transcription of: the epithelial sodium channel (ENaC) to promote sodium and water retention in the kidney and colon; the L-type calcium channel (LTCC) in smooth muscle to regulate blood vessel constriction; and modulates the function of the sympathetic nervous system and immune system, all of which contribute to increasing blood pressure. Feedback mechanisms lead to a decline in renin when blood pressure and aldosterone are elevated and chronic MR activation by aldosterone leads to MR degradation in cells. Illustration credit: Sceyence Studios.

Like most endocrinologic systems, the RAAS has feedback mechanisms to prevent overactivation and maintain homeostasis. Under physiological conditions, when aldosterone levels or blood pressure rise, renin release from the kidney becomes suppressed, thus attenuating aldosterone production and preventing hypertension. Another feedback mechanism common to hormone receptor signaling is enhanced degradation of the receptor in response to chronic ligand stimulation.^12,13 One study has demonstrated that the MR protein is similarly degraded by the proteosome when chronically stimulated by aldosterone.¹⁴

Once released by the adrenal gland, the steroid hormone aldosterone travels through the bloodstream and diffuses across the cell membrane to bind to its intracellular receptor, the mineralocorticoid receptor (MR).¹⁵ In addition to aldosterone, the other natural ligand for the MR is cortisol, which circulates at up to 1000 fold higher concentrations in the plasma compared to aldosterone.⁸ While the MR has similar affinity constants for binding to aldosterone and cortisol, kinetic studies have revealed a 5-fold slower off-rate of aldosterone relative to glucocorticoids from the MR, suggesting intrinsic ligand specificity of the receptor.^16,17 In addition, the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11b-HSD2) converts cortisol to cortisone, which does not bind or activate the MR (Figure 2A).¹⁸ Thus, in tissues in which 11b-HSD2 is expressed, including the kidney and the vasculature, cortisol is locally inactivated, further allowing preferential MR binding by aldosterone, whereas in tissues with lower expression of 11b-HSD2, including cardiomyocytes and leukocytes, MR may be more likely to be activated by cortisol.^15,18 As such, changing levels of 11b-HSD2 can modulate the MR ligand and level of activation of the receptor. Conversely, 11ß-HSD1 catalyzes the regeneration of cortisol from cortisone and hence increased 11ß -HSD1 would be expected to enhance MR activation by cortisol, as demonstrated in the brain of aging male mice.¹⁹

Figure 2: Mechanisms of Mineralocorticoid Receptor Activation, Function, and Inhibition:

(A) Mineralocorticoid receptor (MR) activating mechanisms and inhibitory drug classes: Aldosterone and cortisol both bind to the intracellular MR with equal affinity but with faster cortisol dissociation. Cortisol can also be dehydrogenated to cortisone, which does not bind to the MR, in cells expressing the enzyme 11ß-HSD2. The MR can also activated in a ligand-independent fashion by angiotensin II binding to angiotensin type 1 receptors (AT1R) via PKC-delta signaling and by reactive oxygen species via the Rac1 pathway. Mineralocorticoid receptor antagonists (MRA) block both ligand-dependent and ligand-independent activation of mineralocorticoid receptors. Aldosterone synthase inhibitors (ASI) prevent the formation of aldosterone, thereby preventing ligand-dependent MR activation only by aldosterone. (B) MR modes of action: The activated MR mediates cellular changes through both non-genomic and genomic actions. In the non-genomic pathway, the MR is tethered to the plasma membrane by the scaffolding protein striatin in caveolin-1 (CAV1)-containing domains and mediates cellular effects via signaling pathways involving growth factor receptors, MAPKs, and G-protein coupled receptors including G-protein coupled estrogen receptor (GPER) also known as GPR30. The genomic pathway involves translocation of liganded MR to the nucleus where it binds to MR responsive elements in the DNA to regulate transcription of cellular target genes. Illustration credit: Sceyence Studios.

Once the MR is activated by ligand, it modulates cellular functions via genomic and non-genomic mechanisms (Figure 2B). The genomic effects of aldosterone are mediated by activated MR in the nucleus, where it binds to MR responsive elements in the DNA sequence to regulate gene transcription.⁸ The non-genomic effects occur rapidly, via activation of intracellular signaling cascades that modulate cellular functions independent of gene transcription and protein translation. While originally thought to be mediated by an alternative aldosterone receptor, substantial literature now supports that these non-genomic effects are inhibited by traditional MR antagonists and hence are thought to be mediated by the classical MR localized at the plasma membrane (Reviewed in²⁰). MR can be tethered to the plasma membrane by scaffolding proteins including striatin and caveolin-1. When this membrane-localized MR is activated, it induces rapid cellular effects via signaling cascades involving growth factor receptors, MAPKs and G-protein coupled receptors (Figure 2B). Some studies have suggested the possibility that aldosterone can bind directly to alternative receptors, such as the G-protein coupled receptor GPR30 (aka GPER1) to induce non-genomic signaling. However, as most studies show that GPER-mediated actions induced by aldosterone are inhibited by MR antagonists, these pathways are likely downstream of the classical MR.²⁰

Genomic effects of MR activation in the kidney induce the transcription of the epithelial sodium channel (ENaC) gene in the renal collecting tubules, thereby stimulating sodium and fluid retention and potassium excretion, and maintenance of intravascular volume.^8,21,22 In addition to the kidney, the MR is expressed in other cells and tissues where it also contributes to blood pressure control including in the colon, salivary and sweat glands, where MR also regulates sodium and water homeostasis. MR is also expressed in the hippocampus where it contributes to central nervous system control of blood pressure. MR is expressed in white blood cells, including T cells, which have been implicated in hypertension via renal and vascular inflammation.^23,24 Finally, MR is expressed in cells of the cardiovascular system, including cardiomyocytes and vascular endothelial and smooth muscle cells. MR in smooth muscle cells has been shown to contribute to the blood pressure by regulating L-type calcium channels that contribute to vasoconstriction and myogenic tone in resistance arterioles, particularly with aging (Figure 1).^22,25

Ligand Independent MR activation

In addition to activation by traditional hormone ligands, steroid receptors, including the MR, have been found to be activated in a ligand-independent fashion via post-translational modifications induced by activation of cellular signaling pathways. In vascular smooth muscle cells, MR was found to be activated by angiotensin II, acting through the AT1 receptor to induce protein kinase C delta (PKCd)-dependent signaling that in turn activates MR genomic function.^26,27 In addition, ample experimental data have demonstrated that the Rho-family small GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), induces ligand-independent MR activation in the heart and kidney. Rac1-mediated MR activation was found to contribute to renal and cardiac fibrosis in multiple preclinical models.²⁸ Rac1 can be activated by a variety of signals including angiotensin II, adrenaline, endothelin-1, integrins, high salt, mechanical stress, cytokines, growth factors and particularly oxidative stress.²⁸ As such, in addition to activation by aldosterone or cortisol, the MR can be activated in a hormone-independent manner, in situations in which oxidative stress and neurohormonal pathways are induced, even when aldosterone is not elevated (Figure 2A). Although Rac1-mediated MR activation has been well studied in preclinical models, its role in aging-related hypertension in patients remains to be studied.

Hypertension as a disorder of aging

While 30% of the US population has hypertension, essential hypertension is predominantly a disorder of aging. Hypertension is relatively uncommon in children and young adults yet blood pressure (BP) rises with age such that more than 70% of people over 60 in the United States and 80% of the growing population over 80 have hypertension.^1,2 Clinical outcomes trials support a systolic blood pressure (SBP) goal of less than 130 mmHg in elderly (>65 years) and less than 140–150 mmHg in very old (>80 years) people with essential hypertension, as tolerated.²⁹ Control of BP to guideline recommended levels with lifestyle interventions and pharmacologic therapy has been shown to improve outcomes in elderly and very old people, reducing cardiovascular (CV) mortality, myocardial infarction (MI), stroke, the development of heart failure and chronic kidney disease (CKD).^5,29,30 However, only about 30% of those over 60 years with hypertension have optimal blood pressure control.¹ Better understanding of mechanisms driving the rise in blood pressure with aging is important to support trials of mechanistically-driven hypertension treatment strategies that are more effective in the elderly and very old populations.

Dysregulated aldosterone production and declining 11bHSD2 with advanced age

Primary aldosteronism (PA) was originally considered a rare cause of hypertension secondary to benign aldosterone-secreting adrenal tumors. More recently, PA pathophysiology has been redefined to include a broader spectrum characterized by dysregulated aldosterone production in the context of low renin. With this new understanding, recent data reveals that PA pathophysiology occurs in 10% of normotensive people, 15–20% of patients with hypertension, >25% of those with treatment-resistant hypertension, and 37–51% of those with concomitant visceral obesity or metabolic syndrome.^7,31–33 As such, approximately 30–45% of the American population, and 60–70% of those with resistant hypertension, have a phenotype of renin-independent aldosterone production, implicating dysregulated aldosterone pathophysiology as a driver of hypertension in a large proportion of individuals.^34,35 This dysregulated aldosterone pathophysiology phenotype is associated with increased risk for worsening hypertension, incident CV disease, CKD and CV death.^36–44 In turn, intervention studies over 50 years have shown that MR antagonists are extremely effective therapy for lowering BP in people with resistant hypertension, particularly when there is a phenotype of renin-independent aldosterone production.^45–48 More recently, early phase studies evaluating aldosterone synthase inhibitors in people with resistant or uncontrolled hypertension, particularly with comorbid obesity,^49–56 have shown substantial BP lowering efficacy of these agents despite the concomitant use of renin-angiotensin system inhibitors. Despite this high prevalence and potential for adverse outcomes, testing for dysregulated aldosterone pathophysiology is difficult and rarely conducted except in specialized centers, thus most patients are classified as having essential hypertension and are treated with a mechanism-agnostic approach.^57–60

Dysregulated aldosterone pathophysiology increases across the lifespan. This is driven by age-related declines in both renin and aldosterone; however, because the decline in renin outpaces that of aldosterone, the resulting biochemical phenotype is increasing renin-independent aldosterone production with older age.^6,7,61,62 Histopathologic and molecular studies of the adrenal gland revealed pathogenic somatic mutations in zona glomerulosa cells that induce over-expression of aldosterone synthase enzyme as well as the presence of autonomous aldosterone-producing cell clusters (AAPCC), both of which are increasingly observed in adrenal glands from older compared to younger individuals.^6,61,63 This histopathologic correlate of PA pathophysiology is strongly associated with increased renin-independent aldosterone production across the lifespan, thus linking cellular genetic and histopathologic alterations in the adrenal gland with biochemical phenotypes (Figure 3).⁶⁴

Figure 3: Dysregulation of Aldosterone Production and Mineralocorticoid Receptor Expression and Activity with Aging and Co-morbidities:

Aging is associated with dysregulated aldosterone production by the adrenal gland due to autonomous aldosterone-producing cell clusters (AAPCC). With co-morbid obesity and diabetes, dysfunctional adipose releases leptin which further induces adrenal aldosterone synthase (CYP11B2) and dysregulated aldosterone production. Aging- and obesity-associated inflammation and oxidative stress activate transcription factors, hypoxia-inducible factor (HIF)-1a and nuclear factor kappa-B (NFkB), which induce transcription of the mineralocorticoid receptor (MR) gene (NR3C2) to increase the cellular amount of the MR, independent of feedback degradation. Finally, with aging, there is increased aldosterone-independent MR activation due to reactive oxygen species (ROS)-mediated Rac1 activation, aging-associated enhanced angiotensin II signaling via the angiotensin type-1 receptor (AT1R) and protein kinase C-delta (PKCd), and the decline in the cortisol-inactivating enzyme 11b-hydroxysteroid dehydrogenase-2 (HbHSD2) resulting in cortisol activation of the MR. Illustration credit: Sceyence Studios.

In addition to dysregulated aldosterone pathophysiology, 11ß -HSD2 activity decreases with age and with the development of kidney disease, and 11b-HSD1 increases, resulting in an increase in the cortisol to cortisone ratio.^65–67 Since cortisol circulates at higher concentrations,⁶⁸ increased cortisol-mediated activation of the MR may also play an increased role in the pathophysiology of hypertension in the elderly and very old.

Mineralocorticoid receptor (MR) transcriptional regulation leads to rising MR expression with aging

In addition to renin-independent aldosterone production and enhanced cortisol-activation of the MR, hypertension in elderly and very old patients may be further exacerbated by changes in the level of the MR with aging. Preclinical studies have demonstrated that the level of the MR increases with age in rodent vessels.^22,69–72 Consistent with data in rodents, MR protein level is increased in human aortic tissue and in vascular smooth muscle cells (VSMCs) from aged versus young individuals and protein levels of the MR strongly correlate with biological age of the tissue donor.^22,69–72 Mechanistically, inflammation and oxidative stress, processes that are enhanced in aged tissues, have been found to transcriptionally induce expression of the MR gene. The hypoxia-inducible transcription factor, HIF1a, is increased in aging vessels in response to oxidative stress and binds to the MR P1 promoter to regulate transcription of the MR-1a isoform.⁷³ Similarly, the inflammatory transcription factor NF-kB is activated in aging vessels and induces transcription of both the MR-1a and MR-1b isoforms.⁷³ This aging-associated rise in MR expression in vascular smooth muscle cells has been associated with aging-associated increases in BP, vascular stiffness, cardiac stiffness and exercise intolerance in mice through modulation of global gene expression patterns in cardiovascular tissues.^22,70–72

Synergy between common aging comorbidities and dysregulated aldosterone and mineralocorticoid activation

Common metabolic and renal comorbidities in the elderly, including visceral obesity, diabetes and CKD, can synergistically exacerbate the dysregulated aldosterone and MR phenotype associated with hypertension. The prevalence of obesity is rising, particularly for people greater than 60 years old.² Diabetes mellitus risk also rises with age, with a prevalence of 20% among adults greater than 65 years old.⁷⁴ There is abundant evidence that plasma aldosterone concentrations correlate with BMI and are higher with visceral obesity and metabolic syndrome, which is consistent with enhanced effectiveness of MRAs in reducing systolic blood pressure in individuals with obesity.^75–78 While some studies originally suggested that adipose itself might production aldosterone, more recent data support that dysfunctional adipose tissue releases factors that act in an endocrine fashion to drive adrenal aldosterone production. Mechanistically, as adipose tissue expands and becomes dysfunctional in individuals with obesity, adipocytes releases maladaptive adipokines, including leptin, which induces adrenal CYP11B2 expression, aldosterone synthesis and release.^79,80 Whether weight loss aided by incretin-based therapies will ameliorate the adipose dysfunction and the specific adipokines that drive dysregulated aldosterone in obese individuals is worth examining in people treated with GLP1 agonists. Due to frequent episodes of hypoxia in those with obstructive sleep apnea, often coexisting with the obesity, MR expression and activation is also increased, which further increases BP and the adverse consequences.⁸¹

Renal function also declines with age and is exacerbated by hypertension and DM, further contributing to comorbid CKD in the elderly and very old.^82,83 CKD is associated with elevated plasma aldosterone as well as an increase in MR expression which further correlates with progression of CKD.⁸⁴ CKD, advanced age, and hypertension also associated with higher risk of atherosclerotic CVD (ASCVD), which is initiated by endothelial dysfunction.⁸⁵ Preclinical studies show that MR expression in endothelial cells drives atherosclerotic plaque formation and plaque inflammation, a marker of plaque rupture risk, which causes most myocardial infarctions and other atherosclerotic disease events.^86,87 MRAs have been shown to reduce endothelial dysfunction and decrease atherosclerotic plaque formation and inflammation in preclinical models.⁸⁸ Patients with PA are known to have an increased risk of ASCVD, independent of an increase in BP⁸⁹, and aldosterone levels are associated with the risk of myocardial infarction (MI), stroke and CV death in patients with underlying coronary artery disease (CAD), even when aldosterone levels are within the normal range.⁹⁰ Furthermore, in a recent study of patients with DM and CKD, the steroidal MRA spironolactone significantly reduced the extent of aortic atherosclerosis as assessed by magnetic resonance imaging (MRI).⁹¹

A vicious cycle of dysregulated aldosterone production and excessive MR activation driving hypertension and associated cardiorenal disease in the elderly and very old

Integration of the preclinical mechanistic data, with evidence of high burden of PA pathophysiology in the elderly and aging-associated comorbidities that further exacerbate MR activation supports the concept that synergistic pathologies in the elderly and very old may be fueling progressive hypertension and associated adverse consequences driven by aldosterone and the MR. Aldosterone production is dysregulated, due to an age dependent increase in autonomous aldosterone-producing adrenal cell clusters and adipose derived leptin in those with obesity, both of which lead to adrenal aldosterone production that lacks the normal feedback inhibition. This coexists with a rise in MR expression driven by aging and cardiometabolic increases in oxidative stress and inflammation, which drive transcription of the MR gene, usurping the feedback control achieved by aldosterone-mediated MR degradation. The excess MR is likely also hyperactivated via several mechanisms. In addition to dysregulated aldosterone production, MR activation by cortisol may be enhanced due to declining 11bHSD2 activity with aging. And finally, MR may be activated by ligand-independent mechanisms by Rac1 and AngII signaling. AngII signaling is enhanced with aging and also contributes to oxidative stress which activates Rac1 to promote MR-induced cardiac and renal fibrosis.⁹² Together, the increase in aldosterone dysregulation, aldosterone-independent MR activation, and MR expression with ageing without feedback inhibition (Figure 3) would be expected to contribute to the inexorable rise in blood pressure with advancing age. Furthermore, hypertension itself and the impact of excessive MR activation in tissues contributes to increased vascular stiffening and vasoconstriction which further increases blood pressure.^{22,72,93–95} Vascular stiffness increases systolic blood pressure transmitted to small vessels, leading to microvascular damage in the brain, heart and kidney, which contributes to neurodegeneration, heart failure and CKD. As a consequence of the increase in BP, and in part independent of BP, the increase in MR expression and activation also drives development of left ventricular hypertrophy (LVH), myocardial fibrosis and myocardial cell death, which contributes to HF with a preserved ejection fraction (HFpEF).⁹⁶ Low renin hypertension and excessive MR activation also increases the risk of CKD and ASCVD.^39,97 Together, these data are consistent with a model in which dysregulated aldosterone and MR activation disproportionately drive hypertension and many of its comorbidities in the aging population. Clinical studies are needed to test this model and determine whether blockade of aldosterone and MR activity would have greater benefit in reducing blood pressure and the adverse cardiorenal consequences of hypertension in the growing elderly and very old population.

Part II: The Growing Therapeutic Armamentarium to Block Aldosterone- and MR-Driven Pathology: Role in the Elderly and Very Old

Steroidal MRAs: old drugs, still useful

Steroidal MR antagonists (sMRA) have been available for use since the approval of spironolactone in 1959. So named for their steroid ring structure that is analogous to the natural ligands for the MR, the sMRAs bind to the MR ligand-binding domain and inhibit genomic and non-genomic actions, whether activated by aldosterone, cortisol or ligand-independent mechanisms (Figure 2A). The sMRAs include spironolactone, eplerenone and canrenone.⁹⁸ Spironolactone is a potent inhibitor of the MR that is metabolized to canrenone, which is also an active sMRA with a long half-life (>20 hours). While potent at blocking the MR and lowering blood pressure via MR blockade in the kidneys, vessels, and other tissues, spironolactone is less specific for the MR. Spironolactone has off target pro-progestogenic and anti-androgenic actions that result in gynecomastia and sexual side effects resulting in lower compliance and higher rates of drug discontinuation. Eplerenone is a sMRA that became available 4 decades later. Eplerenone is less potent, but much more MR specific, and hence induces less gynecomastia, impotence and dysmenorrhea. A small head-to-head study revealed 25% lower efficacy of eplerenone for BP lowering, consistent with less impact on increasing aldosterone, renin, and potassium, all of which track with lower MR inhibitory potency.⁹⁹ Subsequent studies have revealed that the sMRAs lower blood pressure and improve long term outcomes in patients with heart failure with reduced ejection fraction (HFrEF).^100–102 A side effect of all sMRAs is a rise in serum potassium, the extent of which is dependent on dose and relative potency for renal MR inhibition.

Non-steroidal MRAs: new drugs with clinical benefits

A new class of non-steroidal MRAs (nsMRAs) has recently been developed with a chemical structure lacking the steroid moiety. The nsMRAs also bind the MR to prevent its genomic and non-genomic actions (Figure 2A). Finerenone is the first drug in this class followed by esaxrenone and others that are in development. Finerenone is highly specific for the MR, hence lacking off target sexual side effects and it is a more potent MR inhibitor than eplerenone. As such, finerenone combines some advantages of spironolactone (potency) and eplerenone (specificity). An early study by the developers of finerenone showed equal distribution of C14-radiolabeled finerenone between the heart and kidney in a rat.¹⁰³ This finding was contrasted with a study of H3-labeled spironolactone published in 1972, suggesting predominant renal distribution.¹⁰⁴ This difference was touted as a potential differentiator of the nsMRAs, with the authors speculating that tissue distribution might differ between sMRA and nsMRAs and suggesting that finerenone might have lower renal accumulation and could theoretically induce less hyperkalemia while achieving similar non-renal benefits. That study showed improved cardiorenal protection by finerenone compared to eplerenone in a rat hypertension model.¹⁰³ Since potassium handling differs between rodents and humans, the impact on hyperkalemia cannot be assessed in these preclinical models, thus requiring testing in human patients.

An attempt was made to address this theoretical benefit of nsMRAs versus sMRAs by comparing the results of the AMBER trial, which tested spironolactone with and without the potassium binder patiromer in pateints with resistant hypertension and CKD, attempting to match this data to a subset of patients in the FIDELITY trial.¹⁰⁵ That post hoc analysis concluded that a dose of finerenone that achieved about half the BP lowering of spironolactone, resulted in less hyperkalemia than spironolactone.¹⁰⁶ However, since this was a post hoc analysis, without evidence of similar effective doses, with outcomes evaluated at different durations of treatment, and with different patient populations, a conclusion about relative risk of hyperkalemia cannot be drawn. Head-to-head comparison at similar MR-blocking doses would be needed to assess the relative impact on potassium regulation. One such trial provides some more rigorous data. In the ARTS-HF trial, the sMRA eplerenone (max 50 mg/day, average achieved 38.6 mg/day) was compared to 5 doses of the nsMRA finerenone in patients with HFrEF to determine the dose of finerenone (target 5–20 mg) that mediates the same cardiac benefits as eplerenone, as reflected by the fraction of patients with a decline in NT-proBNP of at least 30%.¹⁰⁷ In that study, doses of finerenone (10–20 mg/day) that achieved the same cardiac biomarker benefit as eplerenone, also had a similar safety profile to eplerenone. Specifically, with regards to hyperkalemia, potassium levels increased in all treatment groups with no significant difference between the sMRA and the nsMRA. Importantly, severe hyperkalemia (serum potassium >6mmol/L) was very rare, with only 5 events in 1023 subjects, with no difference in severe hyperkalemia events between sMRA and nsMRA.¹⁰⁷ Hence, head-to-head clinical data supports that doses of finerenone and eplerenone that produce similar impact on cardiac biomarkers also have similar impact on hyperkalemia risk. Whether there is a difference in the hyperkalemia risk when sMRAs and nsMRAs are directly compared in patients with CKD requires further head-to-head evaluation.

Esaxerenone is a nsMRA that is currently only approved for use in Japan, therefore the knowledge and experience with its use stem from a single country. Several studies from Japan have demonstrated the efficacy of esaxerenone in lowering BP in patients with primary aldosteronism in a durable and safe manner, including in elderly individuals.^108,109 Studies in patients with essential hypertension have also shown that esaxerenone serves as an effective anti-hypertensive agent with similar BP lowering capacity to eplerenone.^110,111

ASIs: A new class of agents to block PA pathophysiology

Aldosterone synthase inhibitors (ASI) are an emerging new class of agents with potential to lower blood pressure by inhibition of aldosterone synthase (CYP11B2), the rate limiting enzyme in adrenal aldosterone biosynthesis.¹¹² An important limitation in prior development of aldosterone synthase inhibitors for blood pressure control is the biochemical similarity between aldosterone synthase and the cortisol producing enzyme 11ß-hydroxylase (CYP11B1). Early ASIs were less specific for CYP11B2, also inhibiting CYP11B1 at similar concentrations. For example, the first ASI studied was LCI-699, for which a randomized control trial demonstrated a statistically significant decrease in systolic blood pressure compared to placebo at all doses of the drug studied (Table 2).⁴⁹ However, 20% of patients receiving the highest dose of the study drug had suppression of cortisol due to off-target effects on 11ß-hydroxylase. Subsequently, this compound was renamed osilodrostat and approved for use in Cushing’s syndrome.¹¹³ Baxdrostat, lorundrostat, and dexfodrostat are three highly specific ASIs under development. These agents decrease aldosterone production and hence may have benefits in hypertension in the setting of dysregulated aldosterone.

Table 2:

Review of randomized control clinical trials investigating the use of aldosterone synthase inhibitors for the management of (a) hard to control blood pressure and (b) for the management of primary aldosteronism.

Study (year)	Aldosterone synthase inhibitor	Study design, number of patients	Patient population	Primary outcome	Treatment groups	Primary outcome result	Incidence of significant hyperkalemia
Calhoun et al (2011)49	Osilodrostat	Phase II RCT, 524	Adults with stage 1 or 2 HTN, untreated or treated with ≥ 2 anti-hypertensives, eGFR > 60 mL/min	Change in trough mean DBP at 8 weeks compared to baseline	Placebo, osilodrostat (0.25 mg daily, 0.5 mg daily, 1 mg daily, 0.5 mg twice daily), eplerenone 50 mg twice daily	1 mg qd osilodrostat decreased DBP by −7.1 mmHg. Secondary outcome notable for statistically significant reduction in SBP compared to placebo for all doses of osilodrostat studied.	Incidence of K > 6: one in each osilodrostat group, hyperkalemia resolved on repeat lab draw.
BrigHTN (2023)50	Baxdrostat	Phase II RCT, 275	Adults with resistant HTN: 3 anti-hypertensive medications with BP > 130/80. Patient with eGFR <45 mL/min were excluded	Change in mean systolic BP at 12-week visit compared to baseline	Placebo, baxdrostat (0.5 mg daily, 1 mg daily, 2 mg daily)	Decrease in SBP compared to placebo for 2 mg dose of −11 mmhg (CI −16.4 to −5.5), for 1 mg group −8.1 mmHg (−13.5 to −2.8)	6 cases of hyperkalemia requiring interruption or treatment, 4 patients were able to resume baxdrostat and complete trial with normokalaemia.
Target-HTN (2023)53	Lorundrostat	Phase II RCT, 200	Adults with BP > 130/80 despite 4 weeks of ≥ 2 anti-hypertensives, eGFR > 60 mL/min	Change in systolic automated office BP at 8 weeks compared to baseline	Placebo, lorundrostat (12.5 mg daily, 12.5 mg twice daily, 25 mg twice daily, 50 mg daily, or 100 mg daily)	Decrease from placebo in least-squares mean BP of −11.9 mmHg (CI −14 .1 to −1.5) for 100 mg daily, −9.6 mmHg (−15.8 to −3.4) for 50 mg daily. Lower doses did not reach statistical significance.	6 patients had hyperkalemia above 6, managed through holding or decreasing dose of lorundrostat, complete the trial
BaxHTN (2025)52	Baxdrostat	Phase III RCT, 794	Adults with uncontrolled HTN: BP > 140 despite treatment with 2 antihypertensives, resistant HTN: BP > 140 despite treatment with 3 antihypertensives with a diuretic	Change in seated systolic BP at 12-week visit compared to baseline	Placebo, badxrostat (1 mg daily, 2 mg daily)	Treatment difference from placebo was −8.7 mmHg (CI −11.5 to −5.8) for 1 mg, −9.8 mmHg (CI −12.6 to −7) for 2 mg.	Clinical intervention due to hyperkalemia: 7 of 264 for.1 mg, 21 of 266 patients with 2 mg, 0 of 264 in placebo.
Advance-HTN (2025)51	Lorundrostat	Phase IIb, 282	Adults with SBP 140–180 mmHg and DBP 65–110 or adults with DBP 90–110, taking 2–5 anti-hypertensives. Patient with eGFR <45 mL/min were excluded. Home anti-hypertensives were discontinued and were replaced with standard therapies.	Change in 24-hour average systolic BP at 12 weeks compared to baseline	Placebo, lorundrostat 50 mg daily (stable dose), lorundrostat 50 mg daily until 4 weeks after randomization, then increased to 100 mg daily if office SBP remained > 130 mmHg (dose-adjustment group)	Decrease compared to placebo of −7.9 mmHg (CI −13.3 to −2.6) for stable dose group, −6.5 mmHg (CI −11.8 to −1.2) for dose-adjustment group	Hyperkalemia leading to dose adjustment: 5 of 94 in stable dose group, 8 of 95 in dose-adjustment group, 0 of 95 in placebo group
LAUNCH-HTN (2025)54	Lorundrostat	Phase III, 1083	Adults with SBP 140–180 mmHg and DBP 65–110 or adults with DBP 90–110, taking 2–5 anti-hypertensives. Patient with eGFR <45 mL/min were excluded. Home anti-hypertensives were discontinued and were replaced with standard therapies.	Change in office SBP at 6 weeks compared to baseline	Placebo, lorundrostat 50 mg once daily, lorundrostat 50 mg once daily until 6 weeks, then 100 mg if SBP > 130 mmHg	Mean group difference between placebo and stable 50 mg dose of −9.1 mmHg (CI −13.3 to −4.9)	Dose reduction, interruption, or discontinuation due to hyperkalemia: 11 of 538 in standard dose group 7 of 270 in higher dose group, 1 of 270 in placebo group
Mulatero et al (2024)55	Dexfadrostat	Phase IIa, 35	Adults with primary aldosteronism and office SBP of 145–190 mmHg	Change in aldosterone to renin ratio and mean 24 hour ambulatory SBP at 8 weeks compared to baseline	Dexfadrostat (4 mg, 8 mg, 12 m daily)	Decrease in least-squares mean 24 hour ambulatory SBP decreased by 10.7 mmHg (CI −13.6 to −7.9)	No instances of hyperkalemia noted during treatment period.
SPARK (2025)56	Baxdrostat	Phase IIa, 15	Adults with hypertension and primary aldosteronism	Change in office systolic BP at 12 weeks compared to baseline	Baxdrostat (2 mg daily for 2 weeks, then increased to 4 mg or 8 mg as tolerated)	Mean reduction in SBP by −24.9 mmHg (CI −19 to −30.8)	No patients had hyperkalemia during the primary study period of 12 weeks.

Mechanistic differences between MRAs and ASIs:

All MRAs block MR activity, whether induced by aldosterone, cortisol or ligand-independent MR activation by Rac1 or AngII. It is through these combined mechanisms that sMRAs and snMRAs lower blood pressure and prevent cardiorenal damage in preclinical animal models. MRAs also raise aldosterone levels, due to negative feedback in the adrenal gland. ASIs, on the other hand, lower aldosterone production thereby preventing aldosterone-induced MR activation. A theoretical advantage of ASIs would be blockade of MR-independent aldosterone effects. As such, early speculation of an alternative non-MR aldosterone receptor mediating non-genomic actions provided a potential rationale for ASI benefits that could not be achieved with an MRA. However, the synthesis of evidence supports the conclusion that the non-genomic actions of aldosterone are mediated by traditional MRs tethered to the membrane, thereby mitigating this theoretical benefit of ASIs.²⁰ Another piece of evidence supporting the concept that the detrimental cardiovascular effects of aldosterone are mediated by the traditional MR comes from rare genetic mutationd in the MR that renders the receptor non-functional. A case control study comparing patients with primary hyperaldosteronism to essential hypertension reveals that high aldosterone with functional MR associates with a very high risk of cardiovascular disease, independent of blood pressure.⁸⁹ Conversely, a case control study in patients with pseudohypoaldosteronism type 1 patients with high aldosterone due to feedback from non-functional MR, shows no increased risk of CVD when aldosterone is elevated in the absence of MR function.¹⁰⁶ Furthermore, ASIs do not impact cortisol or ligand-independent MR activation. To the extent that those aldosterone-independent effects are driving hypertension or cardiorenal pathology in humans, one might expect ASIs to be less effective at mitigating those pathologies. Conversely, if there are some benefits to the aldosterone-independent effects of the MR, specific blockade of aldosterone effects with ASIs could have theoretical benefits, although such cardiovascular benefits from aldosterone-independent MR activity remain to be identified. Finally, all classes of drugs that attenuate the actions of the MR in the kidney result in a rise in serum potassium. The extent of the rise in potassium depends on the degree of aldosterone excess or MR activation in the patients, the drug dose, the potency of MR inhibition, and the renal function of the subject. Importantly, one can consider these theoretical benefits but only head-to-head studies of sMRAs, nsMRAs and ASIs in human subjects will be able to determine if there are any differential effects of these drug classes for BP lowering, cardiorenal benefits, or hyperkalemia risk.

Clinical data for sMRAs for blood pressure control

Steroidal mineralocorticoid receptor antagonists (MRAs) are effective blood pressure lowering agents, but their use can be limited by side effects.²⁹ Many studies support the concept that low-renin hypertension is common and that sMRAs are particularly effective in this subset of hypertensive patients. The ASPIRANT trial studied spironolactone as an additional agent in resistant hypertension revealing significant additional systolic BP lowering effect compared to placebo.¹¹⁴ Patients with higher aldosterone-renin ratios (ARR) appeared to have more significant systolic blood pressure reduction with spironolactone. The PATHWAY-2 trial was a crossover study that compared spironolactone, doxazosin, bisoprolol versus placebo as add-on therapy for resistant hypertension.⁴⁶ Spironolactone had superior BP lowering effects compared to the other agents studied⁴⁶ and BP lowering with spironolactone was enhanced when renin was lower and aldosterone-to-renin ratio was higher.⁴⁷ Patients in the spironolactone group had an increase in plasma renin concentration that correlated with SBP lowering that was not seen with the other agents. The HOMAGE trial tested galectin-3 as a biomarker of collagen turnover in patients treated with spironolactone.⁷⁶ A pre-specified secondary analysis showed that patients with low renin physiology had improved blood pressure response to spironolactone in comparison to patients with higher renin levels.⁴⁸

Several meta-analyses provide further evidence of spironolactone’s efficacy for lowering both office and ambulatory blood pressure.^115–117 Canrenone, an active metabolite of spironolactone, has also demonstrated efficacy as an add-on therapy for resistant hypertension, although it is not currently broadly approved for use.^118,119 Eplerenone also has demonstrated efficacy in BP lowering as an add-on therapy for patients with resistant HTN. A randomized controlled trial demonstrated a statistically significant reduction in ambulatory but not clinic SBP in the eplerenone group, although the SBP lowering effect was modest, approximately −2 mmHg.¹²⁰ Treatment with low dose eplerenone (50 mg) has also been demonstrated to improve markers of aortic stiffness independent of effect on SBP.¹²¹

Overall, the sMRAs are effective in lowering blood pressure, especially in resistant hypertension, with spironolactone being more effective than eplerenone, consistent with higher MR-inhibiting potency. The superior efficacy of spironolactone over non-MR modulating agents in the PATHWAY-2 trial, combined with the hormonal profile data suggests that many patients with resistant hypertension have renin-independent aldosterone production (or primary aldosteronism pathophysiology) that was unrecognized and that those patients are particularly responsive to MR inhibition.

Regarding side effects, eplerenone is a more specific MRA and hence is much less likely to cause gynecomastia and other anti-androgenic effects in comparison to spironolactone.¹²² Hyperkalemia is an important potential complication of steroidal MRA use, although there were no events noted in the ASPIRANT trial and hyperkalemia occurred in approximately 2% of patients in the PATHWAY-2 trial.^46,114

Steroidal MRAs are also used for guideline directed medical therapy among patients with heart failure with reduced ejection fraction with the potential for stimulating positive remodeling and improvement in left ventricular ejection fraction.¹²³ The benefit of spironolactone in heart failure patients is likely secondary to reducing the inflammatory and profibrotic milieu of aldosterone over-activation.¹²⁴ In addition, steroidal MRAs remain the standard of care for treatment of patients with primary aldosteronism who are not candidates for adrenalectomy.¹²⁵ Despite their demonstrated efficacy, the use of steroidal MRAs has been limited due to concern for adverse effects including hyperkalemia as well as off-target anti-androgenic effects leading to gynecomastia.^126,127

Clinical trials supporting non-steroidal mineralocorticoid receptor antagonists

More recently, clinical trials have also demonstrated that the nonsteroidal MRAs are effective in reducing adverse cardiovascular and renal outcomes and improving blood pressure (Table 1). Finerenone was compared to placebo in the FIDELIO-DKD trial in patients with diabetes mellitus and advanced CKD¹²⁸, focusing on renal outcomes, and the paired FIGARO-DKD trial in those with diabetes and mild renal impairment, focusing on cardiac outcomes.¹²⁹ Both trials demonstrated a modest blood pressure effect with finerenone compared to placebo (−3–4 mm Hg, see Table 1). Despite these modest reductions in BP, finerenone significantly reduced renal failure progression or death from renal causes in FIDELIO-DKD and adverse cardiovascular outcomes in FIGARO-DKD, driven primarily by a reduction in heart failure hospitalization. The incidence of hyperkalemia in FIDELIO-DKD was higher than in most MRA trials (18% vs 9% in placebo) in the setting of patients with advanced CKD but there were relatively few serious adverse events related to hyperkalemia. The incidence of hyperkalemia and hyperkalemia-related discontinuation in the trial was lower in FIGARO-DKD compared to FIDELIO-DKD in the context of less advanced CKD. Finerenone was also studied among patients with mildly reduced ejection fraction (greater than 40%) in the FINEARTS-HF trial.¹³⁰ Once again, there was a modest BP lowering effect and a significant decrease in the composite outcome of worsening heart failure or death from cardiovascular cause among patients treated with finerenone with a risk of hyperkalemia (>6 mmol/l) of 3% in this population with relatively normal kidney function (Table 1). The FINALITY-HF trial (NCT06033950) will study the effect of finerenone among patients with heart failure with reduced ejection fraction who do not tolerate steroidal MRAs.

Table 1:

Review of Phase III randomized control clinical trials investigating the use of nonsteroidal mineralocorticoid receptor antagonists.

Study (year)	Mineralocorticoid receptor antagonist	Study design, number of patients	Patient population	Primary outcome	Treatment groups	Primary outcome result	Effect on blood pressure	Incidence of significant hyperkalemia
FIDELIO-DKD (2020)128	Finerenone	Phase III, 5674	Adult patients with type 2 diabetes mellitus and advanced CKD (stage 3 or 4 with albuminuria)	Composite of renal failure, sustained decrease in eGFR by 40% over at least 4 weeks, death from renal causes	Placebo, finerenone (10 mg or 20 mg as tolerated)	Incidence of primary outcome in finerenone group (504 patients, 17.8%) versus placebo (600 patients, 21.1%), HR of 0.82 (CI 0.73–0.93)	Change of BP of −2.1 mmHg with finerenone and 0.9 mmHg with placebo at 12 months	Hyperkalemia related adverse events: finerenone (18.3%), placebo (9%). Discontinuation of trial due to hyperkalemia: finerenone (2.3%) or placebo (0.9%)
FIGARO-DKD (2021)129	Finerenone	Phase III, 7352	Adult patients with type 2 diabetes mellitus and CKD (stage 2–4 with moderate albuminuria or 1–2 with severe albuminuria)	Composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, hospitalization for heart failure	Placebo, finerenone (10 mg or 20 mg as tolerated.	Incidence of primary outcome in finerenone (458 patients, 12.4%) versus placebo (519 patients, 14.2%), HR of 0.87 (CI 0.76–0.98)	Decrease in BP in finerenone group compared to placebo of −3.5 mmHg at 4 months and −2.6 mmHg at 24 months	Hyperkalemia: finerenone (10.8%), placebo (5.3%), discontinuation of trial due to hyperkalemia: finerenone (1.2%), placebo (0.4%)
FINEARTS-HF (2024)130	Finerenone	Phase III, 6001	Adults 40 years or older, symptomatic HF, LVEF of 40% or greater, elevated natriuretic peptide levels	Composite of worsening HF event (HF hospitalization or urgent visit), death from cardiovascular cause	Placebo, finerenone (20 mg or 40 mg per eGFR)	Incidence of primary outcome in finerenone (624 of 3003 patients), placebo (719 in 2998), HR 0.84 (CI 0.74–0.95)	Decrease in BP in finerenone group compared to placebo of −3.4 mmHg (CI −2.4 to −4.2) at 6 months	Hyperkalemia greater than 6 mmol/L: finerenone (3%), placebo (1.4%)
Rakugi (2019)110	Esaxrenone	Phase III, 368	Adults 20 years or older, untreated essential HTN or 1 anti-hypertensive (RAS inhibitor or calcium channel blocker), sitting SBP > 140 mmHg or DBP > 90 mmHg, 24 hour ambulatory BP > 130/80 mmHg, eGFR > 60 mL/min	Change in baseline of sitting BP after 12 weeks, 28 weeks, and 52 weeks	Esaxrenone (2.5 mg or 5 mg as tolerated) monotherapy, esaxrenone (2.5 mg or 5 mg as tolerated) combined with RAS inhibitor or CCB	Overall change in sitting SBP: 12 weeks: −16.1 mmHg (CI −17.3 to −14.9), 28 weeks: −18.9 mmHg (CI −20.2 to −17.7), 52 weeks: −23.1 (CI −25 to −21)	As in primary outcome	Hyperkalemia greater than 6 mmol/L or greater than 5.5 mmoL/L on two measurements: monotherapy group: 4 patients (1.1%), combination group 0 patients. 1 patient withdrawn for elevated serum potassium due to study drug
ESAX-HTN (2020)111	Esaxrenone	Phase III, 998	Adults 20 years or older, SBP 140–170 mmHg, DBP 90–109 mmHg, eGFR > 60 mL/min	Change in sitting BP at baseline compared to 12 weeks	Esaxrenone 2.5 mg, esaxrenone 5 mg, eplerenone 50 mg	Change in SBP in esaxrenone 5 mg/day compared to eplerenone 50 mg/day: −4.8 mmHg (CI −6.4 to −3.1)	As in primary outcome	Hyperkalemia greater than 6 mmol/L or greater than 5.5 mmoL/L on two measurements: 3 of 331 in esaxrenone 2.5 mg/day group, 2 of 338 in esaxrenone 5 mg/day group, 0 of 332 in eplerenone group. 1 patient in esaxrenone 5 mg/day group discontinued trial due to hyperkalemia.
EXCITE-HT (2024)132	Esaxrenone	Phase III, 585	Adults aged 20–75 years old, 1 anti-hypertensive (ARB or CCB), SBP >125 mmHg or DBP > 75 mmHg	Change in home morning BP at baseline compared to 12 weeks	Esaxrenone (2.5 mg or 5 mg as tolerated), trichlormethiazide (dose per clinician)	Least means square change in SBP in esaxrenone compared to trichlormethiazide: −2.2 mmHg (CI −3.6 to −0.8)	As in primary outcome.	Hyperkalemia greater than 5.5 mmol/L: 2% in esaxrenone group, 0% in trichlormethiazide group. No patients had serum potassium above 6 mmol/L

Finerenone may be non-inferior to spironolactone for blood pressure control among patients with primary aldosteronism. A small pilot study comparing finerenone to spironolactone for patients with primary aldosteronism revealed similar BP control with fewer hormonally mediated adverse events in the finerenone compared to the spironolactone group.¹³¹ An additional clinical trial is underway, FAIRY (NCT06457074), to further study finerenone as a treatment for primary aldosteronism.

Another nonsteroidal MRA, esaxrenone, has been studied for its efficacy as a second-line blood pressure agent in multiple trials. The ESAX-HTN trial compared esaxrenone to eplerenone for blood pressure control in patients with poorly controlled hypertension.¹¹¹ Esaxrenone was non-inferior to eplerenone, and esaxrenone 5 mg/day was superior to eplerenone with a reduction in SBP of 4.8 mmHg. There were few instances of significant hyperkalemia in this population with normal renal function and only one patient discontinued due to hyperkalemia in the esaxrenone group. Another trial examined esaxrenone in patients with essential hypertension showing significant SBP lowering effect compared to baseline, with sitting BP reduced by −16.1 mmHg at 12 weeks and sustained decrease with follow-up through 52 weeks.¹¹⁰ The EXCITE-HT trial compared esaxrenone to trichlormethiazide for patients with persistent hypertension despite treatment with either an ARB or CCB showing non-inferiority between esaxrenone and trichlormethiazide and superiority for home systolic BP lowering in the esaxrenone group.¹³² Overall, esaxrenone demonstrates efficacy comparable to steroidal MRAs for hypertension and appears well tolerated, without significant hyperkalemia despite combination therapy with RAS inhibitors or CCB (Table 1).

Overall, nsMRAs are well-tolerated, including in patients with CKD, and have significant cardiovascular and renal benefits. Both finerenone and esaxrenone are likely to be of benefit among patients with primary aldosteronism and resistant hypertension. Additional studies are needed to investigate the benefit of esaxrenone for protection against cardiac and renal adverse outcomes. In addition, rates of hyperkalemia were relatively low in the major clinical trials, but with higher incidence of hyperkalemia among patients with more advanced CKD. A random-effects meta-analysis of clinical trials of the safety and efficacy of sMRAs and nsMRAs in uncontrolled hypertension, concluded that no significant difference is observed regarding their effects on systolic BP or serum potassium.¹³³ Overall, nsMRAs and sMRAs function by similar mechanisms with similar efficacy and safety. The nsMRAs are useful in circumstances for which off target side effects limit use of spironolactone and improve upon the lack of potency of eplerenone.

Aldosterone synthase inhibitors

New aldosterone synthase inhibitors are being developed with high selectivity for aldosterone synthase as compared to 11ß-hydroxylase (Table 2). The first in the class, baxdrostat, was studied in the BRIG-HTN trial, showing dose-dependent reduction in systolic BP in uncontrolled hypertension patients,⁵⁰ which was confirmed in Bax-HTN with resistantn hypertension in a larger patient population and longer follow-up.⁵² There were similar decreases in BP in both the uncontrolled hypertension and the resistant hypertension patient populations. The study included a randomized withdrawal period where patients in the baxdrostat treatment group were monitored off baxdrostat and demonstrated a sustained reduction in BP, suggesting lasting hormonal changes after even short-term use of ASI. Additional trials are ongoing for baxdrostat for hypertension (BAX24, NCT06168409) and uncontrolled or resistant hypertension (BAXASIA, NCT06344104). Baxdrostat is also under active investigation both for preventing adverse cardiovascular outcomes in high-risk patients (NCT06677060) and for the prevention of adverse renal outcomes and disease progression in patients with CKD (NCT06742723, NCT07222917).

Lorundrostat has also been found to decrease BP in patients with resistant hypertension with suppressed renin or with increased plasma renin activity in the Target-HTN trial.⁵³ There was no significant difference between the blood pressure lowering effect of the ASI in patients with suppressed renin or patients with elevated plasma renin activity and no evidence of off-target effect on the cortisol axis. Advance-HTN further demonstrated the effectiveness of lorundrostat for treatment resistant hypertension, after ruling out white coat hypertension (Table 2).⁵¹ The Launch-HTN trial confirmed BP reduction in a larger patient population and extended safety analysis with an ongoing open label study with longer term follow-up (NCT05968430).⁵⁴

Aldosterone synthase inhibitors have also been investigated for their benefit for the treatment of primary aldosteronism (PA). Current management of PA is limited to use of steroidal MRAs or surgical adrenalectomy.¹²⁵ ASIs target the primary pathophysiology of PA by decreasing the excess production of aldosterone (Table 2).⁵⁶ Fifteen patients in the Phase IIa SPARK trial demonstrated a significant decrease in systolic BP with baxdrostat (−24.9 mmHg).⁵⁶ An additional ASI, dexfadrostat, showed BP lowering benefit in primary aldosteronism, revealing no differences in BP control between patients with unilateral, bilateral, or undetermined adrenal disease as the cause of PA.⁵⁵ Together, these studies demonstrate the promise of improved efficacy at lowering BP among patients with PA, but further study is needed for approval and widespread use. The BaxPA trial is studying the effect of baxdrostat on blood pressure and plasma renin activity on patients with PA (NCT07007793).

Additionally, the aldosterone synthase inhibitor vicadrostat was well tolerated in a recent Phase I clinical trial among patients with diabetes and albuminuric CKD.¹³⁴ Ongoing clinical trials combining ASIs with sodium glucose cotransport type 2 (SGLT2) inhibitors are investigating efficacy in preventing progression of CKD as well as heart failure.

The summary at this time is that two aldosterone synthase inhibitors (baxdrostat, lorundrostat) have demonstrated high specificity for aldosterone synthase inhibition as well as a clinically significant decrease in systolic blood pressure with many trials still ongoing. Although the incidence of hyperkalemia increased with treatment in a dose-dependent manner with these medications, the incidence remained low and most patients were able to complete the clinical trial on the study medication.

Potential clinical utility of non-steroidal MRAs and ASIs to improve outcomes among the elderly

As described in Part I, aging is associated with dysregulated aldosterone relative to renin, increased MR expression, and increased MR activity due to aldosterone-dependent and aldosterone-independent mechanisms (Figure 3). The elderly and very old also have a high prevalence of hypertension, heart failure, CKD, MI, stroke and neurodegenerative disease. While not specifically studied in the elderly, clinical trials reveal that nsMRAs, reduce BP to an extent similar to spironolactone in patients with PA¹³¹, reduce heart failure, CV death, and adverse renal outcomes in patients with CKD with DM,^128,129 and reduce CV mortality and hospitalizations in patients with HF with mildly reduced or preserved ejection fraction.¹³⁰

Similarly, ASIs are effective in controlling BP in patients with treatment-resistant hypertension, which is common in the elderly, and these new agents are well-tolerated.^50,53,55 While effective in blocking adrenal aldosterone synthesis, lowering BP, and reducing adverse effects associated with uncontrolled hypertension, ASIs would theoretically not prevent aldosterone-independent activation of the MR, which may contribute to aging-associated CVD. Only clinical studies directly comparing ASIs to MRAs would be able to determine the relative benefits of blocking aldosterone production versus blocking the MR.

Increasing evidence also suggests the importance of glucagon-like peptide-1 receptor antagonists (GLP-1 RAs) in reducing BP and adverse CV outcomes in patients with DM, visceral obesity and heart failure with preserved ejection fraction, independent of their effect on weight loss.^135–137 The reduction in body weight and adipocyte mass associated with the use of a GLP-1 RA could theoretically reduce local adipocyte production of factors (such as leptin) that stimulate adrenal aldosterone synthesis, and potentially decrease MR expression and activation due to a reduction in inflammation or oxidative stress (Figure 3). However, it is important to note that these theoretical benefits have never been explored in humans. It will be important to determine whether weight loss due to GLP-1 receptor agonism mitigates the adverse adipose phenotype that drives adrenal aldosterone production or whether ASIs or MRAs remain beneficial once obesity is treated with these new incretin therapies. There are evolving clinical studies examining whether combination therapy with an SGLT-2-inhibitor may have additive or synergistic benefits with MRAs or ASIs, potentially mitigating hyperkalemia.¹³⁸ However, these new therapies and combinations will need to be tested specifically in the elderly and very old, to fully understand the potential benefits and balance those with risks, in the aging population with multiple comorbidities.

Clinical Perspective and Future Directions

While recent clinical guidelines have expanded the recommendation for screening for primary aldosteronism,²⁹ it may be of benefit to obtain screening aldosterone-to-renin ratio levels for elderly or very old patients with essential hypertension, particularly when blood pressure is poorly controlled. Careful consideration can be made for the addition of a steroidal or nonsteroidal MRAs or ASIs to the blood pressure regimen of elderly and very old people. Renal function and electrolytes should be monitored as per current guidelines, and additional medications may be prescribed to mitigate risks of hyperkalemia. Patients with advanced CKD may benefit from chlorthalidone, given its potassium wasting properties and demonstrated benefit for blood pressure control in this patient population.¹³⁹ In patients with concomitant CKD and DM, an SGLT2 inhibitor may reduce the risk of MRA-induced hyperkalemia and also improves cardiovascular and renal outcomes.^140,141 A potassium lowering agent, such as patiromer, may be used to support adherence to an MRA.¹⁴²

In summary, elderly and very old individuals are at increased risk for dysregulated aldosterone and increased mineralocorticoid receptor activity by a variety of mechanisms, and this may be contributing to poorly controlled hypertension and the associated increased risk of adverse cardiovascular and renal outcomes. sMRAs, nsMRAs and ASIs represent tools for the modulation of abnormal aldosterone production and MR activation. Further studies are needed to investigate their particular benefit in the elderly population and to directly compare the risks and benefits of these three classes of agents in head-to-head clinical trials in the elderly and very old.