Aldosterone Synthase Inhibitors for Cardiorenal Protection: Ready for Prime Time?

Aldosterone is a steroid hormone produced and secreted by the adrenal zona glomerulosa and a key component of the renin-angiotensin-aldosterone system [1]. Aldosterone is the master endogenous mineralocorticoid hormone, which acts on the late distal tubule and collecting duct of nephrons, promoting water and sodium reabsorption and potassium excretion while also maintaining pH balance [2]. The classic action of aldosterone is mediated by mineralocorticoid receptors (MRs). Upon aldosterone binding, MR moves from the cytoplasm to the nucleus to regulate the transcription of target genes and subsequent protein expression, i.e., the genomic pathway [3]. However, aldosterone has rapid effects that cannot be fully explained by the genomic pathway [4]. Some authors hold that an unknown aldosterone receptor embedded within the membrane activates the rapid signaling pathway [3], while other researchers contend that aldosterone rapid effects are at least in part mediated by the cytosolic MR [5]. Additionally, since the epidermal growth factor receptor co-immunoprecipitates with a small fraction of MR, epidermal growth factor receptor had been proposed as potential mediator of aldosterone dependent non-genomic signaling [6]. Finally, the plasma membrane G protein-coupled estrogen receptor GPER (or GPR30) had also been considered a strong candidate to explain aldosterone rapid effects as recently reviewed [7].

Either aldosterone deficiency or excess (hypoaldosteronism and hyperaldosteronism, respectively) had been linked to cardiovascular, renal, and metabolic diseases. Aldosterone deficiency leads to hyponatremia, hyperkalemia, and metabolic acidosis [8]. On the other hand, hyperaldosteronism is an important contributor to arrhythmia, heart failure, and chronic kidney disease (CKD) progression [9, 10]. The profibrotic and inflammatory effects of aldosterone contribute to organ damage, especially in the heart, the vasculature, and the kidney [11]. Studies on animal models showed that aldosterone exacerbates glomerulosclerosis, resulting in severe proteinuria, and contributes to renal fibrosis, through the development of hypertensive kidney disease and vascular injury [12]. The clinical benefit of aldosterone blockade had been successfully tested in clinical trials [13]. Drugs targeting renin-angiotensin system as angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) result in incomplete suppression of serum aldosterone levels. This effect is known as the “aldosterone escape phenomenon” [14]. Further studies showed that the administration of mineralocorticoid receptor antagonists (MRAs) might avoid this phenomenon and reduce proteinuria in CKD patients [15]. However, aldosterone antagonism with classical steroidal MRAs may increase risks of hyperkalemia, gynecomastia, and impaired sexual function [16]. Recently, novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone are more selective for MR than other steroid receptors including the glucocorticoid receptor (GR), androgen receptor, and progesterone receptor [17]. Therefore, NS-MRAs have been identified as compounds with much improved selectivity and safety profile across patients with CKD [18]. Despite the significant advances of S-MRAs and NS-MRAs, these compounds do not completely offset the aldosterone escape. Aldosterone non-genomic and non-MR-mediated effects are not targeted or even worsened by MRAs because of a compensatory increase of aldosterone-circulating levels [19]. Given the above, there is a robust and emerging interest in aldosterone synthase inhibitors (ASIs). Such compounds can block aldosterone production and lower its blood levels by targeting its biosynthesis pathway [11]. ASIs, as opposed to MRAs, could control both genomic and non-genomic aldosterone effects [19]. In recent years, several ASIs had been developed and tested in clinical studies focusing on patients with hypertension with or without CKD [19]. In the present overview, we will summarize aldosterone pathophysiology, the therapeutic role of S-MRAs and NS-MRAs, the development and the clinical potential of aldosterone synthase inhibitors (ASIs).

Aldosterone regulates water and potassium homeostasis. The most effective triggers for aldosterone release are the increase in serum potassium and decrease in plasma volume [20]. At physiological concentration, aldosterone acts through genomic pathways. Like all steroid hormones, the genomic pathway is activated by binding to specific cytoplasmic receptors [21]. MRs are expressed in several organs including the heart and the kidney. Upon aldosterone binding, the MR translocates to the nucleus and acts as a transcription factor, binding to specific regulatory sequences in the promoter level of multiple genes and recruiting several cofactors [22]. GRs and MRs are ubiquitously expressed, either within the same cell or differentially, and they interact at the molecular and functional levels. However, GRs have greater affinity for cortisol than aldosterone, on the contrary, MRs have similar affinity for these steroidal hormones [22]. In epithelial cells, and in a few non-epithelial tissues, MRs are defended from activation by cortisol via the action of the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD2) [23]. The counterregulatory protein 11βHSD2 converts the glucocorticoid hormones cortisol and corticosterone into MR-inactive products, which are cortisone and 11-dehydrocorticosterone (11-DOC), respectively. Due to the gatekeeper function of 11βHSD2 [21], aldosterone remains the primary ligand to MRs [22]. However, 11βHSD2 is not present in all MR-expressing tissues. In these kinds of tissues, glucocorticoid engagement of MRs may drive a mineralocorticoid-like activity [24]. This is the case of cardiomyocytes that do express MRs but not 11βHSD2, so are exposed to non-aldosterone-mediated activation of the MR [23]. This condition is even more exacerbated by inappropriate induction of MR expression in several tissues secondary to state of chronic inflammation.

The pivotal role of MR is the regulation of water and electrolyte balance in the aldosterone sensitive distal nephron, which involves the late distal convolute tubule, the connecting tubule, and the collecting duct [22, 25]. The response to aldosterone in the aldosterone sensitive distal nephron is dependent on the expression of both the MR and 11βHSD2 [25]. Here, aldosterone promotes sodium reabsorption by stimulating the expression on the apical membrane together with transcription of crucial sodium transporters as sodium chloride cotransporter and epithelial sodium channel [25‒28]. However, aldosterone is the main kaliuretic hormone that regulates the expression on the apical membrane of the principal cells of the renal outer medullary potassium channel. The sodium retention and potassium excreting activity do not always occur together [20]. For instance, a phenomenon referred to as “aldosterone paradox” occurs in clinically relevant condition such as dehydration, in which large volume triggers aldosterone-mediated sodium and chloride reabsorption, but do not cause potassium loss. On the contrary, when potassium plasma levels raise, aldosterone is secreted and acts on the kidney to promote the excretion of the excess potassium [29]. Aldosterone is a blood pressure raising hormone [30], but quite paradoxically increased potassium intake decreases blood pressure in patients with hypertension [31], suggesting that potassium may act as a “diuretic” [32]. Gritter et al. [33] recently reviewed clinical and experimental studies showing that high potassium diet inhibits the sodium chloride cotransporter, i.e., thiazide-like effect, leading to increased natriuresis and lower blood pressure [33]. However, a recent randomized crossover study suggests that in healthy normotensives, an increased potassium intake potentiates aldosterone secretion but with no relevant effect on blood pressure [34]. Certainly, these physiological elements must be considered when prescribing any drug interfering with aldosterone activity at any level.

In state of disease, aldosterone triggers several pathologic processes including inflammation and fibrosis [35]. Indeed, aldosterone promotes systemic inflammation by the production of reactive oxygen species such as superoxide and hydrogen peroxide, which stimulates the proinflammatory transcription factors activator protein (AP)-1 and nuclear factor kappa B [35]. Specifically, aldosterone stimulates mitochondrial production of ROS in kidney cells and increases nicotinamide adenine dinucleotide phosphate oxidase activity and oxidative stress in podocytes and mesangial cells. Beyond the inflammatory effects ROS-mediated, aldosterone can also stimulate NFκB activity directly by activating the MR [35]. Aldosterone stimulates also innate immunity through the activation of a multiprotein cytosolic complex which is the nucleotide-binding oligomerization domain protein 3 (NLRP3) inflammasome [19]. In bone marrow-derived murine macrophages, aldosterone increased levels of ROS and gene expression of NLRP3 and IL-1b [36]. Similarly, in human leukocytes, aldosterone increased NLRP3 expression and caspase-1 [36]. The inflammasome activation aldosterone-mediated has also been associated with podocyte damage [37] and tubular injury [38]. This inflammatory environment leads to subsequent fibrotic mechanisms, promoted by the same aldosterone. Broadly speaking, fibrosis occurs when there is an imbalance between production of collagen and matrix their degradation by matrix metalloproteinases [35]. Specifically, aldosterone provides directly the expression of molecules with profibrotic activity, such as transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor 1, endothelin 1, placental growth factor, and osteopontin [35]. Through its inflammatory and fibrotic effects, aldosterone can lead to dysfunction of heart, vasculature, and kidney [35]. In the heart, excess aldosterone promotes profibrotic effects inducing myofibroblast proliferation, TGF-β expression, and matrix remodeling [39]. Within the vasculature, MR activation leads to local inflammation and endothelial dysfunction though NFκB and leukocyte adhesion molecules such as intercellular adhesion molecule-1 [40]. MR activation also enhances stiffness and arterial fibrosis by myogenic tone and attenuation of vasodilatory molecules [41]. In the nephron, MR activation is related to inflammation by ROS-mediated effects, glomerulosclerosis by serum- and glucocorticoid-regulated kinase-1 upregulation, and tubulointerstitial fibrosis by TGF-β. Indeed, elevated blood levels of aldosterone are associated with CKD progression and increased proteinuria [19].

Although, aldosterone pathophysiology is largely related to genomic effects [3], there is growing knowledge on its rapid non-genomic effects [42]. It is currently held that aldosterone has non-genomic, non-MR-mediated, effects in various tissues and organs (Fig. 1) [43]. Despite a lively scientific debate, the identified receptor, responsible for the non-genomic effects, seems to be the G protein-coupled estrogen receptor GPER/GPR30, which may trigger MR-independent pathways and amplify the MR-mediated signaling [44].

The activation of non-genomic pathways had been reported in several cellular and animal models of cardiovascular diseases [43]. Interestingly, even in MR knockout models, non-genomic effects may still persist [43]. Moreover, non-genomic effects may modulate aldosterone’s genomic pathway [43] and do not seem to be influenced by MRA treatment, which incidentally determines a compensatory increase of aldosterone levels [45]. Even though aldosterone’s non-genomic effects are not completely elucidated, they include increase in intracellular calcium levels, modulation of vascular resistance, increase in ROS production, and enhancement of inflammation [19].

Specifically, the non-genomic pathway seems mediated by protein kinases C (PKC) and cellular homolog of the transforming gene of Rous sarcoma virus family kinases signaling pathway [3]. On cardiomyocytes, in vitro, rapid aldosterone stimulation triggers a ROS-mediated damage and promotes the release of atrial natriuretic peptide (ANP) and A-kinase anchor protein (AKAP) contributing to cell hypertrophy [46]. On the other hand, in rabbit microdissected connecting tubule associated with afferent arterioles, aldosterone triggers the dilatation of the afferent arterioles in a GPER- and sodium-hydrogen exchanger 1-dependent way. This effect called connecting tubule glomerular feedback could be relevant in the pathogenesis of the aldosterone-mediated glomerular damage [47].

Mineralocorticoid receptor antagonists inhibit aldosterone from binding to the MR [48] and are currently classified as S-MRAs and NS-MRAs [49].

International guidelines consistently recommend S-MRAs, such as spironolactone and eplerenone, for treating primary aldosteronism [50], resistant hypertension (rHTN) [51], and heart failure [52]. However, spironolactone is a nonselective progesterone receptor agonist and an androgen receptor antagonist, in turn, responsible for adverse effects such as gynecomastia, menstrual irregularities, and decreased libido [53]. Such off-target side effects are somewhat less frequent with eplerenone, but both S-MRAs carry an increased risk of hyperkalemia [53]. In the ROTATE-3 study [54], hyperkalemia was more frequently reported with eplerenone (17.4%) than with dapagliflozin (0%) or dapagliflozin-eplerenone (4.3%; p value = 0.003). Thus, the addition of dapagliflozin to eplerenone substantially reduced S-MRA-induced hyperkalemia [54]. In summary, hyperkalemia, endocrine adverse effects, and worsening renal function [55] often limit the clinical use of these effective compounds.

A consensus report [56] by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) recommended NS-MRA for patients with type 2 diabetes with albumin-to-creatinine ratio ≥30 mg/g and normal serum potassium concentration. Finerenone is the only ns-MRA with proven renal [57] and cardiovascular [58] efficacy. In July 2021, the Food and Drug Administration (FDA) approved finerenone to reduce the risk of kidney function decline, kidney failure, cardiovascular death, nonfatal heart attacks, and hospitalization for heart failure in adults with CKD associated with type 2 diabetes [59]. The decision was driven by the results of two randomized trials [57, 58] and their pooled analysis [60]. Besides CKD, finerenone was also investigated in patients with heart failure. In the phase III FINEARTS-HF [61], finerenone met the primary composite efficacy endpoint (worsening heart failure and cardiovascular death) in patients with heart failure with mildly reduced or preserved ejection fraction. Finally, the recently published FINE-HEART pre-planned individual-level pooled analysis [62] of 18,991 participants enrolled in the above-mentioned efficacy trials [57, 58, 61], confirmed finerenone efficacy on all-cause mortality, cardiovascular events, and kidney outcomes in patients with overlapping cardiovascular-kidney-metabolic diseases.

Beyond finerenone, other NS-MRA are in clinical development: esaxerenone (recently approved in Japan for hypertension) and ocedurenone [63]. Esaxerenone efficacy was investigated in two phase III studies ESAX-HTN and ESAX-DN. In the ESAX-HTN superiority analysis [64], esaxerenone 5 mg/day was more effective on blood pressure reduction than eplerenone 50 mg/day. In ESAX-DN [65], 455 patients with type 2 diabetes and microalbuminuria were randomized to esaxerenone or placebo. Active treatment resulted in a higher proportion of patients reaching UACR remission than placebo (22% and 4%, respectively; p < 0.001). Ocedurenone safety and efficacy were investigated in 162 patients with resistant or poorly controlled hypertension and advanced CKD (stage 3b/4) enrolled in BLOCK-CKD study [66]. The primary endpoint was systolic blood pressure (SBP) change from baseline at day 84. After 84 days, both doses of ocedurenone resulted in a significantly lower SBP. Based on the promising findings, a phase III “Efficacy and Safety of KBP-5074 in Uncontrolled Hypertension and Moderate or Severe CKD” (Clarion-CKD) [67] study was designed to evaluate the efficacy, safety, and durability of ocedurenone in adult participants with 3b/4 CKD and uncontrolled hypertension. Unluckily, based on the interim analysis, the CLARION-CKD trial was stopped early for futility [68].

Despite the significant advance of newer MRAs, these drugs can induce a compensatory increase in aldosterone levels [19], which potentially enhances the deleterious effects of MR-independent, non-genomic pathway. Hence, MRAs were not able to sufficiently abolish aldosterone-mediated cardiorenal damage. Bases on these considerations, during the last years, directly blocking aldosterone production by targeting its biosynthesis has been actively followed as an alternative therapeutic approach, which may confer additional benefits compared to current MRAs treatments [11].

In the mitochondria, aldosterone synthase (AS), encoded by CYP11B2, catalyzes the conversion of 11-deoxycorticosterone (11-DOC) to corticosterone and then to aldosterone, in the final rate-limiting step of the biosynthesis cascade [11, 29, 30]. Silencing CYP11B2 leads to reduced aldosterone production and lower circulating levels, which might be an effective strategy to control primary aldosteronism [69‒71]. Since ASIs lower aldosterone blood levels, as opposed to MRAs, both genomic and non-genomic effects may be attenuated [19] (Fig. 2). ASI treatment preserves MR function so that other MR ligands, e.g., glucocorticoids, could maintain a basal mineralocorticoid activity [19]. In recent decades, ASIs research lead to the development of several compounds and to a number of potential clinical candidates [72]. Initially, ASIs development had to face some important differences between humans and rodents, from adrenal cortex physiology to CYP11B2 sequence, a major issue for the selection of proper animal models for preclinical studies [11]. The lack of selectivity for CYP450 family and the strong similarity between CYP11B2 and CYP11B1 dampened the development of early ASIs compounds [11, 19, 73]. More recently, different and highly selective compounds targeting AS (CYP11B2) have been developed [19, 72] and tested for safety and efficacy in completed (Table 1) and ongoing (Table 2) phase II and phase III randomized controlled trials. In the next sections, we will summarize the findings of ASIs clinical studies.

LCI699 (Osilodrostat) was originally developed as a CYP11B2 inhibitor for the treatment of hypertension and primary aldosteronism [72, 87]. It was the first ASI evaluated in a proof-of concept non-randomized trial in patients with primary aldosteronism [88]. In this study, Osilodrostat, initially at 0.5 mg b.i.d., for 2 weeks and thereafter at 1.0 mg b.i.d., significantly reduced the mean plasma and urinary aldosterone concentration (p < 0.0001), with a prompt correction of hypokalemia (p < 0.0001), and a modest, though formally significant, decrease in blood pressure (−4.1 mm Hg; p = 0.046). However, osilodrostat at 1 mg/day intensely blunted (p < 0.0001) cortisol response to adrenocorticotropic hormone (ACTH) administration [88]. Further studies confirmed that osilodrostat had clinically meaningful safety issues due to unwanted effects on glucocorticoid synthesis and the hypothalamic-pituitary-adrenal axis response [19]. The reduction in cortisol synthesis caused by the off-target inhibition of CYP11B1 [89] and the subsequent ACTH increase, which in turn stimulates increased production of 11-DOC, a steroid precursor with MR-activity, counterbalancing the effect of a reduced aldosterone synthesis [89]. The undesirable increase in 11-DOC levels, might explain why osilodrostat had only mild effects on blood pressure as compared to eplerenone [74, 90] in patients with rHTN. In these patients, Schumacher et al. [74], found that the blood pressure-lowering effect of osilodrostat was inferior to eplerenone (mean change from baseline of SBP: osilodrostat 1.0 mg/day, −13.1 mm Hg; eplerenone 50 mg/bid, −18.7 mm Hg). Conversely, in a multiarm phase II trial [75], 524 patients with primary hypertension were randomized to osilodrostat (0.25 mg/day; 0.5 mg/day, 1.0 mg/day, or 0.5 mg/bid) or eplerenone (50 mg/bid) or placebo. The primary outcome was the mean change in diastolic blood pressure (DBP) at 8 weeks. Statistically significant DBP reductions were obtained with 1.0 mg/day osilodrostat (−7.1 mm Hg; p = 0.0012, vs. placebo) or eplerenone 50 mg/bid (−7.9 mm Hg; p < 0.0001 vs. placebo) but not with lower doses of osilodrostat. In the same study, all doses of osilodrostat significantly lowered SBP (p < 0.005 or better) but on average to a lesser extent than eplerenone (−13.8 mm Hg; p < 0.0001 vs. placebo). However, in a subgroup of patients submitted to ACTH stimulation test, osilodrostat treatment was associated with dose-dependent reductions in cortisol levels were observed 1-h post-ACTH stimulation with osilodrostat. Specifically, over 20% of patients receiving osilodrostat 0.5 mg twice daily or 1.0 mg once daily exhibited a blunted cortisol response to ACTH stimulation. Thereafter osilodrostat clinical development focused on Cushing’s disease. Two phase III pivotal trials, the LINC 3 [91] and LINC 4 [92], tested the efficacy of osilodrostat in patients with nonsurgical Cushing’s disease. Collectively, osilodrostat vs. placebo rapidly lowered mean urinary free cortisol to a significant extent in most patients. In summary, while osilodrostat was approved by regulatory agencies for Cushing disease, the development as ASI was closed [19, 93].

Baxdrostat is a second-generation ASI that has a 100-fold increase in CYP11B2 selectivity over CYP11B1 [94].

Bogman et al. [94] conducted a single-center, placebo-controlled first-in-man study in which they demonstrated 10 mg of baxdrostat led to a complete suppression of aldosterone production without affecting cortisol synthesis [89, 94]. Elevation of 11-DOC blood levels only occurred at a ≥90 mg dose, confirming high selectivity of baxdrostat for AS [94]. Specifically, the increase in 11-DOC with baxdrostat was modest (approximately two-fold to three-fold), unlike the 10-fold rise observed with osilodrostat. Freeman et al. [95] enrolled 54 healthy volunteers in a phase 1 trial designed to evaluate baxdrostat safety, pharmacokinetics, and pharmacodynamics. At doses ≥1.5 mg baxdrostat reduced aldosterone blood levels, with reductions sustained up to 10 days and no significant influence on plasma cortisol levels. The subsequent “Baxdrostat for Treatment-Resistant Hypertension” (BrigHTN) study was a phase 2, multicenter, randomized, placebo-controlled trial [76] designed to evaluate baxdrostat among patients with treatment-rHTN. The trial randomly assigned 248 patients (55% men, mean age 62 years, 28% African Americans, 38% with type 2 diabetes), predominantly recruited at community practices, to oral baxdrostat (0.5 mg, 1 mg, 2 mg) once daily or placebo for 12 weeks. The trial primary endpoint was the change from baseline in SBP. The study outcomes showed a significant dose-dependent relationship between changes in SBP and baxdrostat vs. placebo. The largest difference (−11.0 mm Hg; 95% confidence interval [CI]: −16.4 to −5.5; p < 0.001) was achieved with the 2-mg dose, while in the 1-mg arm, the change was −8.1 mm Hg (95% CI: −13.5 to −2.8; p = 0.003). Notably, a persistent dose-dependent reduction in serum and urinary aldosterone levels was found in baxdrostat treated patients, with no meaningful change in serum cortisol levels and no cases of adrenal insufficiency. Overall, baxdrostat had an acceptable safety profile and no deaths occurred during the trial. There was no substantial difference in the incidence any adverse events incidence. There were three cases of moderate hyperkalemia (potassium levels between 6.0 and 6.3 mmol/L) and other three of mild hyperkalemia (potassium levels between 5.5 and 5.9 mmol/L) compared with none in the placebo group. Per protocol, hyperkalemia required temporary discontinuation of the study drug, and baxdrostat was permanently discontinued in 2 patients, whereas 4 patients resumed baxdrostat and completed the trial with normal potassium. Apparently, hyperkalemia was not related with renal function at screening, but the study did not include patients with eGFR <45 mL/min/1.73 m² [76]. More recently, at the 2023 American College of Cardiology Annual Scientific Session, Deepak Bhatt presented the preliminary findings of “Efficacy and Safety of Baxdrostat in Patients with Uncontrolled Hypertension” (HALO) [77], a phase II trial conducted in 249 patients with uncontrolled treated hypertension. Participants were randomized to baxdrostat once daily (0.5 mg, 1.0 mg, or 2.0 mg) versus matched placebo. As expected, baxdrostat dose-dependently reduced plasma aldosterone, but active treatment at any dose failed to achieve formal significance on the primary endpoint (baxdrostat 0.5 mg vs. 1 mg vs. 2 mg vs. placebo: −17.0 vs. −16.0 vs. −19.8 vs. −16.6 mm Hg; p > 0.05). Notably, a sizeable proportion of patients on baxdrostat had very low drug levels, suggesting possible non-adherence. Moderate hyperkalemia, serum potassium levels over 6.0 mmol/L occurred in 1.6% of patients in the placebo group, compared with 0%, 1.6%, and 3.3% in the 0.5 mg, 1.0 mg, or 2.0 mg baxdrostat arms, respectively. Interestingly, baxdrostat pharmacokinetics was also assessed in 33 patients with moderate to severely impaired renal function. In a phase I open-label trial, Freeman et al. [96] found that impaired renal function did not affect baxdrostat systemic exposure or its clearance, advocating that dose adjustment in patients with moderate to severe renal damage should not be unnecessary.

The phase II trial “A Study to Evaluate CIN-107 for the Treatment of Patients with Uncontrolled Hypertension and Chronic Kidney Disease” (FigHTN-CKD) [80] will randomize 200 patients with uncontrolled hypertension and albuminuric CKD already on maximum tolerated dose of ACEi/ARBs, to low- or high-dose baxdrostat vs. placebo. The primary outcome is the change in mean seated systolic BP from baseline to week 26. The study was completed on February 2024, but, to date, there are no results on ClinicalTrials.gov [80]. The phase III trial “A Study to Investigate the Effect of Baxdrostat on Ambulatory Blood Pressure in Participants with Resistant Hypertension” (Bax24) [81] is currently recruiting participants with rHTN. This is a multicenter, randomized, double-blind, placebo-controlled, parallel group study designed to evaluate the safety, tolerability, and efficacy of baxdrostat 2 mg/qd versus placebo. The primary outcome measure is the change from baseline in ambulatory 24-h average SBP at week 12. The study will recruit 212 patients, and the estimated completion date is May 2025. The “Efficacy and Safety of Baxdrostat in Participants with Uncontrolled Hypertension on Two or More Medications Including Participants with Resistant Hypertension” (BaxHTN) [82] is currently recruiting participants. It is a phase III, randomized, double-blind, placebo-controlled, parallel group study designed to test the efficacy of once daily baxdrostat (1 or 2 mg) versus placebo on the reduction of SBP. The estimated enrollment is 720 participants with uncontrolled or rHTN. The primary outcome measure is the change from baseline in seated SBP for 2 mg and 1 mg baxdrostat versus placebo. The study started on November 2023, and the estimated completion date is October 2025. Finally, also the “Phase III Study to Investigate the Efficacy and Safety of Baxdrostat in Combination with Dapagliflozin on CKD Progression in Participants with CKD and High Blood Pressure” is actively recruiting [83]. This trial will test the superiority of baxdrostat/dapagliflozin versus dapagliflozin alone in adults with CKD and HTN. After screening, eligible participants, naïve to SGLT2i, will enter a 4-week dapagliflozin run-in, followed by a 24-month double-blind period in which participants will receive either baxdrostat/dapagliflozin or dapagliflozin. The study design also embraces a 6-week open-label extension during which baxdrostat/placebo will be discontinued, and all patients will be switched to dapagliflozin alone. The primary outcome is the change from baseline in eGFR to posttreatment, and completion is expected by December 2027.

In the phase II randomized, dose-ranging, multicenter trial, the “Safety and Efficacy of MLS-101 in Patients with Uncontrolled Hypertension” (Target-HTN) study [78]. Lorundrostat (MLS-101) safety and efficacy on BP was evaluated in 200 patients with uncontrolled hypertension defined as a systolic automated office BP (AOBP) of ≥130 mm Hg on ≥2 antihypertensive agents. The study involved 2 cohorts. Cohort 1 included 163 patients with plasma renin activity (PRA) ≤1.0 ng/mL/h and serum aldosterone ≥1 ng/dL. Participants were randomly assigned to placebo or lorundrostat 12.5 mg, 50 mg, or 100 mg once daily, or 12.5 mg or 25 mg twice daily. Cohort 2 included 37 participants with PRA >1.0 ng/mL/h, randomized in a 1:6 ratio to placebo or lorundrostat 100 mg once daily. Enrolled patients had mean age of 65.7 years, 40% men, 36% African Americans, 48% with BMI >30 kg/m², and 40% with type 2 diabetes. The primary outcome was the change in systolic AOBP from baseline to week 8. The placebo-adjusted change in systolic AOBP was −9.6 mm Hg (p = 0.01) with 50 mg lorundrostat vs. placebo and −7.8 mm Hg (p = 0.04) with 100 mg lorundrostat vs. placebo. In cohort 2, lorundrostat 100 mg lowered systolic AOBP by 11.4 mm Hg in-line patients randomized to 100 mg in cohort 1, suggesting that lorundrostat effect was independent of PRA. Lorundrostat lowered serum aldosterone levels and increased PRA and morning serum cortisol. Adrenocortical insufficiency was not observed during the trial, and the response to ACTH stimulation test was normal in participants randomized to lorundrostat 100 mg. Prespecified exploratory analyses showed that use of thiazide diuretics was associated with a larger response to lorundrostat, and obese patients (BMI >30 kg/m²) had greater systolic AOBP reduction with lorundrostat compared with those with lower BMI. Finally, lorundrostat safety was acceptable, no death occurred, and adverse events were generally considered mild by investigators. Change from baseline in serum potassium ranged between 0.21 and 0.35 mmol/L among lorundrostat-treated patients, and 6 cases of hyperkalemia requiring discontinuation or reduction of lorundrostat dose were observed.

The phase II trial “A Pivotal Study to Evaluate the Efficacy of Lorundrostat in Subjects with Uncontrolled Hypertension on a Standardized Antihypertensive Medication Regimen” (Advance-HTN) [84] will investigate lorundrostat blood pressure-lowering effect on top of a standardized antihypertensive treatment, in patients with uncontrolled and/or treatment-rHTN. The study design includes a run-in phase followed by a multiarm, randomized, double-blind, placebo-controlled 12-week period. The primary outcome is the change from baseline in 24-h average ambulatory SBP (aSBP). The trial is recruiting and the completion is expected on October 2024. The ongoing phase II “Efficacy and Safety of lorundrostat in Subjects with Uncontrolled and Resistant Hypertension” will evaluate the efficacy and safety of lorundrostat in combination with dapagliflozin in hypertensive patients with albuminuric CKD [85]. The study design consists of two parts: part A is a double-blind, placebo-controlled, parallel arm study, with a 2-week screening period, followed by two 8-week treatment periods (period 1 and period 2) separated by a 4-week single-blind washout phase. Part B is an open-label, single-arm, dose-escalation phase. The primary outcome of part A is the change from baseline to week 8 of automated office blood pressure (AOBP) SBP, and of part B is the incidence and severity of adverse events. The final data collection date for primary outcome measure is estimated in October 2024. Finally, the phase III study “Efficacy and Safety of Lorundrostat in Subjects with Uncontrolled and Resistant Hypertension” (Launch-HTN) [86] will evaluate the BP-lowering efficacy of 50 mg lorundrostat in patients with uncontrolled and rHTN. The study will enroll 1,000 patients, excluding those with eGFR <45 mL/min/1.73 m² or serum potassium >5.0 mmol/L, as well as those with recent (within 6 months) history of heart failure, myocardial infarction, stroke, or transient ischemic attack. The primary outcome measure is change from baseline in AOBP SBP at week 6 in subjects randomized to lorundrostat 50 mg compared to subjects randomized to placebo. The study is actively recruiting and the estimated completion date is July 2025.

Vicadrostat (BI 690517) is a novel, potent, and highly selective ASI in development for people with CKD to slow the decline in kidney function and to reduce the risk of cardiovascular events [97, 98]. A phase 1 double-blind [99], placebo-controlled study evaluated the safety and early efficacy of vicadrostat in diabetic patients with albuminuric CKD. UACR responses (≥20% decrease from baseline) were observed for 80.0% receiving vicadrostat 40 mg versus 37.5% receiving placebo. Drug-related adverse events ranged from mild to moderate and only 1 patient experienced severe hyperkalemia (serum potassium 6.9 mmol/L). Subsequently, a phase 2 trial evaluated efficacy and safety of vicadrostat in patients with CKD on top of ACEI/ARB and with or without the SGLT2i empagliflozin [79]. After the initial screening, patients were first randomized to empagliflozin 10 mg/day or placebo for 8 weeks, then in a second randomization to vicadrostat in doses of 3, 10, or 20 mg orally once daily or placebo for 14 weeks. Type 2 diabetes was present in 71% of patients and ranged from 62 to 88% among different groups. The primary outcome was the change in UACR from the end of run-in period (week 8) to 14 weeks after starting vicadrostat. In subjects receiving vicadrostat without empagliflozin, the percentage change in UACR from baseline to end of treatment at week 14 was −3%, −22%, −39%, and −37% with placebo, vicadrostat 3 mg, 10 mg, and 20 mg, respectively. Interestingly, vicadrostat showed a dose-dependent reduction of albuminuria, and when used on top of empagliflozin exhibited additive efficacy. The placebo-adjusted SBP decrease was 4–6 mm Hg with vicadrostat, and such effect was somewhat larger (7–8 mm Hg decrease vs. placebo) when vicadrostat was added to empagliflozin. In a secondary analysis [100], vicadrostat, with or without empagliflozin, consistently lowered SBP with similar reductions in patients with and without elevated BP at baseline. A higher incidence of hyperkalemia was noted with vicadrostat than placebo, although median increases in serum potassium were lower when vicadrostat was given with empagliflozin [79]. Finally, the Oxford Population Health and Boehringer Ingelheim recently announced the international phase III EASi-KIDNEY trial [101] which will recruit and follow about 11,000 participants. The trial is designed to evaluate whether vicadrostat, given on top of standard of care including empagliflozin, will reduce the risk of kidney disease progression, hospitalization for heart failure, or death from cardiovascular disease in people with CKD.

Dexfadrostat phosphate is a novel ASI, whose safety and efficacy was investigated in a recently published phase II study [102]. This 3-arm study enrolled 36 adult patients with a diagnosis of primary aldosteronism within 1 year before recruitment. Overall, 35 participants were randomized to once daily dexfadrostat phosphate 4, 8, or 12 mg. Primary endpoints were the changes in aldosterone-to-renin ratio and in mean 24-h ambulatory SBP (aSBP) from baseline with study drug arms combined. Hierarchical testing showed a significant decrease of the primary endpoints (ARR: 15.3 vs. 0.6, p < 0.0001; aSBP: 142.6 vs. 131.9 mm Hg, p < 0.0001). Dexfadrostat phosphate had acceptable tolerability with mild to moderate adverse events, and no cases of adrenal insufficiency or hyperkalemia were observed during the 8-week study period.

Aldosterone is essential for maintaining BP and volume under hypovolemic conditions, but excessive aldosterone levels can lead to the development of various cardiorenal and metabolic diseases that affect millions of people [1]. Excess aldosterone, through inflammatory and oxidative effects, can induce fibrosis in the heart, kidneys, and vasculature [19]. Blocking aldosterone deleterious effects on cardiac and renal disease had been established and validated by MRAs clinical trials. However, the routine clinical use of S-MRAs is often hindered by negative side effects due to off-target activity or aldosterone deficiency, which has encouraged the exploration of alternative strategies [19]. Among recent progress, the identification of NS-MRAs such as finerenone is quite resolving the challenge. However, the binding to MR with S-MRAs or NS-MRA, leaves yet an unsolved problem. The undesirable aldosterone effects are actually mediated by the rapid effects of MR-independent, non-genomic signaling [19]. Although still debated, the most putative receptor responsible for the non-genomic effects seems to be the GPER, which may trigger cardiorenal damage through its signaling cascades [3]. To overcome an antagonism of MR, inhibition of CYP11B2, a key enzyme involved in aldosterone biosynthesis pathway could provide a valid answer to block genomic and non-genomic aldosterone effects [69]. ASIs’ safety and efficacy have been well documented in preclinical and clinical studies [11]. The early development of these compound was complicated by a lack of specificity for the AS enzyme [73], but newer ASIs showed enhanced specificity over closely related enzymes. Baxdrostat and lorundrostat effectively lowered blood pressure in patients with resistant [76, 86] or uncontrolled hypertension [76, 80], but their effects on renal outcomes [85, 103] are not currently available. More recently, vicadrostat was tested in CKD patients [79]. This potent and highly selective ASI showed a dose-dependent reduction of albuminuria, and when used on top of empagliflozin exhibited additive efficacy. As far as safety is concerned, ASIs were well tolerated in a large proportion of randomized patients [104]. Adrenal insufficiency occurred in 7 of 436 (1.6%) patients receiving vicadrostat versus 1 out of 147 (0.6%) with placebo [79]. No cases of adrenal insufficiency were reported with baxdrostat [76] and lorundrostat [78]. ASI treatment resulted in higher rates of any hyperkalemia than placebo, but most cases did not necessitate medical intervention [78, 79]. Severe hyperkalemia (serum potassium ≥6 mmol/L), requiring dose reduction or treatment discontinuation, was infrequent and occurred in 1.3%, 2.4%, 3.6% randomized to vicadrostat [79], baxdrostat [76], and lorundrostat [78], respectively, versus none with placebo. Interestingly, the incidence of severe hyperkalemia in patients with type 2 diabetes and CKD treated with vicadrostat was likely attenuated in the presence of empagliflozin [79, 105]. Nonetheless, treatments that block aldosterone might offer additional benefits for kidney and cardiovascular protection, if hyperkalemia is properly managed. As previously reported with spironolactone [106], favoring the use of modern potassium binders [107, 108] may enable more patients to continue treatment with less hyperkalemia.

In conclusion, based on the preliminary evidence collected so far, it appears premature to recommend ASIs for clinical use. Further outcome based clinical trials are eagerly awaited to confirm the promising role of ASIs, as a safe and effective therapeutic option for cardiorenal protection.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Conceptualization and writing – original draft preparation: A.M. and G.R.; writing – review and editing: A.M., F.T., F.P., F.T., M.B., and G.R.; visualization: A.M.; and supervision: G.R. All authors have read and agreed to the published version of the manuscript.