Effectiveness of nonsteroidal mineralocorticoid receptor antagonists in patients with diabetic kidney disease

ABSTRACT

Nonsteroidal mineralocorticoid receptor antagonists (MRAs) are a new class of drugs developed to address the medical need for effective and safer treatment to protect the kidney and the heart in patients with diabetic kidney disease (DKD). There are several drugs within this class at varying stages of clinical development. Finerenone is the first nonsteroidal MRA approved in the US for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). In clinical studies, finerenone slowed CKD progression without inducing marked antihypertensive effects. Esaxerenone is a nonsteroidal MRA with proven blood pressure–lowering efficacy that is currently licensed in Japan for treating hypertension. There are also three other nonsteroidal MRAs in mid-to-late stages of clinical development. Here we overview evidence addressing pharmacological and clinical differences between the nonsteroidal MRAs and the steroidal MRAs spironolactone and eplerenone. First, we describe a framework that highlights the role of aldosterone-mediated pathological overactivation of the mineralocorticoid receptor and inflammation as important drivers of CKD progression. Second, we discuss the benefits and adverse events profile of steroidal MRAs, the latter of which are often a limiting factor to their use in routine clinical practice. Finally, we show that nonsteroidal MRAs differ from steroidal MRAs based on pharmacology and clinical effects, giving the potential to expand the therapeutic options for patients with DKD. In the recently completed DKD outcome program comprising two randomized clinical trials – FIDELIO-DKD and FIGARO-DKD – and the FIDELITY analysis of both trials evaluating more than 13,000 patients, the nonsteroidal MRA finerenone demonstrated beneficial effects on the kidney and the heart across a broad spectrum of patients with CKD and T2D. The long-term efficacy of finerenone on cardiac and renal morbidity and mortality endpoints, along with the anti-hypertensive efficacy of esaxerenone, widens the scope of available therapies for patients with DKD.

Plain Language Summary

This review discusses a group of drugs called mineralocorticoid receptor antagonists (MRAs for short). Some people with diabetes develop kidney and heart problems because their body is producing too much steroid hormone. This causes a protein called the mineralocorticoid receptor inside kidney and heart cells to be overactive, causing excessive inflammation and damage. Over time these excesses can lead to loss of organ function. MRAs can block this effect on the mineralocorticoid receptor and so reduce associated kidney and heart problems. Older types of MRAs called steroidal MRAs have been used clinically for many years. They have side effects such as high blood potassium levels. Nonsteroidal MRAs are a newer type of MRA. Finerenone is the first nonsteroidal MRA approved by the United States’ Food and Drug Administration for reducing kidney and heart damage in people with diabetic kidney disease. Two clinical studies involving more than 13,000 people with Diabetic Kidney Disease have completed. People in these studies who took finerenone had slower worsening of kidney disease and less heart and blood vessel damage compared with people who did not take finerenone (took placebo). Finerenone also has a lower risk of causing side effects compared with steroidal MRAs. Another type of nonsteroidal MRA is esaxerenone, which is currently only available in Japan. Other types of nonsteroidal MRAs are going through clinical trials so are not available for use yet. See Supplementary Figure 1 for an infographic version of this summary.

KEYWORDS:

• Chronic kidney disease
• diabetic kidney disease
• type 2 diabetes
• finerenone
• spironolactone
• esaxerenone
• mineralocorticoid receptor antagonist

1. Introduction

Chronic kidney disease (CKD) is defined by abnormalities in kidney function or structure or both, present for at least 3 months with implications for health [1]. In order to correctly diagnose CKD, the glomerular filtration rate (GFR) and spot urine albumin-to-creatinine ratio (UACR) are needed. This is illustrated in clinical practice guidelines for the evaluation and management of CKD [1] in the CKD staging grid depicted in Figure 1.

Figure 1. Kidney disease: Improving Global Outcomes (KDIGO) staging heat map [1]. Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk. Republished with permission of Elsevier Science & Technology Journals, from KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, KDIGO CKD Work Group, Kidney Int Suppl. 3:1–150. Copyright 2021. Permission conveyed through Copyright Clearance Center, Inc. CKD, chronic kidney disease; GFR, glomerular filtration rate.

Despite advancements in treatment options for slowing CKD progression over the past 30 years [2–10], the target annual decline rate has not been reached (Figure 2) [11]. Patients need to be apprised of the fact that they have CKD, as it is one of the ‘silent killers’ in clinical medicine. Fewer than 50% of people who have advanced-stage kidney disease are aware of it, based on an analysis of a large US database [12].

Figure 2. Historical perspective on slowing CKD progression associated with T2D [11]. Reprinted with permission from The American Diabetes Association. Copyright 2021 by the American Diabetes Association. RENAAL, Reduction of End Points in Non-Insulin Dependent Diabetes With the Angiotensin II Antagonist Losartan; IDNT, Irbesartan Diabetic Nephropathy Trial; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease; FIDELIO, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease.

Diabetes, hypertension, and prediabetic hyperglycemia are contributing factors in approximately 75% of CKD cases [11]. Diabetic kidney disease (DKD) is a complication of type 2 diabetes (T2D) that can progress to CKD. Approximately 1 in 3 adults with T2D in the US has CKD (36%), with almost 1 in 5 of these individuals (19%) at stage 3 or worse [13]. The number of people affected by CKD in the US has remained stable between 2003 and 2018 (~15%) but is likely to rise due to the expanding size of the T2D population [14] and the associated increased incidence of DKD [15].

CKD is associated with considerable economic burden. Over the past decade, the number of Medicare beneficiaries with CKD increased by 89% [16], and the per person–per year estimated Medicare spending on a CKD patient is $24,674, almost double the spending on an average Medicare beneficiary ($12,899) [17]. The rate of T2D-associated inpatient visits was almost tripled among stage 4 vs stage 1 CKD patients between 2009 and 2012 [18], while the total 12-month health-care spending was increased by $6,949 for stage 4 vs stage 1 CKD patients in this time period [18].

Worsening kidney function increases the risk of death, cardiovascular events, and hospitalization [19], and patients with CKD are more likely to die as a consequence of CKD than progress to kidney replacement therapy (transplant or dialysis) [20]. There is a medical need for novel approaches aimed at preventing or slowing CKD progression, particularly in advanced-stage CKD and/or in patients with comorbid CKD and T2D [11].

2. Targeting inflammation and fibrosis as a treatment approach in DKD

2.1. Mineralocorticoid receptor overactivation as a driver of CKD progression

Inflammation plays an important role in the pathophysiology of CKD [21–23]. Excessive levels of steroid hormones, such as aldosterone and cortisol, may trigger inflammation by inducing pathological overactivation of the mineralocorticoid receptor (MR) in the kidneys and the heart [21]. In healthy kidneys, aldosterone and the MR maintain electrolyte homeostasis by regulating sodium reabsorption and potassium secretion [21]. However, under conditions of elevated aldosterone release or high salt intake, overactivation of the MR is believed to initiate an inflammatory response that may ultimately lead to end-organ damage [24].

2.2. Preclinical and clinical studies

In preclinical studies, the effects of chronically elevated aldosterone on the kidneys include proteinuria, decreased blood flow through the kidneys, and kidney injury [21]. Accordingly, treatment with an aldosterone antagonist prevents or ameliorates kidney damage in experimental models [25]. In patients with kidney disease, increasing serum aldosterone concentrations are associated with kidney scarring, and kidney biopsies from patients with heavy albuminuria show a significant increase in MR expression and inflammatory mediator levels compared with patients with no albuminuria [26]. Targeting MR-mediated inflammation and fibrosis through the use of MR antagonists, therefore, presents a clinically meaningful target in DKD [27].

3. Introducing mineralocorticoid receptor antagonists in DKD

Mineralocorticoid receptor antagonists (MRAs) are pharmacological agents that inhibit the interaction between the MR and its ligands, such as aldosterone [28]. There are two distinct groups of MRAs: steroidal MRAs, and the newer, distinct, nonsteroidal MRAs.

3.1. Steroidal MRAs

Spironolactone and eplerenone are types of steroidal MRAs, and the use of these MRAs in treating patients with cardiovascular disease (CVD) has been documented in a number of clinical trials [29–31], leading to clinical indications for improving survival outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) [32,33]. Adding spironolactone to the standard of care (SOC) among patients with severe HF improved survival and reduced morbidity in the landmark Randomized Aldactone Evaluation Study (RALES) trial [29]. Subsequently, it was shown that treatment with a more selective steroidal MRA, eplerenone, improved survival and reduced the rate of hospitalizations for HF among patients with acute myocardial infarction complicated by left ventricular dysfunction and HF [30] and among patients with systolic HF with mild symptoms [31]. Both spironolactone and eplerenone appear to have beneficial effects on the kidney. Evidence from separate meta-analyses show that steroidal MRAs improved albuminuria across several clinical trials evaluating 24-hour urinary albumin excretion (UAE) [34,35]. Section 4.0 will explore some of the limitations of steroidal MRAs in terms of potential side effects of treatment.

3.2. Nonsteroidal MRAs

Nonsteroidal MRAs are designed to protect the kidney and the heart with a more manageable side-effect profile compared with steroidal MRAs [27,36–38]. The most developed nonsteroidal MRAs that are approved for clinical use are finerenone [39] and esaxerenone [40]. Finerenone is indicated in the US (first approval, 2021) to reduce the risk of sustained estimated GFR (eGFR) decline, end-stage kidney disease, cardiovascular death, nonfatal myocardial infarction, and hospitalization for HF in patients with CKD associated with T2D. Figure 3 gives an overview on the functional differences between the steroidal MRAs and finerenone. Esaxerenone has been clinically available in Japan since 2019 for treating hypertension [40]. Other nonsteroidal MRAs currently being evaluated in clinical trials include apararenone [41,42] and KBP-5074 [43,44].

Figure 3. A table summarizing comparison between steroidal MRAs (spironolactone and eplerenone) and nonsteroidal MRA finerenone [37]. Figure (by Kintscher, Bakris, and Kolkhof) reused under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) license. BP, blood pressure; CNS, central nervous system; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist.

Finerenone significantly reduced DKD-associated morbidity and mortality vs placebo without inducing substantial blood pressure (BP)-lowering effects in patients with stage 2 to 4 CKD and T2D on the background of a maximally tolerated dose of a RAS inhibitor [10]. By contrast, treatment with esaxerenone was effective in lowering BP in patients with essential hypertension [45], and was associated with a higher incidence of urinary albumin remission in patients with T2D and high levels of albuminuria who were receiving a RAS inhibitor [46]. Additionally, KBP-5074 reduced BP in patients with stage 3b or 4 CKD who had well-characterized uncontrolled hypertension [43]. More information on the clinical effects of finerenone and esaxerenone are provided in Section 6.0 (Clinical Effects of Nonsteroidal MRAs on the Kidney in Patients with T2D) and Section 7.0 (Clinical Effects of Nonsteroidal MRAs on the Heart in Patients with CKD and T2D/Hypertensive Patients with Decreased Kidney Function) of this review.

3.3. Aims of this review

In light of recent advances in the development of nonsteroidal MRAs as a new treatment option for patients with DKD, we have reviewed the available evidence on the clinical effectiveness of the nonsteroidal MRAs. The differences between steroidal and nonsteroidal MRAs will be discussed, covering pharmacology, clinical efficacy, and safety, with an emphasis on differentiating nonsteroidal MRAs from steroidal MRAs as a new class of drugs with enhanced therapeutic potential.

4. Limitations of the steroidal MRAs in clinical practice

The clinical effectiveness of traditional steroidal MRAs can be offset by their challenging side effects. Among patients with advanced CKD (stage 3–4), spironolactone users had a 34% lower risk of progressing to end-stage kidney disease but showed a 3-fold increase in the risk of hyperkalemia-associated hospitalizations compared with spironolactone nonusers [47]. Spironolactone is contraindicated in patients with hyperkalemia and is administered at 25 mg/day if serum potassium is lower than 5.0 mEq/L [32]. Evidence suggests that the potassium level of 5.0 mEq/L or higher marks increased risk of all-cause mortality in both HF and CKD patient populations [48]. Eplerenone is contraindicated if serum potassium exceeds 5.5 mEq/L at initiation and/or if creatinine clearance is 30 mL/min or lower [33]. The increased risk of hyperkalemia may also limit the therapeutic use of steroidal MRAs in patients treated with a RAS inhibitor, such as an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) [32,33]. Advanced CKD, T2D, and CVD and the use of RAS inhibitors are documented risk factors of hyperkalemia [48,49]. Underutilization of steroidal MRAs in the clinical setting may therefore be prevalent in patients susceptible to experiencing hyperkalemia due to advancing CKD, presence of T2D and/or CVD, or background treatment with ACE inhibitors or ARBs.

For example, a long-term pan-European prospective registry study reported a steroidal MRA prescription rate of 59.3% among 7041 ambulatory patients with chronic HF [50]. The most-prescribed MRA was spironolactone (68.3%), followed by eplerenone (23.7%) and canrenone, the metabolite of spironolactone (4.3%) [50]. However, steroidal MRAs were contraindicated in 13.8% of patients, most frequently due to kidney dysfunction (56.1%) and/or hyperkalemia (31.7%) [50]. Similarly, nonuse of steroidal MRAs due to intolerance was documented in 9.7% of patients, most frequently due to worsening kidney function (33.7%) and hyperkalemia (32.3%) [50]. In addition, more than two-thirds of patients treated with the steroidal MRA (69.5%) were not at target dose regimen [50]. Specifically, approximately a third of these patients were still in up-titration (29.4%), while hyperkalemia, worsening kidney function, and gynecomastia prevented dose escalation in 11.9%, 9.7%, and 2.0% of patients, respectively [50]. Spironolactone and eplerenone may therefore be underutilized or inappropriately utilized in routine clinical care either due to nonprescription or suboptimal dose utilization.

Data from the AMBER trial [51] showed that patients with resistant hypertension and stage 3 to 4 CKD (eGFR of 25 to ≤45 mL/min/1.73 m²) experienced more prolonged antihypertensive benefit from spironolactone with less hyperkalemia with the addition of a potassium binder, patiromer, to SOC. Specifically, a significantly greater proportion of patients receiving patiromer (86%) vs placebo (66%) on the background of a RAS inhibitor remained on spironolactone at 12 weeks [51]. Increased serum potassium was the most common reason for drug discontinuation in this trial, occurring in more patients treated with placebo (23%) than patiromer (6.8%) [51]. Data from AMBER suggest that prescribing a potassium-binding agent for controlling hypertension may be one means to enable the use of a steroidal MRA in patients with advanced CKD. An alternative strategy for reducing the risk of CKD progression involves the use of an approved nonsteroidal MRA [39] or a sodium-glucose cotransporter-2 (SGLT-2) inhibitor [52].

5. Differences in pharmacological effects between nonsteroidal and steroidal MRAs

5.1. Selectivity and Potency to the MR

Nonsteroidal MRAs have been developed as therapeutically effective chemical agents with a potential for an improved efficacy and safety profile compared with steroidal MRAs [27,36–38,44]. Figure 4 illustrates the differences in chemistry within and between classes [37]. Finerenone and esaxerenone are nonsteroidal MRAs that inhibit MR with greater potency than the steroidal MRAs spironolactone and eplerenone [53,54]. The inhibitory action of these nonsteroidal MRAs is also more selective for the MR than for other steroid receptors within the same superfamily, including the glucocorticoid, androgen, and progesterone receptor [54,55]. This contrasts with the steroidal MRA spironolactone, which shows off-target interaction with both androgen and progesterone receptors [56], which in clinical practice may manifest as an increased incidence of antiandrogenic and progestagenic side effects, such as gynecomastia and impotence in men and menstrual irregularities in women [27,56]. Furthermore, the steroidal MRA eplerenone shows lower potency of MR inhibition relative to both spironolactone and nonsteroidal MRAs [53,54]. Higher doses of eplerenone may be required for achieving an adequate clinical response. Preclinical data showed significantly greater efficacy of 10 mg/kg of finerenone than the highest tested dose of eplerenone (100 mg/kg) in attenuating the markers of kidney damage, including increased kidney weights and proteinuria [57]. By extension, the antihypertensive effect of 0.5 mg/kg esaxerenone was equivalent to that of 100 mg/kg eplerenone and 100 mg/kg spironolactone in rats fed a high-salt diet [58].

Figure 4. A figure illustrating differences in chemical structure between steroidal MRAs (spironolactone and eplerenone) and five nonsteroidal MRAs currently undergoing clinical development [37]. Figure (by Kintscher, Bakris, and Kolkhof) reused under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) license.

5.2. Organ distribution

Nonsteroidal and steroidal MRAs show different organ distribution patterns. Finerenone is detected at equivalent concentrations in the kidneys vs the hearts of healthy rats [57]. This contrasts with eplerenone, which builds up to at least a threefold higher concentration in the kidneys vs the heart, and spironolactone, which shows higher concentrations within the kidneys and below the detection limit concentration in the heart [24,57]. Specifically, MRAs prevent sodium retention and potassium loss by blocking aldosterone binding to MR [59]. Sodium release and concomitant mild potassium retention are effects of MRA activity in the kidneys [24]. It has been suggested that the balanced heart-relative-to-kidney distribution of finerenone in rodents may confer lower risk of electrolyte disturbances, such as hyperkalemia, in clinical research [57]. In patients with HFrEF and mild-to-moderate CKD, the incidence of investigator-reported hyperkalemia in the pooled finerenone group was lower (5.3%) than in the spironolactone group (12.7%) [60].

5.3. Half-life

Nonsteroidal and steroidal MRAs show differences in half-life duration (Figure 3). Finerenone has no active metabolites [27] and has a half-life of approximately 2 hours in healthy volunteers with normal kidney function [61,62]. Comparably, eplerenone has no active metabolites but has a slightly longer elimination half-life of 3 to 6 hours [33]. Spironolactone has a mean half-life of 1.4 hours but breaks down into several active metabolites that have considerably longer half-life values of 13.8 to 16.5 hours [32]. Furthermore, the elimination half-life of a single dose of esaxerenone (5–200 mg) was in the range of 18.7 to 22.9 hours in healthy Japanese adults [63], suggesting that doses of ≤5 mg/day of esaxerenone may be sufficient for achieving BP-lowering effects [45,63].

5.4. Effect on blood pressure

Nonsteroidal and steroidal MRAs show different BP-lowering effects across different patient populations. For example, in patients with HFrEF and mild-to-moderate CKD, treatment with a mean 37 mg/day of spironolactone demonstrated greater BP-lowering effect relative to baseline (–10.1 mmHg) vs 10 mg/day of finerenone (–4.2 mmHg) (ARTS) [60]. In patients with resistant hypertension and CKD, treatment with spironolactone and patiromer conferred a systolic BP (SBP) change of –11.7 mmHg after 12 weeks (AMBER) [51]. In a study involving patients with hypertension associated with primary aldosteronism, the antihypertensive efficacy of spironolactone was much higher than that of eplerenone [64], and this is supported by a systematic review and meta-analysis of 84 randomized comparisons that showed that the antihypertensive potency of spironolactone was 5.5 mmHg greater than that of eplerenone [65]. These BP effects of spironolactone contrast with the relatively modest antihypertensive effects of finerenone reported in patients with HFrEF and mild-to-moderate CKD [60] and in patients with DKD (Supplementary Table S1) [66]. Spironolactone’s antihypertensive efficacy may thus be due to the persistent hemodynamic effects of its metabolites [27]. Patients who discontinued spironolactone in the AMBER trial continued to show a persistent SBP reduction from baseline (mean change of –7.1 mmHg) at 2 weeks after treatment discontinuation [51]. In a separate study involving Japanese patients with essential hypertension, treatment with 2.5 mg/day and 5 mg/day of esaxerenone was associated with SBP changes of –13.7 and –16.9 mmHg, respectively, at 12 weeks [45].

5.5. Equivalent dose

Nonsteroidal MRAs have been evaluated for clinical efficacy in humans at lower doses compared with the prescribed antihypertensive therapeutic doses of spironolactone (25–100 mg once daily) [32] and eplerenone (50 mg once daily to 50 mg twice daily) [33]. For example, 2.5 to 20 mg/day of finerenone was as effective as a mean 39 mg/day of eplerenone in decreasing the levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a diagnostic biomarker of cardiac dysfunction, in patients with chronic worsening HFrEF and T2D and/or CKD in the ARTS-HF trial [67]. The mean dose of eplerenone evaluated in ARTS-HF (39 mg/day) [67] was proven clinically effective in reducing mortality and morbidity in patients with mild HFrEF in the EMPHASIS-HF trial [31]. Furthermore, 10 mg/day of finerenone was at least as effective as the average dose of 37 mg/day of spironolactone in reducing the levels of NT-proBNP in patients with HFrEF and mild-to-moderate CKD in the exploratory analysis of the ARTS trial [60]. In addition, 2.5 mg/day of esaxerenone was noninferior to the recommended 50 mg/day of eplerenone in lowering BP in the ESAX-HTN trial of Japanese patients with essential hypertension [45]. The ESAX-HTN trial also showed superiority for the higher dose of esaxerenone (5 mg/day) to 50 mg/day of eplerenone in lowering BP [45].

6. Clinical effects of nonsteroidal MRAs on the kidney disease in patients with T2D

6.1. Overview of clinical data

The nonsteroidal MRAs – finerenone, esaxerenone, and apararenone – reduced albuminuria in several early-stage clinical trials [42,66,68]. Clinical effects of steroidal MRAs (spironolactone and eplerenone) and the most clinically advanced nonsteroidal MRAs (finerenone and esaxerenone) on urine albumin, major adverse kidney endpoints (MAKEs), and eGFR are summarized in Supplementary Table S1.

The addition of finerenone (7.5–20 mg/day) to a RAS inhibitor dose-dependently reduced the UACR by 21% to 38% vs placebo among patients with DKD (ie T2D, high or very high albuminuria [UACR ≥30 mg/g], and eGFR >30 mL/min/1.73 m²) at 3 months vs at baseline in the ARTS–DN trial [66].

Patients with T2D, moderately increased albuminuria (UACR ≥45 to <300 mg/g), or eGFR ≥30 mL/min/1.73 m² with or without hypertension experienced a significant reduction of 38% to 56% in UACR with the addition of 1.25 to 5 mg/day of esaxerenone to a RAS inhibitor compared with placebo at 3 months relative to baseline [68]. Multiple daily doses of apararenone (dosage groups: 2.5–10 mg/day) reduced UACR by 37% to 54% from baseline at 6 months in Japanese patients with T2D and early-stage nephropathy [42].

The studies reviewed so far were designed to evaluate the reduction in proteinuria with MRAs. However, proteinuria could not be considered an established surrogate endpoint of slowed CKD progression [38]. There are no clinical outcome trials to date that have assessed CKD progression with steroidal MRAs due to the high risk of hyperkalemia at effective doses. The eGFR reduction of 30% to 40% may be a reliable surrogate marker of slowed CKD progression in interventional studies [38].

The FIDELIO-DKD trial evaluated the long-term efficacy and safety of finerenone vs placebo using a composite kidney outcome that included a sustained decrease in eGFR from baseline in patients with CKD and T2D [10]. In this trial, 5,734 patients with T2D and stage 2 to 4 CKD (UACR, 30–5000 mg/g and eGFR, 25–75 mL/min/1.73 m²) underwent randomization to either 10 or 20 mg/day of finerenone or placebo on top of the maximally tolerated labeled dose of a RAS inhibitor over a median period of 2.6 years [10]. Patients treated with finerenone experienced 18% lower risk than patients treated with placebo in the rate of the primary kidney endpoint defined as a composite of time to kidney failure, a sustained decrease of ≥40% in eGFR from baseline over ≥4 weeks, or death from renal causes [10]. The safety profile of finerenone was comparable to that of placebo, except for hyperkalemia, which occurred at a higher incidence with finerenone (18.3%) than with placebo (9.0%). The incidence of hyperkalemia leading to discontinuation of the treatment regimen was 2.3% in patients treated with finerenone and 0.9% in patients on placebo [10,39]. The hyperkalemia rates described above are lower than those reported in previous trials using dual RAS blockade in patients with T2D and CKD [69,70]. Additionally, results from the pooled analysis of data from the FIDELIO-DKD and FIGARO-DKD studies (FIDELITY; further detail in Section 7) found discontinuation rates due to hyperkalemia of 1.7% with finerenone vs 0.6% with placebo [71]. It should be noted that increasing age, T2D comorbidity, and pretreatment with RAS inhibitors are also well-documented risk factors for hyperkalemia [48,49].

6.2. Initiation of nonsteroidal MRA in patients with CKD and T2D

Due to a variety of factors that increase the risk of hyperkalemia, a personalized approach to hyperkalemia management has been described [49]. In particular, potassium monitoring before and after treatment initiation, identification of high-risk patient groups, and adequate dosing are required to facilitate hyperkalemia management during the clinical use of nonsteroidal MRAs [39,49]. It is recommended to measure serum potassium levels and eGFR before initiating treatment with finerenone and to not initiate treatment if serum potassium level exceeds 5.0 mEq/L [39]. The eGFR level should be used to adjust the recommended starting dose of finerenone of 10 or 20 mg/day [39]. Additional serum potassium monitoring within the first 4 weeks of treatment initiation is recommended in patients with pretreatment serum potassium >4.8 to 5.0 mEq/L [39].

7. Clinical effects of nonsteroidal MRAs on the heart in patients with CKD and T2D/hypertensive patients with decreased kidney function

A summary of the clinical effects of steroidal MRAs (spironolactone and eplerenone) and nonsteroidal MRAs (finerenone and esaxerenone) on the heart is provided in Supplementary Table S1. The FIGARO-DKD study evaluated the long-term benefit of 10 or 20 mg/day of finerenone on cardiovascular (CV) endpoints in 7,352 patients with CKD and T2D receiving a maximum tolerated labeled dose of a RAS inhibitor over a median follow-up duration of 3.4 years [72]. While patients in the previously mentioned FIDELIO-DKD trial had predominantly stage 3 to 4 CKD (eGFR of 25–75 mL/min/1.73 m²) [10], the FIGARO-DKD trial evaluated a broader spectrum of CKD patients by employing an eGFR cap of ≥25 to ≤90 mL/min/1.73 m² in patients with persistent, moderately elevated albuminuria (UACR, 30 to <300 mg/g; ie stage 2–4) and an eGFR cap of ≥60 mL/min/1.73 m² in patients with persistent, severely elevated albuminuria (UACR, 300–5000 mg/g; ie stage 1–2) [72,73]. The FIGARO-DKD trial evaluated patients with less-advanced CKD, with 61.7% of patients having stage 1 or 2 disease [72]. Patients in the finerenone group experienced significantly lower rates of CV events than patients in the placebo group, showing a 13% reduced relative risk of death from CV causes and nonfatal CV events, including myocardial infarction, nonfatal stroke, or hospitalization for HF (the primary composite outcome) [72]. The benefit of finerenone in this trial was primarily driven by the improved rates of hospitalization for HF vs placebo; specifically, patients in the finerenone group showed a 29% relative risk reduction on this outcome compared with patients in the placebo group [72]. Consistent with the primary CV results from FIGARO-DKD, finerenone-treated patients with advanced-stage CKD in the FIDELIO-DKD trial showed 14% lower relative risk than placebo-treated patients in the rate of a key secondary CV outcome (defined as a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF) [10,74].

In a pre-specified individual patient analysis of FIDELIO-DKD and FIGARO-DKD trials (FIDELITY) 13,026 patients with CKD associated with T2D were evaluated over a median follow-up of 3 years [71]. The pooled analysis in FIDELITY reported a 14% lower risk of the composite CV outcome (time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF) with finerenone vs placebo [71]. Finerenone also reduced the risk of the composite kidney outcome (time to first onset of kidney failure, sustained decrease in eGFR of ≥57% from baseline over ≥4 weeks, or renal death) by 23% vs placebo [71]. More importantly, finerenone reduced dialysis initiation by 20% [71].

Taken together, the findings from FIDELIO-DKD and FIGARO-DKD extend the results from the early-stage clinical studies of finerenone, which were conducted in patients across a range of disease indications. Specifically, in patients with worsening chronic HFrEF and T2D and/or CKD (which restricted eGFR to >30 mL/min/1.73 m² in patients with T2D and to a range of 30–60 mL/min/1.73 m² in patients without T2D), comparable proportions of patients showed a >30% decrease in NT-proBNP concentration from baseline to 3 months across finerenone dosage groups (2.5–20 mg/day) and the eplerenone group (average 38.6 mg/day) (ARTS-HF) [67]. Furthermore, in the exploratory analysis of the ARTS trial conducted in patients with HFrEF and moderate CKD (eGFR, 30–60 mL/min/1.73 m²), 10 mg/day of finerenone was comparable to the average 37 mg/day spironolactone in reducing NT-proBNP from baseline after approximately 4 weeks [60].

Clinical benefit of esaxerenone on BP has been demonstrated in Japanese patient populations [45,75]. In patients with essential hypertension and an eGFR ≥60 mL/min/1.73 m², esaxerenone (2.5–5 mg/day) was associated with sustained SBP changes relative to baseline at week 12 (–16.1 mmHg), week 28 (–18.9 mmHg), and week 52 (–23.1 mmHg) [75]. A subsequent trial conducted in patients with essential hypertension reported greater anti-hypertensive efficacy of 5 mg/day esaxerenone compared with the recommended daily dose of eplerenone (50 mg/day) at 12 weeks [45].

An investigational nonsteroidal MRA, KBP-5074, reduced SBP in 162 patients with uncontrolled grade 1 and 2 systolic hypertension (SBP ≥140 and ≤179 mmHg) and stage 3b/4 CKD (eGFR ≥15 and ≤44 mL/min/1.73 m²) who were concurrently receiving ≥2 antihypertensive medications [43]. Patients treated with 0.5 mg of KBP-5074 showed a significant difference of –10.2 mmHg from baseline in resting trough cuff seated SBP vs patients treated with placebo [43]. Similarly, patients treated with the lower dose of 0.25 mg of KBP-5074 showed a significant SBP difference of –7.0 mmHg from baseline in resting trough cuff seated SBP vs patients in the placebo group [43]. Hyperkalemia occurred in 5 patients on placebo (8.8%), 5 patients on 0.25 mg of KBP-5074 (9.8%), and 7 patients on 0.5 mg of KBP-5074 (13%) [43]. Further research is awaited to verify the clinical effectiveness of KBP-5074 in a powered late-phase clinical trial.

8. Conclusions

Here we provided an overview of pharmacological and clinical research that demonstrates effectiveness of nonsteroidal MRAs in the treatment of DKD, exerting varying effects on blood pressure, albuminuria, and cardiovascular events. Evidence from late-phase randomized clinical trials highlights the benefit of the nonsteroidal MRA finerenone in slowing progression of CKD and reducing cardiovascular risk across the spectrum of patients with CKD and T2D. While finerenone has been reported to induce modest blood pressure lowering effects, nonsteroidal MRA esaxerenone shows potent antihypertensive efficacy in Japanese patient populations. We also described the rationale as to why hyperkalemia, a major concern with steroidal MRAs, may be easier to manage with nonsteroidal MRAs. Finerenone is the first nonsteroidal MRA to be approved by the Food and Drug Administration for reducing cardiac and renal events in CKD and T2D patients in the US based on evidence from the FIDELIO-DKD study. Esaxerenone is the nonsteroidal MRA that has been clinically available for treating hypertensive patients in Japan. Evidence from early-stage and late-stage clinical trials of nonsteroidal MRAs summarized in this review shows pharmacological and clinical differences between nonsteroidal and steroidal MRAs, that have clinical implications for expanding therapy options in patients with CKD.

Disclosure of financial/other conflicts of interest

Edgar Lerma: Employment with Associates in Nephrology; consultancy agreements with Bayer and Vifor; ownership interest in Fresenius Joint Venture; receiving honoraria from Elsevier Publishing, McGraw-Hill Publishing, National Kidney Foundation, UpToDate, and Wolters Kluwer Publishing; serving as a scientific advisor or member of Journal of Clinical Lipidology, International Urology and Nephrology Journal, Journal of Vascular Access, Prescribers Letter, Renal and Urology News, ASN Kidney News, Reviews in Endocrinology and Metabolic Disorders, American Journal of Kidney Diseases Blog, American Heart Association Kidney and Cardiovascular Disease Leadership Group, and SCILL Committee; and speakers bureau for AstraZeneca, Bayer, Otsuka, and Vifor.

George Bakris: Consultant-Merck, Bayer, Vascular Dynamics, KBP Biosciences, Ionis, Alnylam, Astra Zeneca, Quantum Genomics, Horizon, Novo Nordisk. Research support-Steering committee of trials-Bayer, Vascular Dynamics, Quantum Genomics, Alnylam, Novo Nordisk.

William B. White: Cardiovascular safety consultant for Astra-Zeneca, Alnylam, Bristol-Myers Squibb, Cerevel, Horizon, JAZZ, Lipocine, Marius, Millenium (Takeda), Red Hill Pharma, Shanton Pharma, and UCB.

The authors have no other relevant conflicts of interest to disclose. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data sharing statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Acknowledgments

Medical writing assistance was provided by Andreja Varjačić, PhD, of Envision Pharma Group, and was funded by Bayer Corporation. Envision Pharma Group’s services complied with international guidelines for Good Publication Practice (GPP3).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/00325481.2022.2060598

Additional information

Funding

No funding was received for the production of the manuscript.