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Corresponding authors at: Department of Nephrology, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing 100000, China (Jingwei Zhou), Department of Nephrology, Dongzhimen Hospital of Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100000, China (Zhenjie Chen).
Corresponding authors at: Department of Nephrology, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing 100000, China (Jingwei Zhou), Department of Nephrology, Dongzhimen Hospital of Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100000, China (Zhenjie Chen).
Novel nonsteroidal mineralocorticoid receptor antagonists (MRAs) are noted for their potential cardiorenal benefits for patients with type 2 diabetes mellitus and chronic kidney diseases; however, the effect of this regimen on renal outcomes remains uncertain.
Methods
We performed a systematic review and meta-analysis of nonsteroidal MRAs focusing primarily on renal outcomes and safety in randomized, controlled trials. The MEDLINE, Embase, and Cochrane databases were systemically searched for trials published through April 2022. We included randomized, controlled trials assessing the effects of nonsteroidal MRAs on renal outcomes, as well as cardiovascular disease (CVD) effects in patients with chronic kidney disease (CKD). Summary estimates of risk ratios (RRs) reductions were calculated with a random-effects model. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to evaluate the certainty of evidence. This study is registered with PROSPERO under number CRD42022335464.
Findings
In total, 11 trials and 1 pooled analysis including a total of 17,517 participants were enrolled. Nonsteroidal MRAs reduced renal composite endpoints by 17 % [HR = 0.83, 95 % (0.75, 0.91); low quality] with 16 % in kidney failure (high quality), 23 % in ESRD (high quality), 20 % in eGFR decreased to less than 15 mL/min/1.73 m2 (high quality), and 17 % with more than a 40 % decrease in eGFR (high quality); 14 % with cardiovascular composite endpoints [HR = 0.86, 95 % (0.78, 0.94); moderate quality]; and 13 % of all-cause mortality [HR = 0.87, 95 % (0.76, 0.98); moderate quality]. Nonsteroidal MRAs were also associated with additional benefits in lowering UACR levels (moderate quality) and lowering BP levels (moderate quality) compared with the control groups. However, nonsteroidal MRAs did not show a statistically significant effect on the risk of renal death (moderate quality), hospitalization for any cause (moderate quality) or change in GFR (low quality). Regarding safety, there was no significant difference in the risk of adverse events between the participants receiving nonsteroidal MRAs and the control group.
Interpretation
Nonsteroidal MRAs had a statistically beneficial effect on reducing the risk of the composite kidney outcome, the composite of cardiovascular outcomes, and all-cause mortality. Nonsteroidal MRAs were also associated with benefits of proteinuria remission and blood pressure lowering. Although these findings provided positive evidence for the use of nonsteroidal MRAs for cardiorenal protection in patients with or without CKD, the quality of this evidence is potentially uncertain.
Analysis of the Global Burden of Disease 2016 dataset showed an 89 % rise in the incidence of chronic kidney disease (CKD), affecting more than 276 million people, and a doubling of chronic kidney disease deaths over the past two decades, resulting in an 87 % increase in the global burden of CKD [
Xie Y, Bowe B, Mokdad AH, et al. Analysis of the global burden of disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney Int 2018; 94(3): 567-81.
]. It is critical to fully evaluate and understand the effects of new therapies on the progression of CKD and the development of kidney failure, as well as the effects of cardiovascular disease (CVD) in patients with CKD. Novel nonsteroidal mineralocorticoid receptor antagonists (MRAs) have been recommended for patients with type 2 diabetes mellitus and albuminuria despite the maximum tolerated dose of RAS inhibitors, [
] and they act by inhibiting the pathophysiological overactivation of the mineralocorticoid receptors in cardiorenal disease, thereby protecting against inflammation and fibrosis in many tissues/cell types, including the kidney, heart, immune cells, and fibroblasts [
]. In addition, nonsteroidal mineralocorticoid receptor antagonists are more selective for mineralocorticoid receptors and have been noted to offer similar reductions in albuminuria but with a lower risk of hyperkalaemia than steroidal mineralocorticoid receptor antagonists [
Ito S, Kashihara N, Shikata K, et al. Esaxerenone (CS-3150) in patients with type 2 diabetes and microalbuminuria (ESAX-DN): phase 3 randomized controlled clinical trial. Clin J Am Soc Nephrology : CJASN 2020; 15(12): 1715-27.
], revealing an underlying mechanism of action distinct from other emerging agents for cardiorenal medicine in CKD and type 2 diabetes (T2D). The proven kidney or cardiovascular benefits of finerenone were recently reported by two large clinical trials (the FIDELIO-DKD and FIGARO-DKD studies) and, as a consequence, preliminarily established the role of finerenone in cardiorenal medicine [
Because of the different trial populations and the potential that the balance of benefits and risks could differ among individuals with CKD or CVD, the only nonsteroidal MRA (finerenone) that rigorously demonstrated long-term clinical outcomes was limited to albuminuric patients with T2D and mild-to-moderate renal dysfunction. Although FIGARO-DKD and FIDELIO-DKD, respectively, met their primary endpoint outcomes of finerenone for kidney failure and cardiovascular composite outcomes, without sophisticated hierarchical or prespecified planning of multiple outcomes, these trials were not sufficiently powered to examine the broader clinical results and heterogeneity between the trials across the spectrum of CKD studied in these trials [
Adamson C, Jhund PS. Bringing FIDELITY to the estimate of treatment effects of finerenone in chronic kidney disease due to type 2 diabetes. Eur Heart J 2021; 43(6): 485-7.
Network meta-analysis on the effects of SGLT2 inhibitors versus finerenone on cardiorenal outcomes in patients with type 2 diabetes and chronic kidney disease.
] and did not evaluate the deleterious effects of supramaximal doses on specific safety outcomes of interest in patients, such as hyperkalaemia, acute renal injury (AKI), and hypotension. Therefore, we undertook a systematic review and meta-analysis of nonsteroidal mineralocorticoid receptor antagonists, including finerenone, primarily focusing on renal outcomes and safety in RCTs.
2. Methods
2.1 Data sources and search strategy
This systematic review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) statement, was performed to examine the effects of nonsteroidal MRAs on patients with kidney impairment at baseline or endpoint. The predefined protocol for this study is available from PROSPERO (CRD42022335464).
We searched Ovid MEDLINE(R) (1946 to April Week 2 2022), EMBASE (from 1974 to April 13, 2022), and the Cochrane Central Register of Controlled Trials (from inception to 2022 April 13) for relevant clinical trials, with no language restrictions. We used search terms relating to “nonsteroidal mineralocorticoid receptor antagonist,” “clinical trial” and the individual drug names (finerenone, esaxerenone, apararenone, AZD9977 and KBP-5074). The systematic search strategy is outlined in the Appendix. The ClinicalTrials.gov database (https://clinicaltrials.gov) and the websites of the US Food and Drug Administration, the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency were also searched to identify potentially relevant data. In addition, a manual review of references from the included studies and potentially relevant related citations was also performed.
2.2 Study selection
We searched for published randomized, controlled trials (RCTs) or pooled analyses of RCTs that examined the renal outcomes or the risks of nonsteroidal MRAs in CKD patients without language restrictions. Two investigators (Q.C. and Y.L.) independently executed the systematic search and critically reviewed identified studies to ensure that each satisfied the following criteria: 1) subjects within the study were randomly assigned to receive any nonsteroidal MRAs or placebo or other active control; and 2) articles contained the data of CKD patients or information about our predefined renal outcomes. We excluded crossover designed studies and those without a controlled arm. Where there were multiple reports of a single study, the report with the longest follow-up period was included, and if different reports of the same trial provided data for different outcomes, the complete nonoverlapping data were extracted from each report. In cases in which two or more studies provided data for a relevant outcome with similar numbers of participants, we included the study with the largest number of total patient years. Any uncertainty or disagreements were resolved by joint review with a third author (J.Z.).
2.3 Data extraction and quality assessment
From each study that met the criteria for inclusion, two reviewers (Q.C. and Y.L.) independently extracted data on the registered ID, study design, setting, inclusion and exclusion criteria, sample size, baseline patient characteristics, follow-up time, relevant outcomes, and variables that were considered potential confounders. If the data were not provided in detail but were presented as figures, Engauge Digitizer (version 4.1, M Mitchell, https://markummitchell.github.io/engaugedigitizer/) software was used to extract data from graphs or images. Relevant details are summarized in standard extraction sheets. The results of data extraction were then compared, and any discrepancy was resolved by discussion.
The primary endpoints were defined as the composite kidney outcome, including sustained ≥ 40 % or 50 % decrease in eGFR from baseline, doubling of baseline serum creatinine, end-stage renal disease, renal deaths, or kidney failure. The secondary endpoints were: 1) a composite of cardiovascular outcomes of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure; 2) all-cause mortality; and 3) hospitalization for any cause. Relevant biomarkers of interest were also reported, comprising changes from baseline in serum potassium, urinary albumin creatinine ratio (UACR), the annual mean difference in eGFR, and systolic and diastolic blood pressure between the treatment and control groups. Safety endpoints of interest consisted of hyperkalaemia, hypokalaemia, hypertension, urinary tract infections, hypovolaemia, oedema, acute kidney injury, and renal-related adverse events.
Two authors (Q.C. and Y.L.) assessed the risk of bias according to the Cochrane risk of bias tool for the following six aspects: random sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessors, incomplete outcome data, and selective reporting. A third reviewer (J.Z.) resolved any discrepancies in the risk of bias assessment. The quality of evidence was also assessed by two independent reviewers (Q.C. and Y.L.) using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach and GRADEprofiler (GRADEpro) software (version 3.6). Since all included trials were randomized, controlled trials, the certainty of the evidence was graded as high for all outcomes by default and then downgraded based on prespecified criteria. The evidence was rated down for the following five aspects: risk of bias, inconsistency, indirectness, imprecision, and publication bias.
2.4 Data synthesis and analysis
A meta-analysis was conducted for individual overall outcomes obtained from studies. For binary outcome variables, we calculated the pooled effect of nonsteroidal MRAs using hazard ratios (HRs) and 95 % confidence intervals or the risk ratios (RRs) and 95 % confidence intervals. For continuous outcome variables, differences were calculated by weighted mean differences (WMDs) or standardized mean differences (SMDs). Pooled-effect sizes with 95 % CIs were calculated using a random-effects model and the DerSimonian and Laird method. We replaced missing mean data with median data. Missing standard deviation data were imputed using interquartile ranges (dividing by 1.35 only with large sample sizes), full ranges (dividing the range by values from the table of critical values for Pearson’s table), or reported P values. Heterogeneity was evaluated by the χ2 test on Cochrane’s Q statistic, which is quantified by I2 values, assuming that I2 values of 25 %, 50 %, and 75 % represent low, medium and high heterogeneity, respectively. To explore potential sources of heterogeneity, subgroup analyses were planned for drug types, follow-up duration, proportion of CKD population, eGFR categories, and baseline characteristics of included patients, and the interaction differences in treatment effects between subgroups were estimated. Sensitivity analyses were conducted by removal of any study to assess the stability of our meta-analytic findings. Additionally, univariate meta-regression according to available biomarker reduction differences between nonsteroidal MRA and control groups was performed to evaluate whether other factors were related to the magnitude of a possible treatment effect of nonsteroidal MRAs. Publication bias was assessed using Begg’s test, Egger’s test, and a funnel plot. A two-sided p value < 0.05 was regarded as statistically significant. Data were analysed using Stata software (Stata Corp. 2015. Stata Statistical Software: Release 14. College Station, TX, USA: StataCorp LP).
2.5 Role of the funding source
The funders of the study were not involved in the research design, data collection, data analysis, data interpretation, or report writing at all. The newsletter author has full access to all of the data in the study and finally decided to submit the published decision.
3. Results
We identified 1380 articles from the electronic database. After the removal of duplicate data, 42 full-text articles were assessed for eligibility, of which 11 studies met the inclusion criteria, and 1 pooled analysis data point was extracted (Fig. 1). Among the included trials [
Ito S, Kashihara N, Shikata K, et al. Esaxerenone (CS-3150) in patients with type 2 diabetes and microalbuminuria (ESAX-DN): phase 3 randomized controlled clinical trial. Clin J Am Soc Nephrology : CJASN 2020; 15(12): 1715-27.
Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022; 43(6): 474-84.
Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. Jama 2015; 314(9): 884-94.
A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J 2013; 34(31): 2453-63.
Sato N, Ajioka M, Yamada T, et al. A randomized controlled study of finerenone vs. eplerenone in japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. Circulation J: Official J Japanese Circulation Soc 2016; 80(5): 1113-22.
Wada T, Inagaki M, Yoshinari T, et al. Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study. Clin Exp Nephrology 2021; 25(2): 120-30.
Ito S, Itoh H, Rakugi H, Okuda Y, Yoshimura M, Yamakawa S. Double-blind randomized phase 3 study comparing esaxerenone (CS-3150) and eplerenone in patients with essential hypertension (ESAX-HTN Study). Hypertension (Dallas, Tex : 1979) 2020; 75(1): 51-8.
], one study did not report the results of ambulatory blood pressure monitoring according to the original protocol, leading to “high risk” for the selective reporting domain. The overall risk of bias was low except for “some concerns” for unclear randomization, allocation concealment, and blinding methods. The details regarding the risk of bias in each study are presented in Supplementary Fig. 1.
In total, 17,517 participants were enrolled, consisting of 15,607 treated with finerenone, 1,456 with esaxerenone (CS-3150), 292 with apararenone (MT-3995), and 162 with KBP-5074. A total of 16,217 (92.6 %) patients were known to have CKD, with 15,937 (91.0 %) with T2D and 16,137 (92.1 %) in the general population cohorts with hypertension (Table 1). Among the CKD population, there were 9,712 (55.4 %) people whose eGFR was less than 60 mL/min/1.73 m2 and 9,160 (52.3 %) people whose UACR was greater than 300 mg/g. The mean age was 65.7 years old, 70.6 % were men, and 59.3 % were white people. The baseline mean level of GFR was 58.3 (SD of 14.5) mL/min/1.73 m2, serum potassium was 4.3 (SD of 0.1) mmol/L, systolic blood pressure was 135.9 (SD of 12.4) mm Hg, diastolic blood pressure was 80.9 (SD of ± 7.4), and body mass index was 28.6 (SD of 2.4) kg/m2. The mean follow-up time was 289 days (range from 28 days to 3.4 years), with 1,883 composite kidney events, 1,987 composite cardiovascular outcomes, and 1,229 deaths recorded. The inclusion and exclusion criteria for each trial and other clinical baseline characteristics of the population, such as coexisting diseases and medication histories, are listed in Supplemental Table 1.
Table 1Characteristics of studies reporting the effects of non-steroidal MRAs.
Study ID
Year
Trial registry information
Patients
Sample size, N
Treatment
Control
Duration of
follow-up, median
Study design
Age, years
Sex, Male, n (%)
Race, White, n (%)
CKD, n (%)
DM, n (%)
Hypertension
eGFR ≤ 60, mL/min/1.73 m2, n (%)
UACR ≥ 300, mg/g, n (%)
eGFR, mL/min/1.73 m2
UACR, mg/g, median (IQR)
Serum potassium, mmol/L
SBP, mmHg
DBP, mmHg
BMI, kg/m2
FIDELITY
2022
NCT02540993、 NCT02545049
CKD and T2DM
13,026
Finerenone
Placebo
3 years
Pooled analysis
64.8 ± 9.5
9088 (69.8)
8869 (68.1)
13,026 (100)
13,026 (100)
12,566 (96.5)
7828（60.1）
8692 (66.7)
57.6 ± 21.7
515 (198–1147)
4.4 ± 0.4
136.7 ± 14.2
76.4 ± 9.6
31.3 ± 6.0
FIDELIO-DKD
2020
NCT02540993
CKD and T2DM
5734
Finerenone
Placebo
2.6 years
Phase III, RCT
65.6 ± 9.1
3983 (70.2)
3592 (63.3)
5734 (100)
5734 (100)
5505 (97.0)
5016（88.4）
4963 (87.5)
44.3 ± 12.6
852 (446–1634)
4.4 ± 0.5
138.0 ± 14.4
75.8 ± 9.7
31.1 ± 6.0
FIGARO-DKD
2021
NCT02545049
CKD and T2DM
7437
Finerenone
Placebo
3.4 years
Phase III, RCT
64.1 ± 9.8
5105 (69.4)
5277 (71.8)
7437 (100)
7437 (100)
7061 (96.0)
2812（38.2）
3729 (50.7)
67.8 ± 21.7
308 (108–740)
4.3 ± 0.4
135.8 ± 14.0
76.8 ± 9.6
31.4 ± 6.0
ARTS
2013
NCT01345656
HF and CKD
392
Finerenone
Placebo or Spironolactone
4 weeks
Phase II, RCT
72.1 ± 12.3
312 (79.6)
NA
392 (100)
134 (34.2)
261 (66.6)
392 (100)
NA
47.0 ± 10.0
21.3 ± 4.9
4.3 ± 0.4
127.3 ± 24.8
NA
28.8 ± 7.2
ARTS-DN
2015
NCT01874431
T2DM and persistent albuminuria
821
Finerenone
Placebo
90 days
Phase II, RCT
64.6 ± 9.2
639 (77.8)
691（84.2）
821 (100)
821(100)
774（94.3）
328（40.0）
301（36.7）
67.5 ± 21.8
NA
4.3 ± 0.4
138.2 ± 14.4
77.1 ± 9.8
31.8 ± 5.5
ARTS-DN Japan
2017
NCT01968668
T2DM and persistent albuminuria
96
Finerenone
Placebo
90 days
Phase II, RCT
63.0 ± 9.8
77 (80.2)
0(0)
96 (100)
96 (100)
92（95.8）
40（41.7）
45（46.9）
64.7 ± 14.1
249.2 ± 383.7
4.2 ± 0.4
138.7 ± 15.2
76.9 ± 11.2
27.0 ± 4.2
ARTS-HF
2016
NCT01807221
HF
1055
Finerenone
Eplerenone
90 days
Phase II, RCT
71.2 ± 10.1
816 (77.3)
823 (78.0)
768 (72.8)
678 (64.3)
775(73.5)
752 (71.3)
NA
53.0 ± 18.0
45.0 ± 5.0
4.1 ± 0.5
119.0 ± 17.0
NA
NA
ARTS-HF Japan
2016
NCT01955694
HF
72
Finerenone
Eplerenone
90 days
Phase II, RCT
73.1
53 (73.6)
0(0)
60 (83.3)
42 (58.3)
51 (70.8)
65 (90.3)
37 (51.4)
42.3
131
NA
112.5
NA
NA
BLOCK-CKD
2021
NCT03574363
Stage 3B/4 CKD and resistant hypertension
162
KBP-5074
Placebo
84 days
Phase II, RCT
65.4 ± 11.5
89 (54.9)
NA
162 (100)
92 (56.8)
162(100)
162(100)
85 (52.5)
31.9 ± 9.9
NA
NA
155.3 ± 13.6
87 0.7 ± 12.2
NA
ESAX-DN
2020
NA
Hypertension and T2DM with microalbuminuria
455
Esaxerenone(CS-3150)
Placebo
52 weeks
Phase III, RCT
66 ± 9
345 (75.8)
0(0)
455 (100)
455(100)
455(100)
145(31.9)
0(0)
69 ± 18
111 ± 46.3
4.4 ± 0.3
140 ± 10
84 ± 8
26.1 ± 4.0
ESAX-HTN
2020
NCT02890173
Hypertension
1001
Esaxerenone(CS-3150)
Eplerenone
12 weeks
Phase III, RCT
55.5 ± 9.6
721 (72.2)
0(0)
0(0)
156 (15.6)
1001(100)
0(0)
0(0)
78.7 ± 12.3
NA
4.2 ± 0.3
155.3 ± 9.6
98.1 ± 5.6
25.7 ± 4.1
Wada, T.
2021
NCT02517320
Stage 2 diabetic nephropathy
292
Apararenone(MT-3995)
Placebo
24 weeks
Phase II, RCT
61.8 ± 9.3
221 (75.7)
0(0)
292 (100)
292(100)
NA
NA
0(0)
74.9 ± 20.3
138.7 ± 83.5
4.3 ± 0.3
135.3 ± 11.9
77.9 ± 9.7
26.8 ± 4.6
Values are reported as n (%), mean ± standard deviation, or median (interquartile range) unless otherwise indicated.
“NA” represents not available.
Abbreviations: eGFR, estimated glomerular filtration rate; UACR, urinary albumin to creatinine ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, Body mass index; CKD, chronic kidney disease; T2DM, type 2 diabetes mellitus; HF, heart和failure; RCT, randomized controlled trial.
A total of 6 trials with 15,047 participants reported the composite kidney outcomes, and all of them examined the effect of finerenone. Of predefined primary renal events, there were 561 kidney failure events, 339 cases of progression to end-stage kidney diseases, 432 eGFR decreases to less than 15 mL/min/1.73 m2, 1,803 percentage declines in eGFR of more than 40 % or 57 %, and 6 renal deaths in 13,490, 13,719, 13,006, 14,635, and 13,026 patients, respectively. Overall, the results showed that nonsteroidal MRA significantly reduced the risk for the composite kidney outcomes of kidney failure (end-stage renal disease or eGFR ≤ 15 mL/min/1.73 m2), a 40 % or 57 % decrease in eGFR, or renal mortality by 17 % (HR 0.83 [95 % CI 0.75–0.91; p = 0.000, Fig. 2; low quality, Table 2) without heterogeneity (I2 = 0.0 %). In detail, nonsteroidal MRAs were significantly associated with a 16 % reduction in the risk of kidney failure (4 trials, HR 0.84 [95 % CI 0.74–0.94; p = 0.043, heterogeneity I2 0.0 %, Fig. 2; high quality, Table 2), a 23 % reduction in the risk of end stage renal disease (2 trials, HR 0.77[95 % CI 0.56–0.98], p = 0.000, heterogeneity I2 11.8 %; Fig. 2; high quality, Table 2), a 20 % reduction in the risk of eGFR decreasing to less than 15 mL/min/1.73 m2 (2 trials, HR 0.80 [95 % CI 0.65–0.95], p = 0.041, heterogeneity I2 0.0 %; Fig. 2; high quality, Table 2), and a 17 % reduction in the risk of a 40 % or 57 % decrease in eGFR (5 trials, HR 0.83 [95 % CI 0.75–0.91], p = 0.000, heterogeneity I2 0.0 %; Fig. 2; high quality, Table 2), but with no statistically significant effect on renal death (2 trials, HR 0.62 [95 % CI 0.12–3.23], p = 0.573, heterogeneity I2 0.0 %; Fig. 2; moderate quality, Table 2).
Fig. 2Effect of nonsteroidal MRAs on primary renal outcomes. *The composite kidney outcomes was defined as sustained ≥ 40 % or 50 % decrease in eGFR from baseline, doubling of baseline serum creatinine, end stage renal disease, renal deaths, or kidney failure. Abbreviations: CI, confidence interval; HR, hazard ratio; RR, risk ratio; eGRF, evaluate Glomerular Filtration Rate; ESRD, End Stage Renal Disease; UACR, urinary albumin creatinine ratio.
Table 2GRADE summary of findings table for primary renal outcomes and secondary outcomes.
Outcomes
Illustrative comparative risks* (95 % CI)
Relative effect (95 % CI)
No of Participants (studies)
Quality of the evidence (GRADE)
Comments
Assumed risk
Corresponding risk
Control
Treatment
Composite kidney outcomes
Study population
RR 0.83
(0.75 to 0.91)
15,047
(6 studies)
⊕⊕⊝⊝
low
Rated down for serious indirectness considering the factors absent or present relating to the participants, interventions, or outcomes that limited the generalizability of the results and for publication bias due to the evidence of publication bias based on funnel plot asymmetry and/or significant Egger’s or Begg’s tests (p < 0.10) with confirmation by adjustment by Duval and Tweedie trim-and-fill analysis.
146 per 1000
121 per 1000
(110 to 133)
Moderate
58 per 1000
48 per 1000
(44 to 53)
Kidney failure
Study population
RR 0.84
(0.74 to 0.94)
13,490
(4 studies)
⊕⊕⊕⊕
high
45 per 1000
38 per 1000
(34 to 43)
Moderate
28 per 1000
24 per 1000
(21 to 26)
ESRD
Study population
RR 0.77
(0.56 to 0.98)
13,006
(2 studies)
⊕⊕⊕⊕
high
29 per 1000
22 per 1000
(16 to 28)
Moderate
31 per 1000
24 per 1000
(17 to 30)
eGFR ≤ 15 mL/min/1.73 m2
Study population
RR 0.8
(0.65 to 0.95)
13,026
(2 studies)
⊕⊕⊕⊕
high
36 per 1000
29 per 1000
(24 to 35)
Moderate
40 per 1000
32 per 1000
(26 to 38)
40 % or 57 % decrease in eGFR
Study population
RR 0.83
(0.75 to 0.91)
14,635
(5 studies)
⊕⊕⊕⊕
high
143 per 1000
119 per 1000
(107 to 130)
Moderate
91 per 1000
76 per 1000
(68 to 83)
Renal death
Study population
RR 0.62
(0.12 to 3.23)
13,026
(2 studies)
⊕⊕⊕⊝
moderate
Rated down for serious imprecision considering the 95 % confidence interval crossed the minimally important difference [MID] for harm or benefit set.
1 per 1000
0 per 1000
(0 to 2)
Moderate
1 per 1000
1 per 1000
(0 to 3)
The composite cardiovascular outcome
Study population
RR 0.86
(0.78 to 0.94)
14,849
(4 studies)
⊕⊕⊕⊝
moderate
Rated down for serious indirectness considering the factors absent or present relating to the participants, interventions, or outcomes that limited the generalizability of the results.
146 per 1000
125 per 1000
(114 to 137)
Moderate
145 per 1000
125 per 1000
(113 to 136)
Cardiovascular death
Study population
RR 0.87
(0.74 to 1)
14,028
(3 studies)
⊕⊕⊕⊕
high
55 per 1000
48 per 1000
(41 to 55)
Moderate
53 per 1000
46 per 1000
(39 to 53)
Myocardial infarction
Study population
RR 0.88
(0.69 to 1.07)
15,900
(5 studies)
⊕⊕⊕⊝
moderate
Rated down for serious imprecision considering the 95 % confidence interval crossed the minimally important difference [MID] for harm or benefit set.
27 per 1000
23 per 1000
(18 to 29)
Moderate
5 per 1000
4 per 1000
(3 to 5)
Hospitalization for heart failure
Study population
RR 0.79
(0.68 to 0.9)
14,100
(4 studies)
⊕⊕⊕⊕
high
57 per 1000
45 per 1000
(39 to 51)
Moderate
67 per 1000
53 per 1000
(46 to 60)
All-cause mortality
Study population
RR 0.87
(0.76 to 0.98)
15,011
(5 studies)
⊕⊕⊕⊝
moderate
Rated down for publication bias due to the evidence of publication bias based on funnel plot asymmetry and/or significant Egger’s or Begg’s tests (p less than 0.10) with confirmation by adjustment by Duval and Tweedie trim-and-fill analysis.
92 per 1000
80 per 1000
(70 to 90)
Moderate
73 per 1000
64 per 1000
(55 to 72)
Hospitalization for any cause
Study population
RR 0.95
(0.91 to 1)
14,100
(4 studies)
⊕⊕⊕⊝
moderate
Rated down for serious indirectness considering the factors absent or present relating to the participants, interventions, or outcomes that limited the generalizability of the results.
443 per 1000
421 per 1000
(404 to 443)
Moderate
354 per 1000
336 per 1000
(322 to 354)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
Additionally, there were 86 eGFR decreases of more than 30 %, 756 reported renal impairments or worsening of eGFR, 467 AKI, and 550 percentage decreases in UACR ≥ 30 % reported in these trials in 13,490, 13,026, 16,052, 2,226, and 1,461 patients, respectively. It was significantly observed that the nonsteroidal MRA treatment groups achieved more UACR remissions (reductions in UACR of ≥ 30 % from baseline)(3 trials, HR 2.91 [95 % CI 1.47–5.78], p = 0.002, heterogeneity I2 80.2 %; Supplementary Fig. 2; moderate quality, Supplementary Table 2). Nonsteroidal MRAs did not show an effect on the risk of eGFR decreasing by ≥ 30 % (5 trials, HR 1.32[95 % CI 0.62–2.79], p = 0.476, heterogeneity I2 26.5 %; Supplementary Fig. 2; moderate quality, Supplementary Table 2), renal impairment or worsening eGFR events (9 trials, HR 0.80[95 % CI 0.51–1.26], p = 0.338, heterogeneity I2 76.7 %; Supplementary Fig. 2; low quality, Supplementary Table 2), or AKI events (3 trials, HR 0.95[95 % CI 0.79–1.14], p = 0.552, heterogeneity I2 0.9 %; Supplementary Fig. 2; moderate quality, Supplementary Table 2).
There was no significant difference observed in subgroup analyses (Supplementary Fig. 3), and sensitivity analyses did not suggest that any individual study contributed to the heterogeneity in our estimates (Supplementary Fig. 4). Univariate meta-regression did not demonstrate any significant relationships of renoprotective benefit with changes in serum potassium, UACR, GFR, systolic blood pressure, or diastolic blood pressure. Funnel plots suggested no evidence of publication bias for our individual outcomes, but a publication was observed for the composite kidney outcomes (P for Begg's test = 0.133, P for Egger's test = 0.039; Supplementary Fig. 5).
3.2 Secondary outcomes
The composite cardiovascular outcome was available for 4 studies with 14,849 individuals. The pooled result for the composite cardiovascular events showed a 14 % (HR 0.86 [95 % CI 0.78–0.94], p = 0.002; Fig. 3; moderate quality, Table 2) decrease in patients who received nonsteroidal MRAs without heterogeneity (I2 = 0.0 %). Among all cardiovascular events, the risk of cardiovascular death was reduced by 13 % (3 trials, 14,028 participants, HR 0.87 [95 % CI 0.74–1.00], p = 0.006, heterogeneity I2 0.0 %; Fig. 3; high quality, Table 2), the risk of hospitalization for HF events was reduced by 21 % (4 trials, 14,100 participants, HR 0.79 [95 % CI 0.68–0.90], p = 0.001, heterogeneity I2 0.0 %; Fig. 3; high quality, Table 2), and no significant effect was observed in myocardial infarction (5 trials, 15,900 participants, HR 0.88 [95 % CI 0.69–1.07], p = 0.313, heterogeneity I2 0.0 %; Fig. 3; moderate quality, Table 2).
Fig. 3Effect of nonsteroidal MRAs on secondary outcomes. *The composite cardiovascular outcomes was defined as cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure. Abbreviations: CI, confidence interval; HR, hazard ratio; RR, risk ratio;
There were 5 studies (15,011 subjects) and 4 studies (14,100 subjects) that reported all-cause mortality and hospitalization for any cause, respectively. Compared with controls, the application of nonsteroidal MRAs reduced the incidence of all-cause deaths by 13 % (HR 0.87 [95 % CI 0.76–0.98], p = 0.030, heterogeneity I2 0.5 %; Fig. 3; moderate quality, Table 2) but without a statistically significant effect on any-cause hospitalization (HR 0.95[95 % CI 0.91–1.00], p = 0.062, heterogeneity I2 0.0 %; Fig. 3; moderate quality, Table 2). Sensitivity analysis showed stability by removing any of the articles, and there were no other outcomes except for all-cause deaths (P for Begg's test = 0.142, P for Egger's test = 0.007) that showed evidence of publication bias in our results.
3.3 Biomarker outcomes
Among all available trials, nonsteroidal MRAs produced an absolute reduction of 105.13 mg/g compared with controls (95 % CI-159.78 to −50.48, p = 0. 000; 3 trials, 13,632 participants, Fig. 4; moderate quality, Supplementary Table 2) and a 32 % reduction in UACR (95 % CI −55 % to −10 %, p = 0. 000; 6 trials, 15,067 participants, Fig. 4; moderate quality, Supplementary Table 2). Nonsteroidal MRAs were also associated with increased serum potassium levels (MD 0.09 mmol/L [95 % CI 0.02 to 0.17], p = 0.000; 10 trials, 17,220 participants, Fig. 4; moderate quality, Supplementary Table 2) and blood pressure-lowering effects (systolic BP: MD −2.58 mm Hg [95 % CI −4.14 to −1.01], p = 0.000; 11 trials, 17,334 participants, moderate quality; diastolic BP: MD −1.82 mm Hg [95 % CI −2.72 to −0.92, p = 0.000; 8 trials, 16,774 participants, Fig. 4; moderate quality, Supplementary Table 2]. The pooled estimate for the change in GFR and annual decline in eGFR suggested no statistical significance (MD 0.86 mL/min/1.73 m2 [95 % CI −3.34 to 1.63], p = 0.50, low quality; MD 0.01 mL/min/1.73 m2 [95 % CI −7.37 to 7.39], p = 0.99; 9 trials, 8724 participants, Fig. 4; low quality, Supplementary Table 2). However, high heterogeneity was present among the studies evaluating these effects (Fig. 4).
Fig. 4Effect of nonsteroidal MRAs on biomarker outcomes. The efficacy was estimated by weighted mean difference. Abbreviations: CI, confidence interval; MD, mean difference; GRF, glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio.
The high risk of CVD has been the main cause of death in patients with CKD. It is important to prevent the development of CKD and progression to ESRD, as well as to reduce the risk of CVD. In this meta-analysis of 11 trials enrolling 17,517 participants with or without CKD, nonsteroidal MRAs reduced the risk of composite kidney events (17 %) with low quality of evidence, composite cardiovascular events (14 %) with moderate quality of evidence, and all-cause mortality (13 %) with moderate quality of evidence compared with the control groups. Nonsteroidal MRAs were associated with additional benefits for achieving more UACR remissions (RR in ≥ 30 % decrease in UACR: 2.92) with a 105.13 mg/g reduction and 32 % change, as well as lowering BP levels (SBP: −2.58 mm Hg; DBP: −1.89 mm Hg) with moderate quality of evidence compared with control groups. For safety, nonsteroidal MRA did not show a significant potential profile of adverse reactions, including kidney-related adverse events.
The results from this study including a broad range of patients with or without CKD are consistent with a recent individual-level analysis (FIDELITY) pooled from two randomized trials (FIDELIO-DKD and FIDELIO-DKD). The FIDELITY study showed that finerenone reduced the risk of composite cardiovascular outcomes by 14 % and the risk of compound renal outcomes by 15 % in patients with type 2 diabetes and CKD [
Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022; 43(6): 474-84.
]. The results of the subgroup analysis for renal outcomes in this study showed greater renal benefits in CKD (17 %) and DM (16 %) populations than those of FIDELITY when a broader range of populations was included, likely indicating that the long-term therapeutic effect of nonsteroidal MRA should be assessed for more diseases (such as heart failure and hypertension) in the future. In addition, nonsteroidal MRAs reduced the relative risks of components of the kidney composite outcome with high quality of evidence, except for renal deaths (RR: 0.62, likely due to a small number of events without powerful potency). The largest relative risk reduction (23 %) was for ESRD, which is clinically significant because kidney failure requiring dialysis or transplantation is associated with reduced quality of life for patients and a substantial economic burden for society. Although we did not find a statistically significant effect of nonsteroidal MRAs on GFR, we found a trend toward a relative risk of ≥ 57 % eGFR decrease being reduced by 30 %, the ≥ 40 % eGFR decreasing by 17 %, and the ≥ 30 % eGFR decreasing without statistical significance, suggesting that the efficacy of nonsteroidal MRAs might be modified by the follow-up period and that a longer follow-up period will help to further indicate the renal benefits of nonsteroidal MRAs.
Overactivation of MR promotes inflammation, oxidative stress and fibrosis and is one of the key factors leading to the development and progression of kidney and cardiovascular damage [
]. MR antagonists (MRAs) can directly target aldosterone to play an anti-inflammatory and antifibrotic role and can provide cardiorenal protection, including beneficial effects in hypertension, heart failure and chronic kidney disease (CKD) [
Chung EY, Ruospo M, Natale P, et al. Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease. Cochrane Database Systematic Rev 2020; 10(10): Cd007004.
], which could be due to dose-dependent natriuresis produced when the MRAs are blocked in the collector tubule. This meta-analysis of nonsteroidal MRAs obtained consistent results in decreasing the levels of BP and UACR, as well as benefits to hospitalization for heart failure. However, for first-generation (spironolactone) and second-generation (eplerenone) steroidal MRAs, hyperkalaemia and hormonal effects are limiting factors in clinical practice, especially as major concerns in people with impaired renal function. [
]. Novel nonsteroidal MRAs are highly selective for MR and differ from each other concerning tissue distribution, structural properties, MR binding modes and the ability to modulate coregulator recruitment to target genes involved in cardiac and renal tissue damage [
Differentiation between emerging non-steroidal and established steroidal mineralocorticoid receptor antagonists: head-to-head comparisons of pharmacological and clinical characteristics.
]. In this comprehensive meta-analysis of nonsteroidal MRAs regarding kidney outcomes, nonsteroidal MRAs did not increase the incidence of hyperkalaemia, despite slightly increasing blood potassium levels. On the whole, nonsteroidal MRAs provide cardiorenal benefits with equivalent efficacy to steroidal MRAs and a lower risk of adverse events, particularly beyond the outcomes with current standard-of-care treatment in high-risk patients with reduced renal function.
Benefiting from a broad inclusion range of the disease spectrum and a large population, this study is the first meta-analysis of nonsteroidal MRA drugs to focus on kidney outcomes, providing evidence for cardiorenal outcomes in patients with or without CKD. However, this study also had several limitations. First, there is a lack of more clinical data assessing the effects of drugs other than finerenone, causing most of the benefit in efficacy to be driven by finerenone. Second, based on the key considerations of clinical decision making, the composite outcomes of clinical endpoints were set as the primary and secondary outcomes in this meta-analysis. However, although these important outcomes provide positive evidence for the use of nonsteroidal MRAs, the quality of this evidence was downgraded to low or moderated for several reasons. One of these contributions is that the widely varying importance of individual outcomes raises concerns about the indirectness of the certainty of the evidence, and another is that the inclusion of the broader population without baseline restriction could have contributed to the variability of the effect among the included studies. Third, we are unable to assess whether the combination of nonsteroidal MRAs and sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists has a cumulative effect, and the efficacy and safety of these combination strategies must be determined in future clinical trials.
In conclusion, this review and meta-analysis provides evidence that nonsteroidal MRAs, compared with controls, reduced the risk of the composite kidney outcome, the composite of cardiovascular outcomes, and all-cause mortality. Nonsteroidal MRA was also associated with the benefits of proteinuria remission and blood pressure lowering. Nevertheless, the quality of this positive evidence to support the use of nonsteroidal MRAs for cardiorenal protection in patients with or without CKD is potentially uncertain, and more well-controlled trials with therapeutic strategies using novel drugs are needed.
Funding: None.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We would like to acknowledge all the authors.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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Network meta-analysis on the effects of SGLT2 inhibitors versus finerenone on cardiorenal outcomes in patients with type 2 diabetes and chronic kidney disease.
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A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
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Differentiation between emerging non-steroidal and established steroidal mineralocorticoid receptor antagonists: head-to-head comparisons of pharmacological and clinical characteristics.
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