Abstract
OBJECTIVE
Finerenone reduced the risk of kidney and cardiovascular events in people with chronic kidney disease (CKD) and type 2 diabetes in the FIDELIO-DKD and FIGARO-DKD phase 3 studies. Effects of finerenone on outcomes in patients taking sodium–glucose cotransporter 2 inhibitors (SGLT2is) were evaluated in a prespecified pooled analysis of these studies.
RESEARCH DESIGN AND METHODS
Patients with type 2 diabetes and urine albumin-to-creatinine ratio (UACR) ≥30 to ≤5,000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 were randomly assigned to finerenone or placebo; SGLT2is were permitted at any time. Outcomes included cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death) end points, changes in UACR and eGFR, and safety outcomes.
RESULTS
Among 13,026 patients, 877 (6.7%) received an SGLT2i at baseline and 1,113 (8.5%) initiated one during the trial. For the cardiovascular composite, the hazard ratios (HRs) were 0.87 (95% CI 0.79–0.96) without SGLT2i and 0.67 (95% CI 0.42–1.07) with SGLT2i. For the kidney composite, the HRs were 0.80 (95% CI 0.69–0.92) without SGLT2i and 0.42 (95% CI 0.16–1.08) with SGLT2i. Baseline SGLT2i use did not affect risk reduction for the cardiovascular or kidney composites with finerenone (Pinteraction = 0.46 and 0.29, respectively); neither did SGLT2i use concomitant with study treatment.
CONCLUSIONS
Benefits of finerenone compared with placebo on cardiorenal outcomes in patients with CKD and type 2 diabetes were observed irrespective of SGLT2i use.
Introduction
Diabetes is a leading cause of kidney failure, with >50% of end-stage kidney disease cases resulting from diabetes in many countries (1). Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are recommended for patients with type 2 diabetes and chronic kidney disease (CKD) and/or with cardiovascular (CV) disease to reduce the risk of kidney disease progression or CV events (2–4). However, despite the use of guideline-recommended therapies, including SGLT2is and renin-angiotensin system (RAS) inhibitors, there remains a residual risk of patients with CKD and type 2 diabetes still progressing to kidney failure (5,6).
Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) approved for use in adults with CKD associated with type 2 diabetes (7–10). Given the current recommendations for the use of an SGLT2i in patients with CKD and type 2 diabetes (2–4), their combined use with finerenone is of interest. A recent analysis of data from the phase 3 Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study stratified by the use of an SGLT2i at baseline showed that finerenone reduced the urine albumin-to-creatinine ratio (UACR) in patients with CKD and type 2 diabetes already receiving an SGLT2i at baseline (11); however, the analysis had limited power with regard to important clinical cardiorenal outcomes.
In this Finerenone in Chronic Kidney Disease and type 2 diabetes combined with FIDELIO-DKD and FIGARO-DKD trial program analysis (FIDELITY), we expand upon the previous investigations by examining the effect of finerenone and the interaction with SGLT2i use on the prespecified CV and kidney composite outcomes in the pooled populations of the FIDELIO-DKD and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) studies, which included patients across the spectrum of CKD associated with type 2 diabetes. In addition, we evaluated the intermediate changes in UACR and estimated glomerular filtration rate (eGFR) slopes.
Research Design and Methods
Study Design and Participants
This analysis combines individual patient–level data from the FIDELIO-DKD and FIGARO-DKD phase 3 clinical trials. The designs and results of these studies have been published previously (7,8). Briefly, adults (≥18 years of age) with CKD and type 2 diabetes who were receiving a maximum tolerated labeled dose of a RAS inhibitor were eligible to participate if they had a serum potassium level ≤4.8 mmol/L at screening. Patients had either moderately increased albuminuria (i.e., UACR of 30 to <300 mg/g) with an eGFR of either 25 to <60 and diabetic retinopathy (FIDELIO-DKD) or 25 to ≤90 mL/min/1.73 m2 (FIGARO-DKD) or severely increased albuminuria (i.e., UACR 300 to ≤5000 mg/g) with an eGFR of either 25 to <75 mL/min/1.73 m2 (FIDELIO-DKD) or ≥60 mL/min/1.73 m2 (FIGARO-DKD). Standard-of-care therapy, including treatment with a RAS inhibitor, was optimized during the run-in period. Use of SGLT2is was permitted at baseline, as was the initiation of SGLT2i treatment during the trial. Patients were recruited from September 2015 through October 2018, a period during which guidelines and recommendations for SGLT2i use in CKD and type 2 diabetes were being updated. The trial protocol was approved by the institutional review board at each study site, and all participants provided written informed consent.
Randomization and Masking
In both studies, patients were randomly assigned 1:1 to receive double-blind therapy with either oral finerenone (at titrated doses of 10 or 20 mg once daily) or matching placebo. Randomization was stratified by region (North America, Europe, Asia, Latin America, other), albuminuria at screening (30 to <300 mg/g, ≥300 mg/g), and eGFR at screening (25 to <45 mL/min/1.73 m2, 45 to <60 mL/min/1.73 m2, ≥60 mL/min/1.73 m2). In FIGARO-DKD, randomization was additionally stratified by history of CV disease. All participants and study personnel (except for the independent data monitoring committee) were masked to treatment allocation.
Outcomes
Efficacy outcomes of the current prespecified analysis included a CV composite end point of time to the first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure and a kidney composite end point of time to first occurrence of kidney failure, a sustained ≥57% decline in eGFR from baseline, or renal death. Potential end points were prospectively adjudicated by an independent clinical event committee blinded to treatment assignment. Sustained declines in eGFR were confirmed by two consecutive central laboratory measurements over a period of at least 4 weeks. Kidney failure was defined as end-stage kidney disease or sustained eGFR <15 mL/min/1.73 m2. Change in UACR and eGFR slope were also reported. Data for these outcomes and safety data were based on SGLT2i use at baseline. The CV and kidney composite end points were also analyzed by postbaseline SGLT2i use. A post hoc analysis of hospitalization for heart failure as an individual end point was also performed by SGLT2i use at baseline.
Statistical Analysis
The overall statistical analysis methodology for FIDELITY has been published previously (12). Efficacy outcomes were analyzed in the pooled full analysis set (by planned treatment), comprising all patients randomly assigned who did not have critical Good Clinical Practice violations. Treatment effect for time-to-event first outcomes in patients were derived separately by SGLT2i use at baseline (yes/no), based on separate Cox regression models including treatment (finerenone vs. placebo), and stratified by prespecified stratification factors (albuminuria and eGFR at screening, CV disease history, region, and study). Data are expressed as hazard ratios (HRs) with corresponding 95% CIs. P values for the subgroup-by-treatment interaction were derived from a stratified Cox proportional hazards model that included terms for treatment, subgroup, and subgroup-by-treatment interaction. To consider on-treatment SGLT2i use, outcome HRs and associated 95% CIs were based on a stratified Cox model including treatment as a fixed covariate, co-medication use as a time-varying covariate, and the interaction of the fixed and time-varying terms. All Cox models were also adjusted for baseline levels of HbA1c, systolic blood pressure (SBP), UACR (log-transformed), and eGFR.
Changes in UACR and eGFR were analyzed for short-term (baseline to the month 4 visit) and long-term (month 4 to the permanent discontinuation or end-of-study visit) changes by SGLT2i use at baseline. Separate mixed-model repeated-measures analyses were conducted for change in UACR, assuming an unstructured covariance matrix and adjusting for treatment group, stratification factors, visit, treatment-by-visit interaction, treatment-by-study interaction, log-transformed baseline value nested within type of albuminuria at screening, and log-transformed baseline value-by-visit interaction. The annualized change in eGFR from month 4 to permanent discontinuation or the end-of-study visit was evaluated by means of an ANCOVA model, including treatment group, the stratification factors, baseline eGFR (nested within eGFR category), and the study-by-treatment interaction as covariates. All available eGFR measurements were included in the analyses, irrespective of discontinuation of study treatment.
A mediation analysis was performed by SGLT2i use at baseline using a Cox proportional hazards model to determine the proportion of the effect of finerenone on UACR regression from severely increased albuminuria to moderately increased albuminuria and from moderately increased albuminuria to normal albuminuria attributed to time-varying SBP. The model was stratified by region, albuminuria at screening, eGFR at screening, CV disease history, and study, including the covariates of treatment group and time-varying SBP, and compared with the model without SBP adjustment. Albuminuria category changes were considered as shifts if they were accompanied by a UACR change of ≥30% from baseline to each visit. Analysis of safety outcomes, including treatment-emergent hyperkalemia-related adverse events (AEs), were performed in all randomly assigned patients who received one or more doses of study drug (by treatment received) by SGLT2i use at baseline (yes/no).
Results
Patients
Of 13,026 patients included in the analysis, 877 (6.7%) received an SGLT2i at baseline, comprising 438 (6.7%) of 6,519 in the finerenone group and 439 (6.7%) of 6,507 in the placebo group (Supplementary Table 1). Overall, 58% of patients who were taking an SGLT2i at baseline had initiated treatment >6 months before random assignment. The remaining 42% of patients initiated treatment gradually over the preceding 6 months, with <10% starting an SGLT2i within 1 month of random assignment (Supplementary Table 2). Overall, 958 patients (14.7%) in the finerenone group and 1,032 (15.9%) in the placebo group received an SGLT2i at any time concomitant with study treatment (Supplementary Table 1). For finerenone- and placebo-treated patients, 371 (38.7%) of 958 and 387 (37.5%) of 1,032, respectively, received co-medication with an SGLT2i for ≥90% of the treatment period; 203 (21.1%) of 958 and 214 (20.7%) of 1,032 received an SGLT2i 50–90% of the time; and 384 (40.1%) of 958 and 431 (41.8%) of 1,032 received an SGLT2i <50% of the time (Supplementary Fig. 1). The median follow-up period for the FIDELITY analysis was 3.0 years (interquartile range 2.3–3.8 years).
Baseline demographics and patient characteristics were similar between the finerenone and placebo groups (Supplementary Table 3). However, when considering SGLT2i subgroups, there were differences reflecting that use of SGLT2is was not randomly allocated (Table 1 and Supplementary Table 2). For example, a greater proportion of White patients and lower proportion of Black patients were receiving an SGLT2i at baseline compared with patients who were not receiving an SGLT2i at baseline. Additionally, patients receiving an SGLT2i were younger, had a higher HbA1c and lower SBP, and used statins, metformin, and glucagon-like peptide 1 receptor agonists (GLP-1RAs) more frequently. In addition, baseline mean eGFR was higher and median UACR lower in patients who were receiving an SGLT2i at baseline than in those who were not; this observation is consistent with the initiation criteria according to the manufacturers’ labels for SGLT2is at the time the studies were enrolling patients. Use of potassium-lowering agents was low at baseline and at any time throughout the trial (used in <5% of patients), with most patients taking calcium polystyrene sulfonate or sodium polystyrene sulfonate (Supplementary Table 4). Characteristics of patients who initiated an SGLT2i during the on-treatment period were similar to patients who received an SGLT2i at baseline (Supplementary Table 5).
Table 1.
Baseline characteristics in patients receiving or not receiving an SGLT2i at baseline
| SGLT2i at baseline (n = 877) | No SGLT2i at baseline (n = 12,149) | |
|---|---|---|
| Age, years | 61.8 ± 9.7 | 65.0 ± 9.5 |
| Sex | ||
| Male | 671 (76.5) | 8,417 (69.3) |
| Female | 206 (23.5) | 3,732 (30.7) |
| Race | ||
| White | 644 (73.4) | 8,225 (67.7) |
| Asian | 185 (21.1) | 2,709 (22.3) |
| Black/African American | 20 (2.3) | 502 (4.1) |
| SBP, mmHg | 133.3 ± 14.4 | 137.0 ± 14.2 |
| Duration of diabetes, years | 15.6 ± 8.1 | 15.4 ± 8.7 |
| HbA1c | ||
| % | 8.0 ± 1.2 | 7.7 ± 1.4 |
| mmol/mol | 63.5 ± 13.4 | 60.4 ± 14.9 |
| Serum potassium, mmol/L | 4.3 ± 0.4 | 4.4 ± 0.4 |
| eGFR, mL/min/1.73 m2 | ||
| Mean | 66.3 ± 21.1 | 57.0 ± 21.6 |
| Distribution | ||
| <25 | 0 | 162 (1.3) |
| 25 to <45 | 142 (16.2) | 4,090 (33.7) |
| 45 to <60 | 241 (27.5) | 3,193 (26.3) |
| ≥60 | 494 (56.3) | 4,701 (38.7) |
| UACR, mg/g | ||
| Median | 448 (185–945) | 521 (199–1,161) |
| Distribution | ||
| <30 | 16 (1.8) | 214 (1.8) |
| 30 to <300 | 283 (32.3) | 3,816 (31.4) |
| ≥300 | 578 (65.9) | 8,114 (66.8) |
| Medication use at baseline | ||
| RAS inhibitor | 875 (99.8) | 12,128 (99.8) |
| β-Blocker | 432 (49.3) | 6,072 (50.0) |
| Diuretic | 439 (50.1) | 6,271 (51.6) |
| Statin | 737 (84.0) | 8,662 (71.3) |
| Potassium supplement | 24 (2.7) | 361 (3.0) |
| Potassium-lowering agent | 7 (0.8) | 175 (1.4) |
| Glucose-lowering therapies | ||
| Insulin and analogs | 515 (58.7) | 7,115 (58.6) |
| Metformin | 692 (78.9) | 6,865 (56.5) |
| Sulfonylurea | 218 (24.9) | 3,171 (26.1) |
| DPP-4 inhibitor | 256 (29.2) | 3,022 (24.9) |
| GLP-1RA | 167 (19.0) | 777 (6.4) |
| α-Glucosidase inhibitor | 35 (4.0) | 621 (5.1) |
| Thiazolidinedione | 58 (6.6) | 459 (3.8) |
Data are mean ± SD, n (%), or median (interquartile range). DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-1RA, glucagon-like peptide-1 receptor agonist; RAS, renin–angiotensin system; SBP, systolic blood pressure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; UACR, urine albumin-to-creatinine ratio.
Efficacy
The HR for the CV composite end point was 0.87 (95% CI 0.79–0.96) in patients not receiving an SGLT2i at baseline and 0.67 (95% CI 0.42–1.07) in those receiving an SGLT2i at baseline (Fig. 1). Similarly, the HR for the kidney composite end point was 0.80 (95% CI 0.69–0.92) in patients not receiving an SGLT2i at baseline and 0.42 (95% CI 0.16–1.08) in those receiving an SGLT2i at baseline (Fig. 1). Incidence of the composite CV and kidney end points suggested a trend toward a lower risk with the combination of finerenone and an SGLT2i at baseline; however, the corresponding tests for interaction were not significant (Pinteraction = 0.46 and 0.29, respectively). Additionally, the HR for all-cause death was 0.90 (95% CI 0.80–1.02) in patients not receiving an SGLT2i at baseline and 0.58 (95% CI 0.30–1.10) in those receiving an SGLT2i at baseline (Pinteraction = 0.24) (Fig. 1). Analyses considering SGLT2i use at any time during the on-treatment period also showed no clear differences in the response to finerenone in patients who received an SGLT2i at any time concomitant with study treatment versus those who did not (Fig. 1).
Figure 1.
Analysis of kidney and cardiovascular composite outcomes in patients receiving or not receiving an SGLT2i at baseline and in patients receiving or not receiving an SGLT2i at any time during the on-treatment period. Shown are adjusted *HRs for HbA1c, SBP, and UACR at baseline (log-transformed) and eGFR at baseline. †Pinteraction is based on a stratified Cox proportional hazards model including treatment, subgroup, the additional covariates, and treatment-by-subgroup interaction. ‡Comedication use is defined as exposure to comedication in the on-treatment period (i.e., a patient can contribute to the use and nonuse categories based on the actual exposure time with and without comedication). §HR and Pinteraction are based on a stratified Cox model including treatment as simple and comedication use as time-varying covariates as well as their interaction and the additional covariates. eGFR, estimated glomerular filtration rate; HR, hazard ratio; PY, patient-years; SBP, systolic blood pressure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; UACR, urine albumin-to-creatinine ratio.
Post hoc analysis showed that finerenone reduced the risk of hospitalization for heart failure compared with placebo, irrespective of SGLT2i use at baseline (HR 0.80 [95% CI 0.68–0.95] vs. 0.44 [0.19–0.99] in patients not receiving an SGLT2i vs. those receiving an SGLT2i; Pinteraction = 0.16) (Fig. 1). These findings were consistent in analyses that considered SGLT2i use at any time during the on-treatment period versus no SGLT2i use (Fig. 1).
The effect of finerenone versus placebo on reducing UACR from baseline to month 4 also appeared to be independent of SGLT2i use at baseline, with a 37% reduction observed with finerenone in patients receiving an SGLT2i at baseline (ratio of geometric mean changes 0.63 [95% CI 0.57–0.70]) and a 31% reduction in patients without an SGLT2i at baseline (ratio of geometric mean changes 0.69 [95% CI 0.67–0.71]; Pinteraction = 0.17). The reduction in UACR with finerenone was persistent throughout the duration of the trial (Fig. 2).
Figure 2.
Change in UACR over time in patients receiving or not receiving an SGLT2i at baseline. Mixed model with factors included treatment group, region, eGFR category at screening, type of albuminuria at screening, time, treatment-by-time interaction, log-transformed baseline value nested within type of albuminuria at screening, and log-transformed baseline value-by-time interaction as covariates. eGFR, estimated glomerular filtration rate; IQR, interquartile range; SGLT2i, sodium–glucose cotransporter 2 inhibitor; UACR, urine albumin-to-creatinine ratio.
The between-group difference in least squares mean change in eGFR from baseline to month 4 was −3.69 mL/min/1.73 m2 in patients receiving an SGLT2i at baseline and −2.23 mL/min/1.73 m2 in patients not receiving an SGLT2i at baseline. The difference in treatment effects between SGLT2i groups was −1.46 mL/min/1.73 m2 (95% CI −1.89 to −1.04). Chronic eGFR decline was reduced with finerenone. The between-group difference (finerenone vs. placebo) in chronic eGFR slope from month 4 to the end of the study was greater in patients receiving an SGLT2i at baseline than in those not receiving an SGLT2i at baseline (−1.54 and −1.18 mL/min/1.73 m2, respectively) (Supplementary Fig. 2). In patients receiving an SGLT2i at baseline, the least squares mean change in chronic eGFR slope from month 4 to the end of the study was −1.92 (95% CI −2.61 to −1.23) with finerenone and −3.45 (95% CI −4.15 to −2.76) with placebo. Corresponding changes in patients not receiving an SGLT2i at baseline were −2.54 (95% CI −2.81 to −2.27) with finerenone and −3.72 (95% CI −3.99 to −3.45) with placebo.
Modest reductions in SBP were observed with finerenone versus placebo, irrespective of whether patients were receiving an SGLT2i at baseline, with a maximum between-group difference (finerenone vs. placebo) in SBP at month 4 of −3.6 mmHg for patients receiving an SGLT2i at baseline and −3.7 mmHg for those not receiving an SGLT2i at baseline (Supplementary Fig. 3). Mediation analyses demonstrated that the effect of finerenone versus placebo on UACR regression from severely increased to moderately increased, and from moderately increased to normal, was not mediated by the change in SBP in patients with or without SGLT2i use at baseline; time-varying change in SBP accounted for 9.6% and 8.4% of the effect of finerenone in each subgroup category, respectively.
Safety
Overall safety by SGLT2i use at baseline is shown in Table 2; tolerability profiles were similar across all treatment groups. Patients receiving an SGLT2i at baseline exhibited a lower incidence of hyperkalemia than those not receiving an SGLT2i at baseline in both the finerenone and placebo treatment arms (patients receiving an SGLT2i at baseline 10.3% vs. 2.7%; patients not receiving an SGLT2i 14.3% vs. 7.2%). Among patients receiving an SGLT2i at baseline, elevations in laboratory serum potassium to >6.0 mmol/L occurred in 4 patients (0.9%) in the finerenone group vs. 3 (0.7%) in the placebo group, whereas in patients not receiving an SGLT2i at baseline, this occurred in 207 (3.4%) and 77 (1.3%) patients in the finerenone and placebo groups, respectively. Incidences of hyperkalemia events leading to permanent discontinuation were low with finerenone and placebo in both SGLT2i baseline groups (patients receiving an SGLT2i at baseline 1.1% vs. 0.7%; patients not receiving an SGLT2i 1.7% vs. 0.6%).
Table 2.
Overall safety and selected treatment-emergent AEs of interest in patients receiving or not receiving an SGLT2i at baseline
| Investigator-reported, treatment-emergent AE | SGLT2i at baseline | No SGLT2i at baseline | ||
|---|---|---|---|---|
| Finerenone (n = 438) | Placebo (n = 439) | Finerenone (n = 6,072) | Placebo (n = 6,050) | |
| Any AE | 398 (90.9) | 384 (87.5) | 5,204 (85.7) | 5,223 (86.3) |
| Leading to discontinuation | 18 (4.1) | 23 (5.2) | 396 (6.5) | 328 (5.4) |
| Any serious AE | 146 (33.3) | 141 (32.1) | 1,914 (31.5) | 2,045 (33.8) |
| Leading to discontinuation | 7 (1.6) | 8 (1.8) | 138 (2.3) | 146 (2.4) |
| Any AE resulting in death | 2 (0.5) | 9 (2.1) | 108 (1.8) | 142 (2.3) |
| Hyperkalemia-related AEs | ||||
| Any AE | 45 (10.3) | 12 (2.7) | 867 (14.3) | 436 (7.2) |
| Leading to discontinuation | 5 (1.1) | 3 (0.7) | 105 (1.7) | 35 (0.6) |
| Leading to hospitalization | 1 (0.8) | 0 | 39 (1.4) | 8 (0.3) |
| Renal AEs | ||||
| Acute kidney injury | 5 (1.1) | 15 (3.4) | 215 (3.5) | 219 (3.6) |
| Worsening renal function leading to discontinuation | 2 (0.5) | 2 (0.5) | 50 (0.8) | 40 (0.7) |
| Hypertension | 15 (3.4) | 30 (6.8) | 404 (6.7) | 551 (9.1) |
| Hypotension | 21 (4.8) | 14 (3.2) | 261 (4.3) | 163 (2.7) |
| Hypoglycemia | 17 (3.9) | 19 (4.3) | 323 (5.3) | 356 (5.9) |
| Central laboratory assessments | ||||
| Serum potassium >5.5 mmol/L | 34 (7.9) | 13 (3.0) | 1,041 (17.4) | 457 (7.7) |
| Serum potassium >6.0 mmol/L | 4 (0.9) | 3 (0.7) | 207 (3.4) | 77 (1.3) |
Data are n (%). AE, adverse event; SGLT2i, sodium–glucose cotransporter 2 inhibitor.
Renal AEs were similar with finerenone and placebo; there was no increase in renal AEs in patients receiving versus not receiving an SGLT2i at baseline. The incidence of acute kidney injury appeared to be lower with finerenone versus placebo in patients receiving an SGLT2i at baseline (5 [1.1%] vs. 15 [3.4%]), but similar between groups in those not receiving an SGLT2i at baseline (215 [3.5%] vs. 219 [3.6%]) (Table 2).
Conclusions
In the FIDELITY analysis of patients across a broad spectrum of CKD in type 2 diabetes, finerenone reduced the risk of CV and kidney outcomes compared with placebo, and concomitant treatment with an SGLT2i at baseline or at any time concomitant with study treatment did not modify the observed benefits. These results build on the observation from the FIDELIO-DKD trial that demonstrated a consistent reduction in UACR with finerenone irrespective of SGLT2i intake at baseline (11). The greater power from >13,000 participants provided in the present individual patient–level pooled analysis allows us to extend these findings into other, more important clinical outcomes with improved precision. In patients receiving an SGLT2i at baseline, the risk of cardiorenal events was lower than in those not receiving an SGLT2i on the basis of a comparison of the placebo groups. This may be explained by the differences in baseline characteristics of these groups, including higher mean eGFR and lower median UACR. However, the benefit of finerenone compared with placebo was also observed in those treated with an SGLT2i at baseline. A greater reduction in eGFR from baseline to month 4 was observed with finerenone treatment in patients who received an SGLT2i at baseline than in those who did not; however, chronic eGFR slope was improved with concomitant treatment.
We did not detect any safety signals associated with concomitant use of finerenone and an SGLT2i. This would suggest that stopping rules in the FIGARO-DKD and FIDELIO-DKD trials based on serum potassium levels (7,8) were appropriate to limit the risk of hyperkalemia. A lower incidence of hyperkalemia was reported with concomitant treatment with SGLT2i and finerenone than with finerenone alone; however, an increased risk of any hyperkalemia event with finerenone compared with placebo was still observed. Notably, in patients receiving an SGLT2i at baseline, no difference between the finerenone and placebo groups was observed for serum potassium increases to >6.0 mmol/L. Hyperkalemia events with clinical implications remained infrequent, irrespective of SGLT2i treatment at baseline. Taken together, these data suggest that treatment with an SGLT2i may offer protection from hyperkalemia events when used in combination with finerenone; however, these data need to be interpreted with caution because of the low number of events observed. Despite the low number of hyperkalemia events in FIDELITY, data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial appear to support these findings; a subgroup analysis revealed that the incidence of hyperkalemia was reduced with dapagliflozin in patients who also received concomitant treatment with a steroidal MRA (13). Although the incidence of acute kidney injury appeared to be lower with finerenone compared with placebo in patients receiving an SGLT2i at baseline but comparable in those not receiving an SGLT2i at baseline, the low incidences in both groups make it difficult to provide clinical relevance to the results.
The mechanisms by which finerenone provides cardiorenal benefits have yet to be fully elucidated. As reported in this analysis, finerenone had a modest effect on SBP irrespective of SGLT2i treatment at baseline, and data from preclinical studies in rats have also revealed a reduction in SBP at higher doses of finerenone (14). However, the preclinical models suggested that the cardiorenal protective effects of finerenone are multifactorial, with CV and kidney benefits driven by inhibition of inflammation and fibrosis (14). Finerenone may therefore improve cardiorenal outcomes through a combination of hemodynamic and nonhemodynamic mechanisms. Preclinical data have suggested overadditive effects when combining finerenone and empagliflozin, with the strongest survival benefit (93%) observed with a combination of low-dose finerenone and empagliflozin compared with the individual monotherapy arms or placebo in a rat model of hypertension-induced organ damage (15). The largely independent and complementary mechanisms of action of finerenone and SGLT2is provide a basis for their efficacious and safe combined use. Indeed, kidney and CV benefits of SGLT2is on top of concomitant treatment with a steroidal MRA in patients with heart failure and reduced ejection fraction have been reported in the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) (16,17). Recommended treatment for heart failure is based on combination therapy upon a foundation of RAS inhibitors or angiotensin receptor-neprilysin inhibitors, MRAs, and SGLT2is, with the addition of a β-blocker (18). As a parallel, the use of finerenone, SGLT2is, and GLP-1RAs on top of RAS inhibitors is likely to represent combined treatment options for patients with CKD and type 2 diabetes in the future.
There are limitations to the presented analyses that should be considered when interpreting these data. Patients in the FIDELIO-DKD and FIGARO-DKD studies were not stratified in their random assignments on the basis of SGLT2i use, and we also cannot exclude the possibility that patients receiving an SGLT2i at baseline were recruited from centers with more aggressive approaches toward therapy. Indeed, GLP-1RA and statin use in patients receiving an SGLT2i at baseline was higher than in those not receiving an SGLT2i at baseline despite similar proportions of patients with a history of CV disease. While the present analysis was adjusted for HbA1c, SBP, and baseline UACR and eGFR, other imbalances in baseline characteristics, for example, GLP-1RA use, may have confounded the results. However, these limitations are unlikely to impact the observed treatment effects for comparisons of finerenone versus placebo because of the randomized study design. Overall, the analysis lacked statistical power for the composite kidney and CV outcomes because of the relatively small number of patients receiving SGLT2i at baseline in the FIDELITY population and the small number of clinical events in these patients. Given the sample size, we were unable to evaluate whether dose or type of SGLT2i modified the reported outcomes.
Although the study is not powered to affirm a definitive conclusion, this FIDELITY subgroup analysis suggests that finerenone provides kidney and CV outcome benefits in adults with CKD and type 2 diabetes irrespective of treatment with an SGLT2i, with no concerning safety signals observed with the concomitant use of finerenone and an SGLT2i. The role of combination therapies for cardiorenal protection remains unknown. Randomized trials should assess prospectively whether the combination of a selective, nonsteroidal MRA with an SGLT2i on top of RAS inhibition would provide further protection from heart and kidney failure.
Article Information
Acknowledgments. Medical writing assistance was provided by Kate Weatherall from Chameleon Communications International and was funded by Bayer AG.
Funding and Duality of Interest. The FIDELIO-DKD and FIGARO-DKD trials and FIDELITY combined analyses were sponsored by Bayer AG. P.R. reported receiving personal fees from Bayer AG during the conduct of the study, research support and personal fees from AstraZeneca and Novo Nordisk, and personal fees from Astellas Pharma, Boehringer Ingelheim, Eli Lilly, Gilead Sciences, Mundipharma, Sanofi, and Vifor Pharma paid to Steno Diabetes Center Copenhagen. S.D.A. reported receiving research support from Abbott Vascular and Vifor International and personal fees from Abbott Vascular, Bayer AG, Boehringer Ingelheim, BRAHMS, Cardiac Dimensions, Impulse Dynamics, Novartis, Servier, and Vifor Pharma. G.F. reported being a committee member of trials and registries sponsored by Amgen, Bayer AG, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor Pharma, being a senior consulting editor for JACC: Heart Failure, and receiving research support from the European Union. B.P. reported receiving consultant fees from AstraZeneca, Bayer AG, Boehringer Ingelheim, Brainstorm Medical, Cereno Scientific, G3 Pharmaceuticals, KBP Biosciences, PhaseBio, Proton Intel, Sanofi/Lexicon, Sarfez, scPharmaceuticals, SQ Innovation, Tricida, and Vifor/Relypsa, having stock options for Brainstorm Medical, Cereno Scientific, G3 Pharmaceuticals, KBP Biosciences, Proton Intel, Sarfez, scPharmaceuticals, SQ Innovation, Tricida, and Vifor/Relypsa, and holding a patent for site-specific delivery of eplerenone to the myocardium (U.S. patent no. 9931412) and a provisional patent for histone-acetylation–modulating agents for the treatment and prevention of organ injury (provisional U.S. patent no. 63/045,784). L.M.R. reported receiving consultancy fees from Bayer AG. A.L.B. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk during the conduct of the study paid to the University Clinic Tübingen. J.B.M. reported receiving personal consulting fees from Bayer AG, Boehringer Ingelheim, Jaeb Center, Mannkind, Novo Nordisk, and Provention Bio and grant funding to Washington University from Dexcom, Beta Bionics, the National Institutes of Health, and Novo Nordisk. S.E.R. reported attending one scientific advisory board each for AstraZeneca, Bayer AG, Reata, and Relypsa for which she was compensated during the past 3 years and receiving grant support from AstraZeneca, Bayer AG, and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. M.G., L.R., and M.F.S. reported being full-time employees of Division of Pharmaceuticals, Bayer AG, Germany. M.F.S. is also a shareholder in AstraZeneca, Bayer AG, Eli Lilly, and Novo Nordisk. M.G. is also a shareholder in AstraZeneca, Bayer AG, and Gilead Sciences. A.J. reported having been a full-time employee of Division of Pharmaceuticals, Bayer AG, Germany, at the time of the studies and analysis; he is now a full-time employee of Chiesi S.p.A, Parma, Italy. G.L.B. reported receiving research funding, paid to the Department of Medicine, University of Chicago, from Bayer AG during the conduct of the study; receiving research funding, paid to the university from Novo Nordisk and Vascular Dynamics; acting as a consultant and receiving personal fees from Alnylam, Merck, and Relypsa; being an editor of the American Journal of Nephrology, Nephrology, and Hypertension; being a section editor of UpToDate; and being an associate editor of Diabetes Care and Hypertension Research. R.A. reported receiving personal fees and nonfinancial support from Bayer Healthcare Pharmaceuticals Inc. during the conduct of the study as well as personal fees and nonfinancial support from Akebia Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fresenius, Janssen Pharmaceuticals, Relypsa, Sanofi, and Vifor Pharma; personal fees from Ironwood Pharmaceuticals, Lexicon, Merck & Co., and Reata; receiving nonfinancial support from ER Squibb & Sons, Opko Pharmaceuticals, and Otsuka America Pharmaceutical; being a member of data safety monitoring committees for Amgen, AstraZeneca, and Celgene; being a member of steering committees of randomized trials for Akebia Therapeutics, Bayer AG, Janssen Pharmaceuticals, and Relypsa; being a member of adjudication committees for AbbVie, Bayer AG, Boehringer Ingelheim, and Janssen Pharmaceuticals; serving as associate editor of the American Journal of Nephrology and Nephrology Dialysis and Transplantation; having been an author for UpToDate; and receiving research grants from the U.S. Veterans Administration and the National Institutes of Health. No other potential conflicts of interest relevant to this article were reported.
The sponsor participated in the analysis design, data collection, data analysis, data interpretation, and approval of the manuscript. Analyses were conducted by the sponsor, and all authors had access to and participated in the interpretation of the data. The authors made the decision to submit for publication.
Author Contributions. The Executive Committee designed the study in conjunction with the sponsor. P.R. wrote the first draft of the report. P.R., S.D.A., G.F., B.P., L.M.R., A.L.B., J.B.M., S.E.R., A.J., M.G., L.R., M.F.S., G.L.B., and R.A. had access to the study results, were involved in data analysis and interpretation and drafting and critically revising the report, and reviewed and approved the final submitted version of the report. P.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in abstract form at American Society of Nephrology Kidney Week 2021, San Diego, CA, 4–7 November 2021.
Footnotes
Clinical trial reg. nos. NCT02540993 and NCT02545049, clinicaltrials.gov
See accompanying article, p. 2814.
This article contains supplementary material online at https://doi.org/10.2337/figshare.20289009.
This article is featured in a podcast available at diabetesjournals.org/journals/pages/diabetes-core-update-podcasts.
A complete list of the FIDELIO-DKD and FIGARO-DKD Investigators can be found in the supplementary material online.
Contributor Information
FIDELIO-DKD and FIGARO-DKD Investigators:
Diego Aizenberg, Inés Bartolacci, Diego Besada, Julio Bittar, Mariano Chahin, Alicia Elbert, Elizabeth Gelersztein, Alberto Liberman, Laura Maffei, Federico Pérez Manghi, Hugo Sanabria, Augusto Vallejos, Gloria Viñes, Alfredo Wassermann, Walter Abhayaratna, Shamasunder Acharya, Elif Ekinci, Darren Lee, Richard MacIsaac, Peak Mann Mah, Craig Nelson, David Packham, Alexia Pape, Simon Roger, Hugo Stephenson, Michael Suranyi, Gary Wittert, Elizabeth Vale, Peter Colman, David Colquhoun, Chris Ellis, Kim Joshua, Eugenia Pedagogos, Paul Regal, Duncan Topliss, James Vandeleur, Johan Verjans, Gary Wittert, Katie-Jane Wynne, Martin Clodi, Christoph Ebenbichler, Evelyn Fliesser-Görzer, Ursula Hanusch, Michael Krebs, Karl Lhotta, Bernhard Ludvik, Gert Mayer, Peter Neudorfer, Bernhard Paulweber, Rudolf Prager, Wolfgang Preiß, Friedrich Prischl, Gerit-Holger Schernthaner, Harald Sourij, Martin Wiesholzer, Heinz Drexel, Rainer Oberbauer, Hans-Robert Schönherr, Peter Doubel, Wendy Engelen, Pieter Gillard, Jean-Michel Hougardy, Jean-Marie Krzesinski, Bart Maes, Marijn Speeckaert, Koen Stas, Luc van Gaal, Hilde Vanbelleghem, Francis Duyck, André Scheen, Daniela Antunes, Roberto Botelho, Claudia Brito, Luis Canani, Maria Eugenia Canziani, Maria Cerqueira, Rogerio de Paula, Freddy Eliaschewitz, Carlos Eduardo Figueiredo, Adriana Forti, Miguel Hissa, Maurilo Leite, Jr, Emerson Lima, Irene Noronha, Bruno Paolino, Nathalia Paschoalin, Raphael Paschoalin, Roberto Pecoits Filho, Marcio Pereira, Evandro Portes, Dalton Precoma, Rosangela Rea, Miguel Riella, Joao Eduardo Salles, Eduardo Vasconcellos, Sergio Vencio, Marcelo Bacci, Lilia Maia, Aline Villacorta, Emiliya Apostolova, Radostina Boshnyashka, Ghassan Farah, Dimitar Georgiev, Valentina Gushterova, Neli Klyuchkova, Mariya Lucheva, Petya Manova, Dotska Minkova, Boyan Nonchev, Mariyana Pichmanova, Zhulieta Prakova, Rangel Rangelov, Rosen Rashkov, Pavel Stanchev, Bilyana Stoyanovska-Elencheva, Zhivko Tagarev, Theodora Temelkova-Kurktschieva, Svetla Vasileva, Mariana Yoncheva-Mihaylova, Angel Marinchev, Mariya Miteva, Paul Barre, Brian Carlson, James Conway, Serge Cournoyer, Richard Dumas, Sameh Fikry, Richard Goluch, Pavel Hamet, Randolph Hart, Sam Henein, Joanne Liutkus, Francois Madore, Valdemar Martinho, Giuseppe Mazza, Philip McFarlane, Dennis O’Keefe, Sean Peterson, Daniel Schwartz, Daniel Shu, Andrew Steele, Guy Tellier, Karthik Tennankore, Sheldon Tobe, George Tsoukas, Richard Tytus, Louise Vitou, Michael Walsh, Stanley Weisnagel, Igor Wilderman, Jean-Francois Yale, Fadia El Boreky, Alan Kelly, Lawrence Leiter, Ivor Teitelbaum, Jorge Cobos, Juan Godoy, Fernando González, Sergio Lobos, Juan Carlos Palma, Juan Carlos Prieto Dominguez, Eliana Reyes, Carmen Romero, Victor Saavedra, Mario Vega, Marcelo Medina, Paola Varleta, Ruifang Bu, Hanqing Cai, Nan Chen, Qinkai Chen, Dejun Chen, Jinluo Cheng, Youping Dong, Junwu Dong, Tianjun Guan, Chuanming Hao, Wen Huang, Fangfang Jiang, Minxiang Lei, Ling Li, Zhonghe Li, Xuemei Li, Jingmei Li, Yan Li, Xinling Liang, Bo Liang, Fang Liu, Yinghong Liu, Yuantao Liu, Zhihong Liu, Gang Long, Guoyuan Lu, Weiping Lu, Yibing Lu, Ping Luo, Jianhua Ma, Zhaohui Mo, Jianying Niu, Ai Peng, Jiansong Shen, Feixia Shen, Bingyin Shi, Qing Su, Zhuxing Sun, Shuifu Tang, Nanwei Tong, Hao Wang, Xinjun Wang, Guixia Wang, Jianqin Wang, Yangang Wang, Li Wang, Jiali Wei, Tianfeng Wu, Chaoqing Wu, Changying Xing, Fei Xiong, Xudong Xu, Ning Xu, Tiekun Yan, Jinkui Yang, Aiping Yin, Longyi Zeng, Hao Zhang, Yanlin Zhang, Ying Zhang, Wenjing Zhao, Zhiquan Zhao, Hongguang Zheng, Ling Zhong, Dalong Zhu, Yongze Zhuang, Yuming Du, Yi Fang, Weiying Guo, Sheng Jiang, Jian Kuang, Dongmei Li, Hongmei Li, Yinan Li, Yuxiu Li, Jian Liu, Yu Liu, Heng Miao, Wen Peng, Lihua Wang, Mingtong Xu, Liyong Zhong, Jun Zhu, Clara Arango, Sandra Barrera, Nelly Beltrán López, Diego Benitez, Guillermo Blanco, Andrés Cadena, Julian Coronel, Carlos Cure, Carlos Durán, Alexander González, Gustavo Guzmán, Eric Hernández, Jaime Ibarra, Carlos Jaramillo, Nicolás Jaramillo, William Kattah, Dora Molina, Gregorio Sánchez, Mónica Terront, Freddy Trujillo, Miguel Urina, Ruben Vargas, Iván Villegas, Hernán Yupanqui, Edgar Arcos, Gustavo Aroca, Germán Barreto, Andres Bermudez, Rodrigo Botero, Tatiana Cárdenas, Wilmer Figueroa, Mónica Jaramillo, Manuel Liévano, Mónica López, Dora Molina, Ricardo Rosero, Pedro Trillos, Dino Alferi, Michal Brada, Jiri Brezina, Petr Bucek, Tomas Edelsberger, Drahomira Gulakova, Jitka Hasalova Zapletalova, Olga Hola, Lucie Hornova, Jana Houdova, Helena Hrmova, David Karasek, Sarka Kopecka, Richard Kovar, Eva Krcova, Jiri Kuchar, Vlasta Kutejova, Hana Lubanda, Ivo Matyasek, Magdalena Mokrejsova, Libor Okenka, Martin Prazny, Jiri Pumprla, Pavel Tomanek, Ulla Andersen, Alin Andries, Jesper Bech, Jens Faber, Gunnar Gislason, Jørgen Hangaard, Grzegorz Jaroslaw Pacyk, Claus Juhl, Thure Krarup, Morten Lindhardt, Sten Madsbad, Joan Nielsen, Ulrik Pedersen-Bjergaard, Per Poulsen, Ole Rasmussen, Peter Rossing, Karoline Schousboe, Jeppe Gram, Thomas Lauridsen, Erling Pedersen, Birger Thorsteinsson, Päivi Flöjt, Mikko Honkasalo, Mikko Honkasalo, Kari Humaloja, Kristiina Kananen, Ilkka Kantola, Arvo Koistinen, Pirkko Korsoff, Jorma Lahtela, Sakari Nieminen, Tuomo Nieminen, Karita Sadeharju, Jorma Strand, Sakari Sulosaari, Bertrand Cariou, François Chantrel, Sylvaine Clavel, Christian Combe, Jean-Pierre Fauvel, Karim Gallouj, Didier Gouet, Bruno Guerci, Dominique Guerrot, Maryvonne Hourmant, Alexandre Klein, Christophe Mariat, Michel Marre, Rafik Mesbah, Yannick Le Meur, Arnaud Monier, Olivier Moranne, Ronan Roussel, Pierre Serusclat, Benoit Vendrely, Bruno Verges, Philippe Zaoui, Christoph Axthelm, Andreas Bergmann, Andreas L. Birkenfeld, Hermann Braun, Klaus Busch, Christel Contzen, Stefan Degenhardt, Karl Derwahl, Thomas Giebel, Andreas Hagenow, Hermann Haller, Christoph Hasslacher, Thomas Horacek, Wolfgang Jungmair, Christof Kloos, Thorsten Koch, Thilo Krüger, Anja Mühlfeld, Joachim Müller, Andreas Pfützner, Frank Pistrosch, Andrea Rinke, Ludger Rose, Lars Rump, Volker Schettler, Ingolf Schiefke, Heike Schlichthaar, Bernd Schröppel, Norbert Schöll, Kristin Schubert, Thomas Schürholz, Helena Sigal, Lutz Stemler, Georg Strack, Heidrun Täschner, Nicole Toursarkissian, Diethelm Tschöpe, Achim Ulmer, Markus van der Giet, Christoph Wanner, Bernhard R. Winkelmann, Ioannis Boletis, George Dimitriadis, Erifili Hatziagelaki, Christos Iatrou, Ioannis Ioannidis, Theodora Kounadi, Ioanna Makriniotou, Dorothea Papadopoulou, Aikaterini Papagianni, Ploumis Passadakis, George Piaditis, Ioannis Stefanidis, Tai Pang Ip, Paul Lee, On Yan Andrea Luk, Ronald Ma, Wing Sun Chow, Angela Wang, Vincent Yeung, Dora Bajcsi, Peter Danos, Eleonora Harcsa, Akos Kalina, Szilvia Kazup, Katalin Keltai, Robert Kirschner, Julianna Kiss, Laszlo Kovacs, Beata Lamboy, Botond Literati-Nagy, Margit Mileder, Laszlo Nagy, Ebrahim Noori, Gabor Nyirati, Gizella Petro, Karoly Schneider, Judit Simon, Albert Szocs, Szilard Vasas, Krisztina Wudi, Zsolt Zilahi, Marianna Zsom, Joe Eustace, John Holian, Donal Reddan, Yvonne O’Meara, Rosane Abramof Ness, Faiad Adawi, Zaher Armaly, Shaul Atar, Amir Bashkin, Sydney Ben Chetrit, Noa Berar Yanay, Gil Chernin, Mahmud Darawsha, Shai Efrati, Mazen Elias, Evgeny Farber, Mariela Glandt, Ehud Grossman, Majdi Halabi, Ilana Harman-Boehm, Khaled Khazim, Idit Liberty, Oscar Minuchin, Ofri Mosenzon, Farid Nakhoul, Assy Nimer, Doron Schwartz, Julio Wainstein, Yoram Yagil, Robert Zukermann, Angelo Avogaro, Giovanni Giorgio Battaglia, Maurizio Tiziano Bevilacqua, Enzo Bonora, Carlo Antonio Bossi, Paolo Calabrò, Franco Luigi Cavalot, Roberto Cimino, Mario Gennaro Cozzolino, Salvatore David, Michele Emdin, Enrico Fiaccadori, Paolo Fiorina, Carlo Bruno Giorda, Maria Cristina Gregorini, Gaetano La Manna, Davide Carlo Maggi, Roberta Manti, Giancarla Meregalli, Antonello Pani, Aneliy Ilieva Parvanova, Norberto Perico, PierMarco Piatti, Antonio Pisani, Antonio Ettore Pontiroli, Paola Ponzani, Gennaro Santorelli, Domenico Santoro, Renzo Scanziani, Ugo Teatini, Giancarlo Tonolo, Roberto Trevisan, Anna Maria Veronelli, Giorgio Luciano Viviani, Hideo Araki, Yukihiro Bando, Osamu Ebisui, Naruhiro Fujita, Hirotaka Fukasawa, Ryuichi Furuya, Yoshiyuki Hamamoto, Akihiro Hamasaki, Kotaro Hasegawa, Masahiro Hatazaki, Terumasa Hayashi, Takayuki Higashi, Yoshihide Hirohata, Shuji Horinouchi, Ayumu Hoshi, Hirofumi Imoto, Akemi Inagaki, Masayuki Inagaki, Daijo Inaguma, Toshihiko Inoue, Masao Ishii, Tamayo Ishiko, Motohide Isono, Hideaki Jinnouchi, Hidetoshi Kanai, Daisuke Kanda, Hideo Kanehara, Masayuki Kashima, Yuko Kataoka, Shigehiro Katayama, Kiyoe Kato, Takeshi Katsuki, Katsunori Kawamitsu, Satsuki Kawasaki, Fumi Kikuchi, Hidetoshi Kikuchi, Rui Kishimoto, Kunihisa Kobayashi, Junko Koide, Rieko Komi, Miyuki Kubota, Genpei Kuriya, Takeshi Kurose, Yoshiro Kusano, Hajime Maeda, Sunao Matsubayashi, Kazunari Matsumoto, Naoya Matsumura, Yasuto Matsuo, Naoki Matsuoka, Hiroaki Miyaoka, Satoshi Miyata, Takeshi Morita, Isao Murakami, Satoshi Murao, Udai Nakamura, Mikihiro Nakayama, Jun Nakazawa, Sakae Nohara, Takashi Nomiyama, Masayuki Noritake, Yoshiaki Oda, Takayuki Ogiwara, Hiroshi Ohashi, Hideki Okamoto, Shinichi Okino, Takeshi Osonoi, Nobuhiro Sasaki, Yoshitaka Sayo, Taiji Sekigami, Taro Shibasaki, Hirotaka Shibata, Tatsushi Shimoyama, Junji Shinoda, Hiroshi Sobajima, Kazuya Sugitatsu, Toshiyuki Sugiura, Toru Sugiyama, Daisuke Suzuki, Hiroyuki Suzuki, Masaaki Suzuki, Asami Takeda, Asami Tanaka, Seiichi Tanaka, Izumi Tsunematsu, Yasuo Ueda, Soichi Uekihara, Makoto Ujihara, Ken Yajima, Daishiro Yamada, Masayo Yamada, Kazuo Yamagata, Ken Yamakawa, Fumiko Yamakawa, Yoshimitsu Yamasaki, Yuko Yambe, Taihei Yanagida, Hidekatsu Yanai, Toshihiko Yanase, Tetsuyuki Yasuda, Dovile Kriauciuniene, Jurate Lasiene, Antanas Navickas, Lina Radzeviciene, Egle Urbanaviciene, Gediminas Urbonas, Audrone Velaviciene, Rohana Abd Ghani, Nor Azizah Aziz, Li Yuan Lee, Chek Loong Loh, Norhaliza Mohd Ali, Nurain Mohd Noor, Nik Nur Fatnoon, Nik Ahmad, Jeyakantha Ratnasingam, Wan Hasnul, Halimi Bin Wan Hasan, Wan Mohd Izani, Wan Mohamed, Rizmy Najme Khir, Masni Mohamad, Tong Boon Alexander Tan, Sandro Avila Pardo, Miriam Bastidas Adrian, Alfredo Chew Wong, Jorge Escobedo de la Peña, Guillermo Fanghänel Salmón, Guillermo González Gálvez, Ramiro Gutiérrez Ochoa, Saúl Irizar Santana, Magdalena Madero Rovalo, Gustavo Méndez Machado, Luis Nevarez Ruiz, Denisse Ramos Ibarra, Gabriel Ramos López, Leobardo Sauque Reyna, Gustavo Solache Ortiz, Rafael Valdez Ortiz, Juan Villagordoa Mesa, Melchor Alpizar Salazar, Pedro García Hernández, José González, José Lazcano Soto, Arturo Saldaña Mendoza, Sergio Irizar Santana, Elvira González Vilchis, R.C. Bakker, J.N.M. Barendregt, A.H. Boonstra, Willem Bos, C.B. Brouwer, M. van Buren, Ron Gansevoort, Adriaan Kooy, Marielle Krekels, Ruud J.M. van Leendert, Louis A.G. Lieverse, P.T. Luik, E. Lars Penne, Peter Smak Gregoor, Liffert Vogt, Bert-Jan van den Born, John Baker, Veronica Crawford, Rick Cutfield, Peter Dunn, Jeremy Krebs, Kingsley Nirmalaraj, Russell Scott, Nine Smuts, Janet Titchener, Erik Eriksen, Trine Finnes, Hans Høivik, Thomas Karlsson, Peter Scott Munk, Maria Radtke, Knut Risberg, Jan Rocke, Leidulv Solnør, Aud-Eldrid Stenehjem, Anne-Beathe Tafjord, Emil Asprusten, Robert Hagemeier, Kjetil Høye, Hilde Selsås, Frode Thorup, Cecilie Wium, Glenda Pamugas, Araceli Panelo, Ronald Perez, Maribel Tanque, Louie Tirador, Michael Villa, Albert Bautista, Elizabeth Catindig, Carlo Manalo, Roberto Mirasol, Patrycja Butrymowicz, Kazimierz Ciechanowski, Grazyna Cieslik, Edward Franek, Janusz Gumprecht, Michal Hoffmann, Jolanta Krzykowska, Ilona Kurnatowska, Katarzyna Landa, Adam Madrzejewski, Katarzyna Madziarska, Stanislaw Mazur, Piotr Napora, Michal Nowicki, Anna Ocicka-Kozakiewicz, Barbara Rewerska, Teresa Rusicka, Jan Ruxer, Ewa Skokowska, Andrzej Stankiewicz, Tomasz Stompor, Agnieszka Tiuryn-Petrulewicz, Katarzyna Wasilewska, Bogna Wierusz-Wysocka, Renata Wnetrzak-Michalska, Krystyna Jedynasty, Izabela Sein Anand, Edgar Almeida, Rosa Ballesteros, Carlos Barreto, Idalina Beirao, Rita Birne, Cesar Esteves, Jose Guia, Susana Heitor, Olinda Marques, Pedro Melo, Fernando Nolasco, Amalia Pereira, Cristina Roque, Francisco Rosario, Gil Silva, Ana Silva, Fernando Teixeira e Costa, Ana Vila Lobos, Ana Rita Alves, Ilidio Brandao, Rui Carvalho, Joao Coelho, Ana Lourenco, Pedro Matos, Vanisa Rosario, Joao Sergio Neves, Gregorio Cortes-Maisonet, Amaury Roman-Miranda, Yudit Brito-Peguero, Gildred Colon-Vega, Adrian Albota, Cornelia Bala, Hortensia Barbonta, Elena Caceaune, Doina Catrinoui, Ciprian Constantin, Adriana Dumitrescu, Nicoleta Mindrescu, Cristina Mistode, Gabriela Negrisanu, Adriana Onaca, Silvia Paveliu, Ella Pintilei, Lavinia Pop, Amorin Popa, Alexandrina Popescu, Gabriela Radulian, Iosif Szilagyi, Liana Turcu, Georgeta Vacaru, Adrian Vlad, Adriana Filimon, Ioan Veresiu, Mikhail Antsiferov, Mikhail Arkhipov, Andrey Babkin, Olga Barbarash, Vitaliy Baranov, Elena Chernyavskaya, Arkadiy Demko, Alexander Dreval, Anton Edin, Polina Ermakova, Valentin Fadeev, Albert Galyavich, Leyla Gaysina, Ivan Gordeev, Irina Ipatko, Marina Kalashnikova, Yuriy Khalimov, Vadim Klimontov, Zhanna Kobalava, Elena Kosmacheva, Natalya Koziolova, Lyudmila Kvitkova, Sergey Levashov, Roman Libis, Vyacheslav Marasaev, Natalia Malykh, Vladimir Martynenko, Sofya Malyutina, Imad Merai, Ashot Mkrtumyan, Galina Nechaeva, Nina Petunina, Shamil Palyutin, Leonid Pimenov, Elena Rechkova, Tatyana Rodionova, Oksana Rymar, Ruslan Sardinov, Olga Semenova, Alexander Sherenkov, Oleg Solovev, Elena Smolyarchuk, Leonid Strongin, Olga Ukhanova, Nadezhda Verlan, Natalya Vorokhobina, Davyd Yakhontov, Sergey Yakushin, Elena Zakharova, Alsu Zalevskaya, Olga Zanozina, Elena Zhdanova, Larisa Zhukova, Tatyana Zykova, Yulia Argunova, Konstantin Nikolaev, Svetlana Villevalde, Chee Fang Sum, Sufi Muhummad Suhail, Ru San Tan, Anantharaman Vathsala, Edmund Wong, Yong Mong Bee, Jana Babikova, Ingrid Buganova, Andrej Dzupina, Zuzana Ochodnicka, Dalibor Sosovec, Denisa Spodniakova, Peter Minarik, Fayzal Ahmed, Aslam Amod, Sindeep Bhana, Larry Distiller, Dirkie Jansen van Rensburg, Mukesh Joshi, Shaifali Joshi, Deepak Lakha, Essack Mitha, Gracjan Podgorski, Naresh Ranjith, Brian Rayner, Paul Rheeder, Mohamed Sarvan, Mary Seeber, Heidi Siebert, Mohammed Tayob, Julien Trokis, Dorothea Urbach, Louis van Zyl, Dirkie Jansen van Rensburg, Bum-Soon Choi, Moon Gi Choi, ChoonHee Chung, YouCheol Hwang, ChongHwa Kim, InJoo Kim, JaeHyeon Kim, SinGon Kim, SungGyun Kim, Tae Hee Kim, WooJe Lee, ByungWan Lee, Kang Wook Lee, Kook-Hwan Oh, Ji Eun Oh, Yun Kyu Oh, Dong-Jin Oh, Junbeom Park, Seok Joon Shin, Su-Ah Sung, Jae Myung Yu, HyeSoo Chung, Ji Hye Huh, JunGoo Kang, ChulSik Kim, HyeSoon Kim, NamHoon Kim, Soo Lim, Young Min Cho, Cheol Young Park, Irene Agraz, Francisco Javier Ampudia, Hanane Bouarich, Francesca Calero, Cristina Castro, Secundino Cigarrán Guldris, Josep Cruzado Garrit, Fernando de Álvaro, Josep Galcerán, Olga González Albarrán, Julio Hernández Jaras, Meritxell Ibernón, Francisco Martínez Deben, Mª Dolores Martínez Esteban, José María Pascual Izuel, Judith Martins, Juan Mediavilla, Alfredo Michán, Julio Pascual Santos, Esteban Poch, Manuel Polaina Rusillo, Carlos Sánchez Juan, Rafael Santamaría Olmo, José Julián Segura de la Morena, Alfonso Soto, Maribel Troya, Fernando Cereto Castro, Pablo Gómez Fernández, Laura Fuentes Sánchez, Mercedes González Moya, Domingo Hernández Marrero, Gonzalo Piedrola Maroto, Josep Redón, Daniel Seron, Annette Bruchfeld, Dan Curiac, Ken Eliasson, Malin Frank, Gregor Guron, Olof Hellberg, Margareta Hellgren, Hans Larnefeldt, Carl-Johan Lindholm, Magnus Löndahl, Erik Rein-Hedin, Inga Soveri, Jonas Spaak, Bengt-Olov Tengmark, Cornelia Lif-Tiberg, Johan Månflod, Han Nguyen, Daniel Ackermann, Stefan Bilz, Michel Burnier, Christian Forster, Stefan Kalbermatter, Andreas Kistler, Antoinette Pechère-Bertschi, Bernd Schultes, Markus Laimer, Gottfried Rudofsky, Christopher Strey, Gregoire Wuerzner, Chiz-Tzung Chang, Cheng-Chieh Hung, Ju-Ying Jiang, Chien-Te Lee, Shuei-Liong Lin, Der-Cherng Tarng, Shih-Te Tu, Mai-Szu Wu, Ming-Ju Wu, Lee-Ming Chuang, Chaicharn Deerochanawong, Chagriya Kitiyakara, Vuddhidej Ophascharoensuk, Chatlert Pongchaiyakul, Bancha Satirapoj, Natapong Kosachunhanan, Piyamitr Sritara, Necmi Eren, Ibrahim Gul, Okan Gulel, Ismail Kocyigit, Abdulbaki Kumbasar, Idris Sahin, Ramazan Sari, Burak Sayin, Talat Tavli, Sedat Ustundag, Yavuz Yenicerioglu, Ozer Badak, Murat Cayli, Aytekin Oguz, Oner Ozdogan, Ibrahim Sari, Ahmet Temizhan, Mustafa Tigen, Ugur Turk, Huseyin Yilmaz, Mehmet Yilmaz, Iryna Bondarets, Volodymyr Botsyurko, Viktoriia Chernikova, Oleksandra Donets, Ivan Fushtey, Mariia Grachova, Anna Isayeva, Dmytro Kogut, Julia Komisarenko, Nonna Kravchun, Kateryna Malyar, Borys Mankovsky, Liliya Martynyuk, Vitaliy Maslyanko, Halyna Myshanych, Larysa Pererva, Nataliia Pertseva, Oleksandr Serhiyenko, Ivan Smirnov, Liubov Sokolova, Vasyl Stryzhak, Maryna Vlasenko, Ganna Isayeva, Oleksandr Larin, Ahmad AbouSaleh, Jonathan Barratt, Cuong Dang, Hassan Kahal, Adam Kirk, Anne Kilvert, Sui Phi Kon, Kieran McCafferty, Dipesh Patel, Sam Rice, Arutchelvam Vijayaraman, Yuk-ki Wong, Martin Gibson, Mona Wahba, Reza Zaidi, Rudy Bilous, Andrew Johnson, Dhanya Kalathil, Anne Kilvert, Christina Kyriakidou, Amit Mathew, Rasha Mukhtar, Imrozia Munsoor, Anton Poterajlo, Pauline Swift, Idalia Acosta, Atoya Adams, Sharon Adler, Dilawar Ajani, Slamat Ali, Radica Alicic, Amer Al-Karadsheh, Sreedhara Alla, D. Allison Nabil Andrawis, Ahmed Arif, Ahmed Awad, Masoud Azizad, Michael Bahrami, Shweta Bansal, Steven Barag, Ahmad Barakzoy, Mark Barney, Joshua Barzilay, Khalid Bashir, Jose Bautista, Srinivasan Beddhu, Diogo Belo, Sabrina Benjamin, Ramin Berenji, Anuj Bhargava, Jose Birriel, Stephen Brietzke, Frank Brosius, Osvaldo Brusco, Anna Burgner, Robert Busch, Rafael Canadas, Maria Caramori, Jose Cardona, Christopher Case, Humberto Cruz, Ramprasad Dandillaya, Dalia Dawoud, Zia Din, Bradley Dixon, Ankur Doshi, James Drakakis, Mahfouz El Shahawy, Ashraf El-Meanawy, Mohammed El-Shahawy, John Evans, George Fadda, Umar Farooq, Roland Fernando, Raymond Fink, Brian First, David Fitz-Patrick, John Flack, Patrick Fluck, Leon Fogelfeld, Vivian Fonseca, Juan Frias, Claude Galphin, Luis Garcia-Mayol, Gary Goldstein, Edgar Gonzalez, Francisco Gonzalez-Abreu, Ashwini Gore, David Grant, Violet Habwe, Maxine Hamilton, Jamal Hammoud, Stuart Handelsman, Israel Hartman, Glenn Heigerick, Andrew Henry, German Hernandez, Carlos Hernandez-Cassis, Carlos Herrera, Joachim Hertel, Wenyu Huang, Rogelio Iglesias, Ali Iranmanesh, Timothy Jackson, Mahendra Jain, Kenneth Jamerson, Karen Johnson, Eric Judd, Joshua Kaplan, Zeid Kayali, Bobby Khan, Muhammad Khan, Sourabh Kharait, M. Sue Kirkman, Nelson Kopyt, Wayne Kotzker, Csaba Kovesdy, Camil Kreit, Arvind Krishna, Saeed Kronfli, Keung Lee, Derek LeJeune, Brenda Lemus, Carlos Leon-Forero, Douglas Linfert, Henry Lora, Alexander Lurie, Geetha Maddukuri, Alexander Magno, Louis Maletz, Sreedhar Mandayam, Mariana Markell, Ronald Mayfield, Caroline Mbogua, Dierdre McMullen, Carl Meisner, Stephen Minton, Bharat Mocherla, Rajesh Mohandas, Manuel Montero, Moustafa Moustafa, Salil Nadkarni, Samer Nakhle, Jesus Navarro, Nilda Neyra, Romanita Nica, Philip Nicol, Paul Norwood, Visal Numrungroad, Richard O’Donovan, A. Odugbesan, Jorge Paoli-Bruno, Samir Parikh, Rakesh Patel, Aldo Peixoto, Pablo Pergola, Alan Perlman, Karlton Pettis, Roberto Pisoni, Mirela Ponduchi, Jorge Posada, Sharma Prabhakar, Jai Radhakrishnan, Mahboob Rahman, Rupesh Raina, Anjay Rastogi, Efrain Reisin, Marc Rendell, David Robertson, Michael Rocco, Hugo Romeu, Sylvia Rosas, Jack Rosenfeld, Dennis Ross, Jeffrey Rothman, Lance Rudolph, Yusuf Ruhullah, Gary Ruoff, Jeffrey Ryu, Mandeep Sahani, Ramin Sam, Garfield Samuels, William Sanchez, Vladimir Santos, Scott Satko, Sanjeev Saxena, David Scott, Gilberto Seco, Melvin Seek, Harvey Serota, Tariq Shafi, Nauman Shahid, Michael Shanik, Santosh Sharma, Arjun Sinha, James Smelser, Mark Smith, Kyaw Soe, Richard Solomon, Eugene Soroka, Joseph Soufer, Bruce Spinowitz, Leslie Spry, Rosa Suarez, Bala Subramanian, Harold Szerlip, Aparna Tamirisa, Stephen Thomson, Tuan-Huy Tran, Richard Treger, Gretel Trullenque, Thomas Turk, Guillermo Umpierrez, Daniel Urbach, Martin Valdes, Shujauddin Valika, Damaris Vega, Peter Weissman, Adam Whaley-Connell, Jonathan Winston, Jonathan Wise, Alan Wynne, Steven Zeig, Emaad Abdel-Rahman, Edel Abreu, Alaa Awad, Nader Bahri, John Bertsch, David Bleich, Jonathan Bornfreund, Harjeet Brar, Susan Brian, Cynthia Brinson, Humberto Bruschetta, Jose Carpio, Steven Cohen, John Cosby, Soni Dhanireddy, Jorge Diaz, Fredrick Dunn, Sabitha Eppanapally, Joseph Fayad, Archana Goel, Kanakadurga Govindaraju, Stephen Halpern, Audrey Jones, William Kaye, Herbert Knight, Stanley Koch, Nandini Kohli, Guido Lastra, Sam Lerman, Jorge Loredo, Dragana Lovre, Mustafa Mandviwala, Earl Martin, Jill Meyer, John Murray, David Oliver, Suzanne Oparil, Jesus Penabad, Isabel Pereira, Larry Popeil, Gonzalo Quesada, Kodangudi Ramanathan, Luis Ramos-Gonez, Mandana Rastegar, Padmashri Rastogi, Juan Rondon, Prabir Roy-Chaudhury, David Smith, Don Williamson, Catherine Womack, Hala Yamout, Michael Yuryev, Phuong Chu, Lam Van Hoang, Tran Khanh, Nguyen Thi Phi Nga, Pham Nguyen Son, Lan Phuong Tran, Thuy Khuong Le, Boi Ngoc Nguyen, Thao Nguyen, Nguyen Minh Nui, Tran Quang Nam, and Kim Chi Tran
References
- 1. United States Renal Data System . Epidemiology of kidney disease in the United States. USRDS Annual Data Report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2020. Accessed 15 November 2021. Available from https://adr.usrds.org/2020
- 2. American Diabetes Association . 10. Cardiovascular disease and risk management: standards of medical care in diabetes–2020. Diabetes Care 2020;43(Suppl. 1):S111–S134 [DOI] [PubMed] [Google Scholar]
- 3. Cosentino F, Grant PJ, Aboyans V, et al.; ESC Scientific Document Group . 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323 [DOI] [PubMed] [Google Scholar]
- 4. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group . KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int 2020;98:S1–S115 [DOI] [PubMed] [Google Scholar]
- 5. Perkovic V, Jardine MJ, Neal B, et al.; CREDENCE Trial Investigators . Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306 [DOI] [PubMed] [Google Scholar]
- 6. Wheeler DC, Stefánsson BV, Jongs N, et al.; DAPA-CKD Trial Committees and Investigators . Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021;9:22–31 [DOI] [PubMed] [Google Scholar]
- 7. Bakris GL, Agarwal R, Anker SD, et al.; FIDELIO-DKD Investigators . Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020;383:2219–2229 [DOI] [PubMed] [Google Scholar]
- 8. Pitt B, Filippatos G, Agarwal R, et al.; FIGARO-DKD Investigators . Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021;385:2252–2263 [DOI] [PubMed] [Google Scholar]
- 9. Kintscher U, Bakris GL, Kolkhof P. Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Br J Pharmacol 2022;179:3320–3234 [DOI] [PubMed] [Google Scholar]
- 10. Bayer Healthcare Pharmaceuticals Inc . KERENDIA (finerenone) prescribing information. 2021. Accessed 17 August 2021 Available from https://labeling.bayerhealthcare.com/html/products/pi/Kerendia_PI.pdf
- 11. Rossing P, Filippatos G, Agarwal R, et al.; FIDELIO-DKD Investigators . Finerenone in predominantly advanced CKD and type 2 diabetes with or without sodium-glucose cotransporter-2 inhibitor therapy. Kidney Int Rep 2021;7:36–45 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Agarwal R, Filippatos G, Pitt B, et al.; FIDELIO-DKD and FIGARO-DKD investigators . Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022;43:474–484 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Provenzano M, Jongs N, Vart P, et al.; DAPA-CKD Trial Committees and Investigators . The kidney protective effects of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, are present in patients with CKD treated with mineralocorticoid receptor antagonists. Kidney Int Rep 2021;7:436–443 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol 2014;64:69–78 [DOI] [PubMed] [Google Scholar]
- 15. Kolkhof P, Hartmann E, Freyberger A, et al. Effects of finerenone combined with empagliflozin in a model of hypertension-induced end-organ damage. Am J Nephrol 2021;52:642–652 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Ferreira JP, Zannad F, Pocock SJ, et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-Reduced. J Am Coll Cardiol 2021;77:1397–1407 [DOI] [PubMed] [Google Scholar]
- 17. Shen L, Kristensen SL, Bengtsson O, et al. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021;9:254–264 [DOI] [PubMed] [Google Scholar]
- 18. McDonagh TA, Metra M, Adamo M, et al.; ESC Scientific Document Group . 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–3726 [DOI] [PubMed] [Google Scholar]