Finerenone + heart failure

BACKGROUND Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed. METHODS In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed. RESULTS Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia. CONCLUSIONS In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.).

BACKGROUND Data on the effect of mineralocorticoid receptor antagonist therapy on HbA1c levels and new-onset diabetes are conflicting. We aimed to examine the effect of oral finerenone, compared with placebo, on incident diabetes in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) trial. METHODS In this randomised, double-blind, placebo-controlled trial, 6001 participants with heart failure with New York Heart Association functional class II-IV, left ventricular ejection fraction 40% or higher, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomly assigned to finerenone or placebo, administered orally. Randomisation was performed with concealed allocation. The primary outcome of the trial was the composite of cardiovascular death and total (first and recurrent) heart failure events (ie, heart failure hospitalisation or urgent heart failure visit). In the present analysis, participants with diabetes at baseline (investigator-reported history of diabetes or baseline HbA1c ≥6·5%) were excluded. New-onset diabetes was defined as a HbA1c measurement of 6·5% or higher on two consecutive follow-up visits or new initiation of glucose-lowering therapy. The full-analysis set comprised all participants randomly assigned to study treatment, analysed according to their treatment assignment irrespective of the treatment received (ie, intention to treat). The safety analysis set comprised participants randomly assigned to study treatment who took at least one dose of the investigational product, analysed according to the treatment actually received. This trial is registered with ClinicalTrials.gov, NCT04435626, and is closed to new participants. FINDINGS Between Sept 14, 2020, and Jan 10, 2023, 6001 participants were recruited and randomly assigned to finerenone or placebo. 3222 (53·7%) participants did not have diabetes at baseline and comprised the study population. During a median duration of follow-up of 31·3 months (IQR 21·5-36·3), 115 (7·2%) participants in the finerenone group and 147 (9·1%) in the placebo group developed new-onset diabetes, corresponding to a rate of 3·0 events per 100 person-years (95% CI 2·5-3·6) in the finerenone group and 3·9 events per 100 person-years (3·3-4·6) in the placebo group. Compared with placebo, finerenone significantly reduced the hazard of new-onset diabetes by 24% (hazard ratio [HR] 0·76 [95% CI 0·59-0·97], p=0·026). Fine-Gray competing risk analysis, accounting for the competing risk of death, yielded a similar finding (subdistribution HR 0·75 [0·59-0·96], p=0·024). Results were similar in sensitivity analyses, in which the definition of new-onset diabetes was expanded to include initiation of SGLT2 inhibitor treatment with diabetes as indication, restricted to HbA1c measurements only, and restricted to new initiation of glucose-lowering drugs only (excluding SGLT2 inhibitor treatment). Findings were similar when participants treated with glucose-lowering drugs at baseline were excluded (n=15). The effect of finerenone, compared with placebo, on new-onset diabetes was consistent across key participant subgroups. Seven participants had an adverse event of new diabetes not captured by any of the definitions above. INTERPRETATION In participants with heart failure with mildly reduced or preserved ejection fraction without diabetes, oral finerenone reduced the hazard of new-onset diabetes, representing a meaningful additional clinical benefit of this treatment in these individuals. FUNDING Bayer.

BACKGROUND Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio are complementary domains of kidney disease staging and independently associated with heart failure (HF) progression. OBJECTIVES The purpose of this study was to evaluate whether the efficacy and safety of finerenone varies according to kidney risk among patients with HF with mildly reduced or preserved ejection fraction. METHODS In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), clinical outcomes and treatment effects of finerenone on the primary endpoint (cardiovascular death and total [first and recurrent] HF events) and key secondary endpoints were evaluated according to baseline KDIGO (Kidney Disease: Improving Global Outcomes) risk category (low, moderately increased, and high or very high). Key exclusion criteria in FINEARTS-HF were eGFR <25 mL/min/1.73 m2 or serum potassium >5.0 mmol/L. RESULTS Overall, 5,797 (97%) FINEARTS-HF participants had classifiable KDIGO risk category at baseline, of whom 2,022 (35%), 1,688 (29%), and 2,087 (36%) were low, moderate, and high/very high risk, respectively. Over a median follow-up of 2.7 years, higher kidney risk was associated with a higher rate of primary outcome events, with similar findings for other key endpoints, including the composite kidney outcome, new-onset atrial fibrillation, and vascular events. Benefits of finerenone vs placebo on the primary endpoint (Pinteraction = 0.24) and Kansas City Cardiomyopathy Questionnaire-Total Symptom Score at 12 months (Pinteraction = 0.36) were consistent irrespective of baseline kidney risk category. Participants with higher kidney risk experienced greater reductions in urine albumin-to-creatinine ratio after 6 months (Pinteraction = 0.031), without differences in eGFR slope. Risks of safety events, including hyperkalemia, with finerenone vs placebo were not enhanced among participants with higher kidney risk. CONCLUSIONS Finerenone appears to consistently improve clinical outcomes, HF-related health status, and albuminuria across a broad spectrum of kidney risk in patients with HF with mildly reduced or preserved ejection fraction. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] and Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF]; NCT04435626).

BACKGROUND Finerenone has kidney protective effects in patients with chronic kidney disease (CKD) with type 2 diabetes, but effects on kidney outcomes in patients with heart failure (HF) with and without diabetes and/or CKD are not known. OBJECTIVES Examine the effects of finerenone on kidney outcomes in FINEARTS-HF, a randomized trial of finerenone vs. placebo among patients with HF with mildly reduced or preserved ejection fraction. METHODS We explored the effects of finerenone on the secondary outcome of a sustained ≥50% eGFR decline or kidney failure (sustained eGFR decline <15 mL/min/1.73 m2; initiation of maintenance dialysis; renal transplant). In this prespecified analysis, we also report effects of finerenone on: 1) sustained ≥57% eGFR decline or kidney failure; 2) eGFR slope; 3) changes in urine albumin/creatinine ratio (UACR). RESULTS Among 6,001 participants, mean baseline eGFR was 62 ±20mL/min/1.73m2; 48% had eGFR <60mL/min/1.73m2. Overall, 5,797 had baseline UACR data (median 18 [7,67]mg/g). Over 2.6 years median follow-up, the incidence of the composite kidney outcome (≥50% eGFR decline or kidney failure) was numerically, but non-significantly, higher for finerenone vs. placebo (75 vs. 55 events; HR 1.33; 95%CI 0.94, 1.89). Similar results were observed for the composite of ≥57% eGFR decline or kidney failure (41 vs. 31 events; HR 1.28; 95%CI 0.80, 2.05), though the overall event frequency was relatively low. During the first 3 months, finerenone led to an acute decline in eGFR of -2.9 mL/min/1.73m2 (95%CI -3.4, -2.4) but did not alter chronic (from 3 months) eGFR slope (+0.2 mL/min/1.73m2/year; 95%CI -0.1, +0.4), vs. placebo. The difference in total slope was -0.7 (95%CI -0.9 to -0.4) mL/min/1.73 m2/year. Finerenone reduced UACR by 30% (95%CI 25%, 34%) over 6 months vs. placebo, an effect that persisted throughout follow-up. Finerenone reduced the risk of new-onset of micro- and macroalbuminuria by 24% (HR 0.76; 95%CI 0.68, 0.83) and 38% (HR 0.62; 95%CI 0.53, 0.73), respectively. CONCLUSIONS In FINEARTS-HF, a population at low risk of adverse kidney outcomes, finerenone did not significantly modify the kidney composite outcomes. Finerenone led to a greater reduction in initial eGFR, but did not result in a significant difference in chronic eGFR slope, vs. placebo. Finerenone led to early and sustained reductions in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria.

Cardiovascular-kidney-metabolic syndrome is an emerging entity that connects cardiovascular diseases, chronic kidney disease and diabetes. The non-steroidal mineralocorticoid receptor antagonist finerenone has been studied in three prospective randomized clinical trials of patients with cardiovascular-kidney-metabolic syndrome: FIDELIO-DKD, FIGARO-DKD and FINEARTS-HF. In light of the strong epidemiological overlap and shared mechanistic drivers of clinical outcomes across cardiovascular-kidney-metabolic syndrome, we summarize the efficacy and safety of finerenone on cardiovascular, kidney and mortality outcomes in this pre-specified participant-level pooled analysis. The three trials included 18,991 participants (mean age 67 ± 10 years; 35% women). During 2.9 years of median follow-up, the primary outcome of cardiovascular death occurred in 421 (4.4%) participants assigned to finerenone and 471 (5.0%) participants assigned to placebo (hazard ratio (HR): 0.89; 95% confidence interval (CI): 0.78–1.01; P = 0.076). Death from any cause occurred in 1,042 (11.0%) participants in the finerenone arm and in 1,136 (12.0%) participants in the placebo arm (HR: 0.91; 95% CI: 0.84–0.99; P = 0.027). Finerenone further reduced the risk of hospitalization from heart failure (HR: 0.83; 95% CI: 0.75–0.92; P < 0.001) and the composite kidney outcome (HR: 0.80; 95% CI: 0.72–0.90; P < 0.001). While in this pooled analysis the reduction in cardiovascular death was not statistically significant, finerenone reduced the risks for deaths of any cause, cardiovascular events and kidney outcomes. PROSPERO identifier: CRD42024570467. This participant-level pooled analysis of the three phase 3 trials that have tested the non-steroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and chronic kidney disease with type 2 diabetes provides an integrated view of the mortality, cardiovascular and renal effects of this treatment.

Key Points Question Do the treatment benefits of finerenone extend to patients with heart failure with improved ejection fraction (HFimpEF)? Findings In this prespecified analysis of a randomized clinical trial involving 6001 patients with symptomatic HF, participants with HFimpEF demonstrated similar elevated residual risk of cardiovascular events to those with left ventricular EF (LVEF) consistently 40% or higher. Finerenone, consistently reduced the relative risk in the HFimpEF population. Although hypotension was more common with finerenone in these patients, there was no difference in serious adverse events compared with those with LVEF consistently 40% or higher. Meaning Patients with HFimpEF remain at heightened risk of adverse outcomes, but finerenone safely and effectively mitigated this risk in this high-risk population.

Key Points Question Is finerenone, a nonsteroidal mineralocorticoid receptor antagonist, a safe and effective therapy in patients with heart failure (HF) with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF), regardless of frailty status? Findings In this prespecified secondary analysis of patients with HFmrEF or HFpEF in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF), frailty was common, and greater frailty was associated with more impairment in health status and worse clinical outcomes, including worsening HF events, hospitalizations, and death. Compared with placebo, finerenone reduced the risk of worsening HF events and cardiovascular deaths and improved symptoms in patients with HFmrEF or HFpEF across the range of frailty studied. Meaning The favorable benefit-risk balance associated with frailty for finerenone should challenge any clinical reluctance to introduce this new treatment in patients considered to be frail.

FINEARTS‐HF demonstrated the efficacy of finerenone in reducing total worsening heart failure (HF) events (first and recurrent) and cardiovascular death, compared to placebo, in patients with HF and mildly reduced or preserved ejection fraction. We examined the effect of finerenone on these events according to their clinical importance using win statistics.

Importance Heart failure (HF) with mildly reduced or preserved ejection fraction and atrial fibrillation (AF) are closely intertwined. Objective To examine the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with HF with mildly reduced or preserved ejection fraction according to the absence or presence of AF and the type of AF (paroxysmal vs persistent or permanent). Design, Setting, and Participants Prespecified analyses were conducted in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial. The trial was conducted across 653 sites in 37 countries. Participants were adults aged 40 years and older with symptomatic HF and left ventricular ejection fraction of 40% or greater, randomized between September 2020 and January 2023. Data analysis was conducted from September 1 to October 1, 2024. Intervention Finerenone (titrated to 20 mg or 40 mg) or placebo. Main Outcomes and Measures The primary outcome was the composite of total HF events and cardiovascular death. New-onset AF or atrial flutter (AFL) was a prespecified exploratory outcome. Results Among 5984 patients (mean [SD] age, 72.0 [9.6] years; 2724 [45.5%] female) with known AF status at baseline, 1384 (23.1%) had paroxysmal AF and 1886 (31.5%) had persistent or permanent AF. Patients with both types of AF were older and had worse HF status compared with those without AF (2714 patients [45.4%]). Both types of AF were associated with a higher unadjusted risk of the primary outcome compared with no AF (event rate per 100 person-years of follow-up, 20.3 [95% CI, 17.9-23.1] with paroxysmal AF, 19.8 [95% CI, 17.8-22.0] with persistent or permanent AF, and 11.9 [95% CI, 10.7-13.3] with no AF; rate ratio [RR], 1.62 [95% CI, 1.37-1.92] with paroxysmal AF and 1.66 [95% CI, 1.43-1.93] with persistent or permanent AF vs no AF); however, the associations were attenuated after adjustment for known prognostic variables. The benefit of finerenone on the primary outcome (overall RR, 0.84 [95% CI, 0.74-0.95]) was not modified by baseline AF status (RR, 0.80 [95% CI, 0.65-0.98] with no AF, 0.83 [95% CI, 0.65-1.06] with paroxysmal AF, and 0.85 [95% CI, 0.69-1.05] with persistent or permanent AF; P for interaction = .94). New-onset AF or AFL occurred in 6.5% of patients and was associated with a higher subsequent adjusted risk of the primary outcome (rate ratio, 3.65 [95% CI, 2.57-5.18]; P < .001). The subdistribution hazard ratio for new-onset AF or AFL among those receiving finerenone vs placebo was 0.77 (95% CI, 0.57-1.04; P = .09). Conclusions and Relevance The efficacy of finerenone was consistent regardless of AF status. New-onset AF was associated with a substantially higher risk of subsequent outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT04435626

Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non‐steroidal MRA finerenone. The FINEARTS‐HF trial is designed to evaluate the long‐term efficacy and safety of the selective non‐steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction.

BACKGROUND: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known. METHODS: FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity on the basis of baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during-trial use of SGLT2i in time-varying analyses. RESULTS: Among 6001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6 years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio, 0.83 [95% CI, 0.60–1.16]) and without an SGLT2i at baseline (rate ratio, 0.85 [95% CI, 0.74–0.98]; Pinteraction=0.76). In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% versus 20.1%; hazard ratio, 0.86 [95% CI, 0.76–0.97]). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary end point. CONCLUSIONS: The treatment benefits of the nonsteroidal mineralocorticoid receptor antagonist finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a nonsteroidal mineralocorticoid receptor antagonist may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.

BACKGROUND The NYHA functional classification remains an important and widely used metric in heart failure (HF)-oriented clinical care and research. OBJECTIVES This study aims to evaluate whether the effect of finerenone varies according to NYHA functional class in HF with mildly reduced or preserved ejection fraction. METHODS In this prespecified analysis of the FINEARTS-HF trial, treatment effects of finerenone according to baseline NYHA functional class (II or III/IV) were examined on the primary endpoint (cardiovascular death and total HF events) and key secondary endpoints. Effects of finerenone on change in NYHA functional class were evaluated using ordinal logistic regression. RESULTS At baseline, 4,146 (69%) and 1,854 (31%) participants were NYHA functional class II and III/IV, respectively. Participants with baseline NYHA functional class III/IV vs II experienced a significantly higher rate of cardiovascular death and total HF events (adjusted rate ratio: 1.28 [95% CI: 1.11-1.46]; P < 0.001). Finerenone consistently reduced the primary endpoint irrespective of baseline NYHA functional class (Pinteraction = 0.54), with greater absolute benefits in NYHA functional class III/IV (absolute rate reduction [ARR]: 4.5 per 100 person-years) vs II (ARR: 2.0 per 100 person-years). Benefits of finerenone on Kansas City Cardiomyopathy Questionnaire-Total Symptom Score at 12 months were consistent irrespective of NYHA functional class (Pinteraction = 0.93). NYHA functional class improved similarly in the finerenone and placebo arms out to 12 months. The safety profile of finerenone was similar among participants with baseline NYHA functional class III/IV vs II. CONCLUSIONS In this FINEARTS-HF analysis, finerenone reduced clinical outcomes and improved patient-reported health status in HF with mildly reduced or preserved ejection fraction irrespective of baseline NYHA functional class. (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [FINEARTS-HF]; NCT04435626).

AIMS N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations serve as markers of prognosis and therapeutic response in patients with heart failure (HF). The effect of the non-steroidal mineralocorticoid receptor antagonist finerenone on NT-proBNP in patients with HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) is currently unknown. METHODS AND RESULTS The FINEARTS-HF trial randomized patients with HFmrEF/HFpEF and NT-proBNP ≥300 pg/ml (≥900 pg/ml if atrial fibrillation) or B-type natriuretic peptide ≥100 pg/ml (≥300 pg/ml if atrial fibrillation) to finerenone versus placebo. Core laboratory NT-proBNP was measured at baseline, 3, and 12 months after randomization. We evaluated the association between log-transformed NT-proBNP and the primary outcome (cardiovascular death and total HF events), whether baseline NT-proBNP modified the effect of finerenone on this outcome, and the effect of finerenone on NT-proBNP concentration. Baseline NT-proBNP was available in 5843 of 6001 patients analysed (median 1041 [interquartile range 449-1946] pg/ml) and was strongly associated with risk of the primary outcome (adjusted rate ratio 1.44 per doubling in biomarker concentration, 95% confidence interval [CI] 1.37-1.51], p < 0.001). Baseline NT-proBNP did not modify the benefit of finerenone on the primary outcome (pinteraction = 0.92). Finerenone reduced NT-proBNP by 12.1% (95% CI 8.5-15.4%) at 3 months and 12.5% (95% CI 8.1-16.7%) at 12 months, compared to placebo. CONCLUSIONS In patients with HFmrEF/HFpEF, finerenone reduced NT-proBNP within months of initiation, and improved clinical outcomes regardless of baseline NT-proBNP concentration. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT04435626, EudraCT 2020-000306-29.

Key Points Question Does the nonsteroidal mineralocorticoid receptor antagonist finerenone reduce outpatient worsening heart failure (HF) events requiring oral diuretic intensification among patients with HF with mildly reduced or preserved ejection fraction? Findings In this secondary analysis of a randomized clinical trial that included 6001 participants, outpatient oral diuretic intensification events were common and associated with greater risk of subsequent death compared with stable outpatients. Finerenone reduced outpatient oral diuretic intensifications by 11%. Meaning Finerenone may prevent outpatient worsening HF in patients with mildly reduced or preserved ejection fraction.

Chronic obstructive pulmonary disease (COPD) is associated with worse outcomes in heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). A post hoc analysis of TOPCAT suggested that the effectiveness of the steroidal mineralocorticoid receptor antagonist (MRA), spironolactone, may be modified by pulmonary disease, with a greater benefit in patients with COPD/asthma. We examined the effects of the non‐steroidal MRA, finerenone, compared to placebo, according to COPD status in a prespecified analysis of FINEARTS‐HF.

OBJECTIVE To evaluate the efficacy and safety of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in individuals with type 2 diabetes (T2D) and either chronic kidney disease (CKD) or heart failure (HF) with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF). RESEARCH DESIGN AND METHODS In this prespecified participant-level pooled analysis of all phase III clinical trials evaluating finerenone versus placebo conducted to date (FINE-HEART), the safety and efficacy of finerenone was evaluated among participants with a history of T2D. Treatment effects on the primary outcome of cardiovascular death and other secondary outcomes were evaluated according to baseline glycated hemoglobin (HbA1c) and glucose-lowering therapy (GLT) regimen using stratified Cox proportional hazards models. RESULTS Of 18,991 FINE-HEART participants, 15,365 (80.9%) had T2D and available HbA1c at baseline (mean age, 66 ± 10 years; 32% women; mean HbA1c, 7.6 ± 1.4%). The most common GLT regimens were insulin alone (n = 2,652), insulin and metformin (n = 2,005), metformin alone (n = 1,616), metformin and sulfonylurea (n = 1,039), and "other" (n = 8,117), including sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide 1 receptor agonist (GLP-1RA). Over a median follow-up of 2.9 years, treatment effects of finerenone versus placebo on cardiovascular death were consistent across baseline HbA1c (Pinteraction = 0.75) and GLT regimen (Pinteraction = 0.46). Finerenone consistently reduced the kidney composite outcome, HF hospitalization, major adverse cardiovascular events, and all-cause mortality, irrespective of baseline HbA1c and GLT regimen. Treatment effects of finerenone were also consistent across number of background GLTs and irrespective of concomitant treatment with a SGLT2i or GLP-1RA. CONCLUSIONS Finerenone consistently reduced morbidity and mortality in individuals with T2D across a broad range of glycemia and glucose-lowering regimens.

Importance Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) have a spectrum of risk, and the effect of therapies may vary by risk. Objectives To validate the Prognostic Models for Mortality and Morbidity in HFpEF (PREDICT-HFpEF) in the phase 3 randomized clinical trial Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to evaluate the effect of finerenone, compared with placebo, across the spectrum of risk in these patients. Design, Setting, and Participants The FINEARTS-HF trial was conducted across 653 sites in 37 countries. Participants were adults 40 years and older with symptomatic HF and left ventricular EF of 40% or greater randomized between September 2020 and January 2023. Intervention Finerenone (titrated to 20 mg or 40 mg) or placebo. Main Outcomes and Measures The 3 PREDICT-HFpEF risk scores for the composite outcome of cardiovascular death or HF hospitalization, cardiovascular death, and all-cause death, respectively, were calculated. Predicted risk was compared with observed outcomes. Model performance was assessed using the Harrell C statistic. The rates of the predicted outcomes (plus the composite of cardiovascular death and worsening HF events, which was the primary end point in the trial) were examined according to quintiles of risk score, as was the effect of finerenone according to risk quintiles. Results A total of 6001 patients (mean [SD] age, 72 [9.6] years; 3269 male [54.5%]) were randomized in the FINEARTS-HF trial. The C statistics for cardiovascular death or HF hospitalization, cardiovascular death, and all-cause death at 2 years were 0.71 (95% CI, 0.69-0.72), 0.68 (95% CI, 0.66-0.71), and 0.69 (95% CI, 0.67-0.71), respectively. The risk of the composite outcomes was approximately 8- to 10-fold higher in those in the highest compared with the lowest risk quintile. The relative risk reduction with finerenone compared with placebo was consistent across the spectrum of risk for all outcomes examined (eg, interaction P value for primary outcome = .24). Conclusions and Relevance Results of the FINEARTS-HF randomized clinical trial demonstrate that the PREDICT-HFpEF models performed well in terms of calibration and discrimination. Baseline risk did not modify the benefit of finerenone. Trial Registration ClinicalTrials.gov Identifier: NCT04435626.

BACKGROUND Pooling data from participants with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) from all completed outcomes trials evaluating finerenone to date may enhance understanding of its safety and efficacy in this high-risk and heterogeneous population. OBJECTIVES In this prespecified participant-level pooled analysis of the FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF trials (FINE-HEART), we evaluated the safety and efficacy of finerenone in individuals with HFmrEF/HFpEF. METHODS The treatment effects of finerenone vs placebo on cardiovascular death or heart failure hospitalization were evaluated using Cox proportional hazards regression models stratified by trial. Additional endpoints included cardiovascular death, HF hospitalization, new-onset atrial fibrillation, and all-cause death. RESULTS Among 18,991 pooled trial participants, 7,008 (36.9%) had HFmrEF/HFpEF (mean age, 71 ± 10 years; 44% female). Over a median follow-up of 2.5 years, finerenone reduced cardiovascular death or heart failure hospitalization compared with placebo (HR: 0.87 [95% CI: 0.78-0.96]; P = 0.008). Consistent effects were observed across trials (Pinteraction = 0.24), key subgroups, and baseline estimated glomerular filtration rate (Pinteraction = 0.47), urine albumin-to-creatinine ratio (Pinteraction = 0.62), and glycated hemoglobin (Pinteraction = 0.93). Finerenone additionally appeared to reduce heart failure hospitalization (HR: 0.84 [95% CI: 0.74-0.94]; P = 0.003) and new-onset atrial fibrillation (HR: 0.75 [95% CI: 0.58-0.97]; P = 0.030), but did not statistically significantly decrease cardiovascular death or all-cause death. Hyperkalemia was more common, and hypokalemia was less common, with finerenone vs placebo. Serious adverse events were similar between the treatment arms. CONCLUSIONS This participant-level pooled analysis of 3 large-scale outcomes trials supports the use of finerenone in individuals with HFmrEF/HFpEF across a broad range of cardiovascular-kidney-metabolic risk. (PROSPERO registration: CRD42024570467).

No abstract available

The nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone is indicated in the United States for use in adults with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). Results from the FIDELIO-DKD and FIGARO-DKD Phase 3 clinical trials showed a statistically significant reduction in the risk of CKD progression and cardiovascular events with finerenone versus placebo when added to maximally tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The cardiovascular event risk reduction was primarily driven by the reduction in the risk of hospitalization for heart failure (HF). Recent results from the Phase 3 FINEARTS-HF trial in patients with HF with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF) showed a significantly lower rate of a composite of total worsening HF events and death from cardiovascular causes with finerenone versus placebo. Further Phase 3 trials in additional HF populations are ongoing. The steroidal MRAs spironolactone and eplerenone are included in clinical practice guidelines for the treatment of symptomatic HF, but the highest class (grade 1) recommendations are in HF with reduced ejection fraction only. Based on the available evidence, finerenone presents as a new evidence-based therapy for HFpEF/HFmrEF in addition to its current application in CKD associated with T2D. The aim of our review article is to present the current evidence available on the potential kidney and cardioprotective effects of finerenone to inform healthcare professionals (particularly those who work in cardiology).

Patient-reported health status is an important assessment of patients with heart failure, but current approaches have substantial methodological and analytical limitations. Changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) are commonly presented as a measure of the effect of drugs and devices, most often as the between-group difference in population means or as the odds of showing threshold changes of 5, 10, 15, and 20 points. However, the presentation of mean differences is based on statistical assumptions that are routinely violated in most trials. The presentation of threshold changes is based on the belief that a within-patient change in KCCQ of 5 points represents a significant treatment difference across diverse populations and trial settings, but the minimal clinically meaningful difference varies substantially depending on patient characteristics, comorbidities, and trial duration and design, with most values for minimally clinically important difference for KCCQ ranging from 10 to 20 points. Furthermore, the assessment of between-group differences is highly distorted by the assignment of a large proportion of randomized patients with very good health status as having substantially improved even if they showed no change after treatment. Any responder analysis is highly sensitive to differences in variance between the 2 treatment groups and cannot account for the stability of changes in the KCCQ score. The imposition of number-to-treat presentations onto KCCQ scores further compounds the lack of interpretability of reported changes. It is therefore not surprising that trials have reported substantial discrepancies between the effect of treatment on KCCQ and on the risk of hospitalizations for heart failure. In the FINEARTS (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure) trial, finerenone produced an 18% reduction in the risk of hospitalizations for heart failure but yielded uninterpretable and clinically questionable changes in KCCQ, with the small possibility of a modest benefit in <2% of randomized patients. Most physicians are unaware of the critically important methodological concerns summarized in the current paper, and, therefore, may make clinical decisions that hinge on unwarranted impressions of the effects of an intervention on health status.

BACKGROUND Finerenone is known to reduce the risk of worsening heart failure (HF) events and cardiovascular (CV) death in patients with HF with mildly reduced or preserved ejection fraction. OBJECTIVES The authors explored whether the benefit of finerenone among patients with HF with mildly reduced or preserved ejection fraction differs according to baseline measures of kidney function. METHODS FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a global, randomized clinical trial of finerenone vs placebo among patients with HF with mildly reduced or preserved ejection fraction. Finerenone was titrated to 20 mg/d if the estimated glomerular filtration rate (eGFR) was ≤60 mL/min/1.73 m2 or 40 mg/d if eGFR was >60 mL/min/1.73 m2. The authors used a semiparametric proportional rates method, stratified by left ventricular ejection fraction (<60%; ≥60%) and region, to assess for differential treatment effects on the composite of total HF events and CV death according to the baseline eGFR (continuous and categories [≥60 mL/min/1.73 m2, 45 to <60 mL/min/1.73 m2, <45 mL/min/1.73 m2] and urine albumin-creatinine ratio (UACR) (<30 mg/g, 30 to <300 mg/g, ≥300 mg/g). RESULTS The effect of finerenone to reduce the primary endpoint of total HF events and CV death did not significantly differ according to baseline eGFR (Pinteraction = 0.14 and 0.07 for continuous and categorical eGFR, respectively) with rate ratio 0.72 (95% CI: 0.59-0.88) for eGFR ≥60 mL/min/1.73 m2, 0.83 (95% CI: 0.65-1.06) for eGFR 45 to <60 mL/min/1.73 m2, and 1.02 (95% CI: 0.83-1.26) for eGFR <45 mL/min/1.73 m2. The corresponding absolute event rates were 9.2 vs 12.5, 16.5 vs 19.9, and 28.0 vs 28.0 per 100 patient-years for finerenone vs placebo, respectively. Similar results were noted for total worsening HF events. Finerenone lowered the risk of the composite CV outcome similarly across baseline categories of UACR (Pinteraction = 0.48). CONCLUSIONS In the FINEARTS-HF trial (where the target dose of finerenone was determined by baseline kidney function), the effect of finerenone to reduce the composite of cardiovascular death and total HF events did not significantly differ across a range of baseline eGFR and UACR.

Information about current use of finerenone in patients with heart failure (HF) finerenone in clinical practice is scarce, and its effectiveness in clinical practice in patients is scarce. We aim to assess both the baseline clinical profile and prognostic role of finerenone in patients with HF, irrespective of ejection fraction.

Background Finerenone has been shown to improve outcomes in patients with heart failure (HF), encompassing those with reduced (HFrEF), mildly reduced (HFmrEF), or preserved ejection fraction (HFpEF). However, its clinical use is accompanied by notable adverse effects. This study aimed to evaluate the relative risks of adverse events associated with finerenone across HF phenotypes. Methods A systematic search of PubMed, Embase, and Web of Science identified six randomized controlled trials involving 8,527 HF patients. The analysis considered hyperkalemia, hypotension, treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and treatment discontinuation due to adverse events. Results Finerenone significantly increased the risk of hyperkalemia (RR = 2.07, 95% CI 1.77-2.44, P < 0.00001) and hypotension (RR = 1.49, 95% CI 1.31-1.68, P < 0.00001) compared to placebo, irrespective of HF phenotype. No significant differences were observed between finerenone and placebo in terms of TEAEs, TESAEs, or treatment discontinuation when analyzing the overall heart failure population. Compared to eplerenone, finerenone was associated with a lower risk of TEAEs (RR = 0.93, 95% CI: 0.89-0.98) and TESAEs (RR = 0.74, 95% CI: 0.66-0.84), with similar discontinuation rates. Additionally, one included study suggested that finerenone may have a lower risk of TEAEs (RR = 0.64, 95% CI 0.56-0.74), treatment discontinuation (RR = 0.37, 95% CI 0.25-0.54) and hyperkalemia (RR = 0.41, 95% CI 0.21-0.79) compared to spironolactone, with similar rates of hypotension (RR = 0.61, 95% CI 0.29-1.30) in HFrEF. Conclusion Finerenone (10-25 mg) showed a similar safety profile to placebo, with no significant differences in TEAEs, TESAEs, or treatment discontinuation. Compared to eplerenone, finerenone was associated with fewer TEAEs and TESAEs, with comparable discontinuation rates. Moreover, in patients with HFrEF, finerenone may offer lower risks of TEAEs, treatment discontinuation, and hyperkalemia than spironolactone, with similar rates of hypotension.

BACKGROUND Heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) lacks effective therapies. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, may offer cardiovascular benefits in this population. METHODS We conducted a retrospective, propensity-matched cohort study using the TriNetX network to compare outcomes in HFpEF/HFmrEF patients treated with finerenone versus no MRA. Primary outcomes included all-cause mortality, acute heart failure hospitalization, and major adverse cardiovascular events (MACE). RESULTS Among 304 matched patients (n = 152 per group), finerenone was associated with significantly lower 1-year mortality (6.6 % vs. 19.7 %, HR 0.24, p = 0.001) and heart failure hospitalization (10.5 % vs. 21.7 %, HR 0.47, p = 0.01). MACE was also reduced at 1 year (35.5 % vs. 47.4 %, HR 0.67, p = 0.022). CONCLUSION Finerenone use was linked to improved short-term cardiovascular outcomes in patients with HFpEF and HFmrEF, supporting its potential role in this highrisk population.

BACKGROUND The nonsteroidal mineralocorticoid receptor antagonist finerenone reduces clinical events in heart failure with mildly reduced ejection fraction/preserved ejection fraction; however, the implications of treatment-related hypotension are unknown. OBJECTIVES The authors investigated predictors of systolic blood pressure (SBP) <100 mm Hg and investigator-reported hypotension and their associations with randomized treatment and clinical outcomes in the FINEARTS-HF (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke]) trial. METHODS FINEARTS-HF was a randomized, placebo-controlled trial of finerenone in symptomatic patients with chronic heart failure (left ventricular ejection fraction ≥40%). Predictors of SBP <100 mm Hg and hypotension were identified using Cox models. Associations between SBP <100 mm Hg and hypotension, treatment, and clinical outcomes were evaluated using time-updated Cox models. The primary outcome was a composite of total heart failure events and cardiovascular death. RESULTS Among the 5,815 participants with available data, post-baseline SBP <100 mm Hg occurred in 899 (538 with finerenone vs 361 with placebo; odds ratio: 1.60; 95% CI: 1.38-1.85) and investigator-reported hypotension in 364 patients (225 with finerenone vs 139 with placebo; odds ratio: 1.67; 95% CI: 1.34-2.08). Participants experiencing SBP <100 mm Hg had lower baseline SBP, were older, had higher N-terminal pro-B-type natriuretic peptide levels, a history of smoking, and no diabetes. Treatment-related risk of the primary endpoint was reduced in patients with no/before SBP <100 mm Hg (rate ratio: 0.78; 95% CI: 0.67-0.90) and appeared to attenuate afterwards (rate ratio: 0.99; 95% CI: 0.70-1.39), although no formal statistical interaction was observed (Pinteraction = 0.33). CONCLUSIONS In this prespecified analysis of the FINEARTS-HF trial, finerenone led to higher rates of post-baseline SBP <100 mm Hg and investigator-reported hypotension. Although hypotension should not prompt automatic treatment discontinuation, these patients should be carefully monitored. (Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone in Participants With Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40% [FINEARTS-HF]; NCT04435626.).

Finerenone is a novel nonsteroidal mineralocorticoid receptor (MR) antagonist (MRA) with unique pharmacological properties that offer potent and selective blockade of the MR with a more favorable side effect profile than spironolactone and eplerenone. In a large phase III clinical trial involving 13,026 patients with type 2 diabetes mellitus and a broad spectrum of chronic kidney disease, finerenone provoked a substantial placebo-subtracted reduction in the risk of hospitalization for heart failure (HF). These preliminary clinical trial data, along with the ongoing uncertainty about the safety and efficacy of MR antagonism in patients with HF and higher levels of ejection fraction have provided the rationale for the design of the FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure) trial. In this multicenter, double-blind, randomized, phase III trial involving 6001 patients with HF and mildly reduced or preserved ejection fraction, finerenone was superior to placebo in improving the primary composite outcome of total (first and recurrent) worsening HF events and death from cardiovascular causes. This benefit was similar in magnitude in patients receiving and in patients not receiving background treatment with a sodium-glucose co-transporter type 2 inhibitor, suggesting a potential additive benefit with combination therapy. We explore the emerging role of the nonsteroidal MRA finerenone as a new therapeutic opportunity to improve the risk of adverse cardiovascular outcomes in patients with HF and mildly reduced or preserved ejection fraction. We discuss preliminary clinical trial data and provide a critical evaluation of the main results of the FINEARTS-HF trial.

BACKGROUND Obesity is associated with excessive adipocyte-derived aldosterone secretion, independent of the classical renin-angiotensin-aldosterone cascade, and mineralocorticoid receptor antagonists may be more effective in patients with heart failure (HF) and obesity. OBJECTIVES This study sought to examine the effects of the nonsteroidal mineralocorticoid receptor antagonist finerenone compared with placebo, according to body mass index (BMI) in FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure). METHODS A total of 6,001 patients with HF with NYHA functional class II, III, and IV, a left ventricular ejection fraction of ≥40%, evidence of structural heart disease, and elevated natriuretic peptide levels were randomized to finerenone or placebo. BMI (kg/m2) was examined using World Health Organization categories, namely, underweight/normal weight (<25.0 kg/m2; n = 1,306); overweight (25.0-29.9 kg/m2; n = 1,990); obesity class I (30.0-34.9 kg/m2; n = 1,546); obesity class II (35.0-39.9 kg/m2; n = 751); and obesity class III (≥40 kg/m2; n = 395). The primary outcome was cardiovascular death and total worsening HF events. RESULTS Data on baseline BMI were available for 5,988 patients (median: 29.2 kg/m2; Q1-Q3: 25.5-33.6 kg/m2). Compared with patients who were underweight/normal weight, those with obesity class II or III had a higher risk of the primary outcome (underweight/normal weight, reference; overweight, unadjusted rate ratio: 0.96 [95% CI: 0.81-1.15]; obesity class I: 1.04 [95% CI: 0.86-1.26]; obesity class II-III: 1.26 [95% CI: 1.03-1.54]). The effect of finerenone on the primary outcome did not vary by baseline BMI (underweight/normal weight, rate ratio: 0.80 [95% CI: 0.62-1.04]; overweight: 0.91 [95% CI: 0.72-1.15]; obesity class I: 0.92 [95% CI: 0.72-1.19]; obesity class II-III: 0.67 [95% CI: 0.50-0.89]; Pinteraction = 0.32). However, when BMI was examined as a continuous variable, the beneficial effect of finerenone seemed to be greater in those with a higher BMI (Pinteraction = 0.005). A similar pattern was observed for total worsening HF events. Consistent effects across baseline BMI were observed for cardiovascular and all-cause death and improvement in the Kansas City Cardiomyopathy Questionnaire scores. CONCLUSIONS In patients with HF with mildly reduced/preserved ejection fraction, the beneficial effects of finerenone on clinical events and symptoms were consistent, irrespective of BMI at baseline, possibly with a greater effect on the primary outcome in patients with higher BMI. (FINEARTS-HF [FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure]; NCT04435626).

BACKGROUND Patients with heart failure (HF) and a recent worsening heart failure (WHF) event are known to be at high risk of recurrent hospitalization and death, regardless of ejection fraction. OBJECTIVES This study examined the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in relation to the recency of a WHF event. METHODS FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. In this prespecified analysis, we assessed the risk of cardiovascular (CV) events and response to finerenone vs placebo in relation to the time from WHF to randomization (during or within 7 days, 7 days to 3 months, >3 months, or no prior WHF). The primary outcome was a composite of total (first and recurrent) WHF events and CV death, analyzed using a proportional rates method. RESULTS Of 6,001 patients validly randomized to finerenone or placebo, 1,219 (20.3%) were enrolled during (749 [12.5%]) or within 7 days (470 [7.8%]), 2,028 (33.8%) between 7 days and 3 months, and 937 (15.6%) >3 months from a WHF event; 1,817 (30.3%) had no prior history of WHF. Rates of the primary composite outcome varied inversely with time since WHF, with >2-fold higher risk in those enrolled during or within 7 days of WHF compared with those enrolled >3 months from WHF or without prior WHF (risk ratio [RR]: 2.13; 95% CI: 1.82-2.55). Compared to placebo, finerenone appeared to lower the risk of the primary composite to a greater extent in those enrolled within 7 days of WHF (RR: 0.74; 95% CI: 0.57-0.95) or between 7 days and 3 months of WHF (RR: 0.79; 95% CI: 0.64-0.97) than in those >3 months from WHF or without prior WHF (RR: 0.99; 95% CI: 0.81-1.21); however, no definitive treatment-by-time interaction could be confirmed (P = 0.07). Greater absolute risk reductions with finerenone were accordingly seen in those with recent WHF (Ptrend = 0.011). The risk of adverse events including hyperkalemia and worsening renal function among patients assigned to finerenone was not increased in those with recent WHF. CONCLUSIONS Compared with those without recent WHF, patients with HF and mildly reduced or preserved ejection fraction who have experienced a recent WHF event are at higher risk for recurrent HF events and CV death; a possible signal of enhanced absolute treatment benefit with finerenone in this population requires further confirmation in future studies. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; A study to gather information on the influence of study drug finerenone on the number of deaths and hospitalizations in participants with heart failure EudraCT 2020-000306-29).

BACKGROUND: The effects of treatments for heart failure (HF) may vary among patients according to left ventricular ejection fraction (LVEF). In FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), the nonsteroidal mineralocorticoid receptor antagonist finerenone reduced the risk of cardiovascular death and total worsening HF events in patients with HF with mildly reduced or preserved ejection fraction. We examined the effect of finerenone according to LVEF in FINEARTS-HF. METHODS: FINEARTS-HF was a randomized, placebo-controlled trial examining the efficacy and safety of finerenone in patients with HF and LVEF ≥40%. The treatment effect of finerenone was examined in prespecified analyses according to LVEF categories (<50%, ≥50% to <60%, and ≥60%) and with LVEF as a continuous variable. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. RESULTS: Baseline LVEF data were available for 5993 of the 6001 participants in FINEARTS-HF. Mean and median LVEF were 53±8% and 53% (interquartile range, 46%–58%), respectively. LVEF was <50% in 2172 (36%), between 50% and <60% in 2674 (45%), and ≥60% in 1147 (19%). Patients with higher LVEF were older, were more commonly female, were less likely to have a history of coronary artery disease, and more frequently had a history of hypertension and chronic kidney disease compared with those with a lower LVEF. Finerenone reduced the risk of cardiovascular death and total HF events consistently across LVEF categories (LVEF <50% rate ratio, 0.84 [95% CI, 0.68–1.03]; LVEF ≥50% to <60% rate ratio, 0.80 [0.66–0.97]; and LVEF ≥60% rate ratio, 0.94 [0.70–1.25]; Pinteraction=0.70). There was no modification of the benefit of finerenone across the range of LVEF when analyzed as a continuous variable (Pinteraction=0.28). There was a similar consistent effect of finerenone on reducing the total number of worsening HF events (continuous Pinteraction=0.26). CONCLUSIONS: In patients with HF with mildly reduced or preserved ejection fraction, finerenone reduced the risk of cardiovascular death and worsening HF events, irrespective of LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626. URL: https://eudract.ema.europa.eu; Unique identifier: 2020-000306-29.

The FDA has approved the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) to reduce the risk of cardiovascular death, hospitalization for heart failure (HF), and urgent HF visits in adults with HF with a left ventricular ejection fraction (LVEF) ≥40%. Finerenone was approved in 2021 to reduce the risk of kidney disease progression and cardiovascular events in adults with chronic kidney disease (CKD) associated with type 2 diabetes.

The estimated glucose disposal rate (eGDR) is a simple, non‐invasive measure of insulin resistance. In this exploratory analysis of FINEARTS‐HF, we evaluated whether lower eGDR, reflecting greater insulin resistance, is associated with adverse outcomes in heart failure (HF).

Insulin resistance is a common metabolic risk factor for heart failure (HF) onset and progression. The estimated glucose disposal rate (eGDR) is a simple and noninvasive three-variable measure of insulin sensitivity, where lower eGDR levels reflect greater insulin resistance. However, whether eGDR is associated with adverse outcomes in individuals with HF is uncertain. To explore clinical outcomes and treatment effects of finerenone according to baseline eGDR in the FINEARTS-HF trial. FINEARTS-HF enrolled individuals with chronic, symptomatic HF with mildly reduced or preserved ejection fraction (HFpEF/HFmrEF), with or without diabetes. Using an established algorithm, eGDR was calculated using baseline waist circumference, glycated hemoglobin (HbA1c), and hypertension status (history of hypertension or baseline blood pressure ≥140/90 mm Hg). Clinical outcomes and treatment effects of finerenone according to baseline eGDR were examined categorically (< median or ≥ median) through multivariable-adjusted Cox proportional hazards regression models and continuously through Poisson regression with restricted cubic splines. Among 5,851 (98%) FINEARTS-HF participants with a calculable eGDR, the median eGDR was 5.1 mg/kg/min. Lower eGDR at baseline was associated with female sex, Asian race, worse health status, and kidney dysfunction. Participants with eGDR <5.1 mg/kg/min experienced a 60% higher rate of cardiovascular death and total HF events compared with those with eGDR ≥5.1 mg/kg/min (adjusted hazard ratio [aHR], 1.60; 95% CI, 1.39-1.84; P<0.001). Similar findings were observed in participants with diabetes (aHR, 1.61; 95% CI, 1.31-1.98) and without diabetes (aHR, 1.30; 95% CI, 1.04-1.63; Pinteraction=0.09). When evaluated continuously, lower eGDR was associated with an increased risk for a wide range of cardiovascular, kidney, and mortality outcomes (Figure 1). Lower baseline eGDR was additionally associated with a higher rate of new-onset diabetes (P<0.001) (Figure 2). Treatment benefits of finerenone on cardiovascular death and total HF events (Pinteraction=0.63) and new-onset diabetes (Pinteraction=0.37) were consistent irrespective of baseline eGDR category. The safety profile of finerenone was similar among participants with eGDR < versus ≥5.1 mg/kg/min. In this FINEARTS-HF analysis, greater eGDR-defined insulin resistance among individuals with HFmrEF/HFpEF was associated with a wide range of adverse cardiovascular-kidney-metabolic outcomes, and did not appear to modify benefits of finerenone. These findings suggest eGDR may enhance risk stratification among individuals with HFmrEF/HFpEF, with or without diabetes.Figure 1  Figure 2

Background: The nonsteroidal mineralocorticoid receptor antagonist finerenone has been shown to reduce adverse clinical outcomes in persons with heart failure (HF) and chronic kidney disease (CKD) with type 2 diabetes. However, the relative timing of these benefits has not been evaluated. Research Question: What is the timing of cardiovascular and kidney protection with finerenone? Methods: In this participant-level analysis of randomized, placebo-controlled, phase 3 outcomes trials evaluating finerenone in persons with HF (FINEARTS-HF) and CKD with type 2 diabetes (FIGARO-DKD and FIDELIO-DKD [FIDELITY]), we evaluated the cumulative number and type of clinical outcomes (time-to-first) prevented over time post-randomization. The timing of first statistically significant benefit of finerenone on selected clinical outcomes was additionally assessed. Estimates of events prevented (per 10,000 treated participants) were calculated using the difference in observed events between treatment arms, and were displayed graphically. Results: In both trial populations, benefits with finerenone occurred early and accrued over time ( Figure ). In both FIDELITY and FINEARTS-HF, HF hospitalization appeared to be the earliest type of event prevented. In FIDELITY, time to first nominal statistical significance for HF hospitalization was 6.1 months (HR, 0.65; 95% CI, 0.43 to 0.999), compared with 10.2 months (HR, 0.59; 95% CI, 0.35 to 0.98) for the composite kidney outcome ( Figure ). Similarly, first statistical significance for HF hospitalization in FINEARTS-HF was attained after 0.9 months (HR, 0.55; 95% CI, 0.32 to 0.96). At 12 months, we estimated 67 and 140 HF hospitalizations per 10,000 patients would be prevented with finerenone vs. placebo, based on findings from FIDELITY and FINEARTS-HF, respectively ( Figure ). While kidney benefits in FIDELITY were initially slower to accumulate compared with cardiovascular benefits, the number of kidney events prevented (216 per 10,000 patients) exceeded the number of cardiovascular events prevented (180 per 10,000 patients) by 43 months ( Figure ). Conclusions: These findings underscore the high short-term risks of HF events in persons with cardiovascular, kidney, and/or metabolic conditions, which are modifiable with finerenone. When used in CKD management, finerenone prevents cardiovascular events even prior to modifying longer-term risks of kidney disease progression.

Background: Heart failure (HF) and diabetes frequently co-exist, but whether worsening HF events are associated with dysglycemia and new-onset diabetes remains uncertain. Aims: To explore glycemic trajectories before and after worsening HF events, the association between HF events and new-onset diabetes, and whether treatment benefits of finerenone on new-onset diabetes are mediated by reductions in HF events among persons with HF and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) in the FINEARTS-HF trial. Methods: FINEARTS-HF enrolled individuals with chronic HFmrEF/HFpEF, with or without diabetes. First, temporal trajectories of glycated hemoglobin (HbA 1c ) were evaluated before and after HF events using repeated-measures linear regression and expressed using restricted cubic splines. Second, multivariable-adjusted Cox proportional hazards regression models were used to examine the rate of new-onset diabetes after (vs. before) worsening HF events. Third, whether reductions in HF events mediated the benefit of finerenone on new-onset diabetes was assessed. Results: Among 6,001 FINEARTS-HF participants, 2,412 (40%) had a history of diabetes at baseline, of whom 1,671 (69%) had a diagnosis of diabetes that preceded HF and 741 (31%) had a diagnosis of diabetes either concurrent with or after HF. Overall, participants who experienced a worsening HF event (n=1,034) had higher HbA 1c levels compared with those who did not ( P <0.001), and HbA 1c levels tended to increase slightly prior to HF events ( Figure 1 ). Similar patterns were observed among participants with and without diabetes. The incidence of new-onset diabetes increased sharply after a HF event ( Figure 2 ), with a >2-fold risk of new-onset diabetes after (vs. before) a worsening HF event (adjusted hazard ratio [HR], 2.61; 95% CI, 1.76-3.85). However, most (87%) new-onset diabetes events occurred before HF events or among participants without a HF event. Reductions in worsening HF with finerenone vs. placebo did not meaningfully attenuate the benefit of finerenone on new-onset diabetes (HR [95% CI] before and after adjustment for worsening HF events: 0.76 [0.59-0.97] and 0.77 [0.60-0.98], respectively). Conclusions: Worsening HF events were associated with a substantially increased risk of new-onset diabetes in FINEARTS-HF, suggesting bidirectional interplay between HF and metabolic function. Benefits of finerenone on new-onset diabetes were independent of its benefits on worsening HF events.

Background: Finerenone has been shown to improve overall health status, as measured by the aggregate summary scores of the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ), in patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). A comprehensive understanding of the improvement in individual KCCQ components would allow clinicians and patients to understand the expected changes in daily living with treatment. Methods: This is a prespecified analysis of the FINEARTS-HF trial, a double-blind randomized comparison of finerenone with placebo in patients with symptomatic HF and left ventricular ejection fraction (LVEF) ≥40%. KCCQ was administered at randomization and at 6, 9, and 12 months. Each of the 23 individual KCCQ components was scaled from 0 (worst symptoms) to 100 (best symptoms). Mean score changes from randomization to 12 months for each 23 KCCQ components were examined using multivariable linear regression models, adjusting for each corresponding baseline KCCQ value. Results: Of the 6,001 randomized participants in the FINEARTS-HF trial, KCCQ data were available for 5,987 at randomization, of whom 5,006 (83% of the overall population) completed KCCQ assessment at 12 months (mean age: 72±10 years, women: 45%, NYHA class II: 71%, and mean LVEF: 53±8%). Among the 23 items of KCCQ, the greatest nominal significant improvements with finerenone were observed in the frequency of lower limb edema (difference: 2.5, 95%CI: 0.9-4.1), burden of fatigue (difference: 2.2, 95%CI: 0.9-3.5), frequency of fatigue (difference: 2.1, 95%CI: 0.7-3.6), and burden of lower limb edema (difference: 1.8, 95%CI: 0.6-2.9) (all P<0.01) ( Figure ). Longitudinal analyses integrating data from months 6, 9, and 12 were consistent with the main results. The proportion of patients with worsening score from randomization to 12 months was numerically lower with finerenone versus placebo for most individual KCCQ components. Conclusions: In the FINEARTS-HF trial of patients with HFmrEF/HFpEF, finerenone was associated with improvement in a broad range of individual KCCQ components, with the greatest benefits seen in domains related to symptom frequency, symptom burden, and social limitations.

No abstract available

Finerenone, a highly selective non‐steroidal mineralocorticoid receptor antagonist, was approved for the treatment of patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (diabetic kidney disease, DKD). Finerenone reduced the composite endpoint of heart failure events and cardiovascular death in patients with heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). This study aimed to investigate the safety and cardiac effects of finerenone in patients with DKD with or without HFpEF/HFmrEF in a real‐world setting.

BACKGROUND An initial decline in estimated glomerular filtration rate (eGFR) often leads to reluctance to continue life-saving therapies in patients with heart failure (HF). OBJECTIVES The goal of this study was to describe the association between initial decline in eGFR and subsequent clinical outcomes in patients randomized to placebo or finerenone. METHODS In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), we examined the association between initial decline in eGFR (≥15%) from randomization to 1 month and subsequent outcomes in patients assigned to finerenone or placebo. The primary outcome was the composite of total HF events and cardiovascular death. RESULTS Among 5,587 patients with an eGFR measurement at both baseline and 1 month, 1,018 (18.2%) experienced a ≥15% decline in eGFR. The proportion of patients experiencing a ≥15% decline in eGFR was 23.0% with finerenone and 13.4% with placebo (OR: 1.95; 95% CI: 1.69-2.24; P < 0.001). After adjustment, an eGFR decline was associated with a higher risk of the primary outcome in patients assigned to placebo (adjusted rate ratio: 1.50; 95% CI: 1.20-1.89) but not in those assigned to finerenone (adjusted rate ratio: 1.07; 95% CI: 0.84-1.35; Pinteraction = 0.04). By contrast, the efficacy of finerenone was consistent across the range of change in eGFR from baseline to 1 month (Pinteraction = 0.50 for percent change in eGFR), and safety, including hyperkalemia, was similar regardless of an early eGFR decline. CONCLUSIONS Although an initial decline in eGFR was associated with worse outcomes in patients assigned to placebo, this relationship was not as strong in those treated with finerenone. An early decline in eGFR can be anticipated with finerenone and should not automatically lead to the discontinuation of this disease-modifying therapy (FINEARTS-HF Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [NCT04435626]; A Multicenter, Randomized, Double-Bline, Parallel-Group, Placebo-Controlled Study to Evaluate the efficacy and safety of finerenone on morbidity and mortality in participants With Heart Failure [NYHA II-IV] and left ventricular ejection fraction ≥40% [EudraCT 2020-000306-29]).

Madam, Heart failure (HF) is one of the major cardiovascular diseases, affecting more than 64 million people worldwide.1 HFmrEF and HFpEF are subtypes of HF characterised by LVEFs of 41-49% and >50%, respectively.1 ARBs, ACE inhibitors, aldosterone antagonists and loop diuretics are some of the drug classes that have been used in the management of these disorders, to generally disappointing results.2 Only SGLT2 inhibitors have demonstrated a tangible response.2 Recently, a new drug, finerenone, has shown extremely promising results in pre-clinical and early clinical trials in patients with HFmrEF and HFpEF. Finerenone is a novel, first-in-class non-steroidal mineralocorticoid receptor antagonist (MRA) approved by the FDA to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalisation for heart failure in adults with chronic kidney disease associated with type 2 diabetes.3 Pre-clinical trials in rodents have shown that finerenone improves many of the pathophysiological findings associated with HFpEF: it has marked anti-inflammatory and anti-fibrotic effects on the heart, it reduces cardiac accumulation of macrophages, cardiac hypertrophy, LV end-diastolic pressure, and improves LV systolic function.3 A recently conducted clinical trial demonstrates that 20 or 40 mg of finerenone, given once daily, significantly reduces the incidence of hospitalization, worsening heart failure events and deaths due to cardiovascular causes in patients with HFmrEF or HFpEF.4 Due to the scarcity of effective drugs available for this disorder, these clinical findings are especially important, as finerenone may improve the prognosis and quality of life of patients suffering from HF. According to a study conducted in 2019, the prevalence of HF in Pakistan is very high: 405.12 per 100,000 population.5 It is, therefore, pertinent that finerenone be tested in our native Pakistani population to determine its safety and efficacy and that it is made readily available across the country so that patients of HF may benefit from this innovative drug.

BACKGROUND Patients with heart failure (HF) are limited by symptoms and have impaired quality of life. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient-reported outcome measure that enables evaluation of the effect of HF and the impact of new therapies on health status in patients with HF. OBJECTIVES This prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) assessed the efficacy and safety of finerenone according to baseline KCCQ Total Symptom Score (TSS) and the effect of finerenone on KCCQ-TSS. METHODS FINEARTS-HF tested the efficacy of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone, compared with placebo, in patients with HF with mildly reduced ejection fraction/preserved ejection fraction. The primary endpoint was the composite of cardiovascular death and total worsening HF events. The KCCQ was completed by patients at randomization and at 6, 9, and 12 months after randomization. Change in KCCQ-TSS was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles at baseline. The association between KCCQ tertile and clinical outcomes was evaluated using semiparametric proportional-rates models for total events and Cox models for time-to-first-event data, and the effects of finerenone vs placebo on the primary endpoint were assessed across tertiles of KCCQ-TSS. RESULTS Of the 6,001 participants in FINEARTS-HF, 5,986 (99.8%) had baseline KCCQ-TSS recorded (median score 69.8 of a possible 100; higher score = better health status). Lower (worse) KCCQ-TSS was associated with a higher risk of the primary endpoint. Finerenone, compared with placebo, reduced the risk of the primary endpoint across the range of KCCQ-TSS: tertile 1 (score 0-<57): RR: 0.82 (95% CI: 0.68-1.00); tertile 2 (57-<81): 0.88 (95% CI: 0.70-1.11); tertile 3 (81-100): 0.88 (95% CI: 0.69-1.14) (Pinteraction = 0.89). Compared with placebo, finerenone significantly improved KCCQ-TSS from baseline with a mean difference at 12 months of 1.62 points (95% CI: 0.69-2.56 points) (P < 0.001). Numerically fewer finerenone-treated patients experienced clinically meaningful deterioration, and more had improvements in KCCQ-TSS. CONCLUSIONS Finerenone significantly reduced HF events and improved health status in patients with HF and mildly reduced ejection fraction/preserved ejection fraction across the spectrum of KCCQ-TSS at baseline. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; EudraCT 2020-000306-29).

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BACKGROUND AND AIMS The comparative effects of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) remain uncertain, including potential differences between steroidal MRAs and finerenone. This Bayesian network meta-analysis (NMA) aimed to compare the efficacy and safety of finerenone, eplerenone, and spironolactone versus placebo in HFpEF/HFmrEF. METHODS AND RESULTS We searched Pubmed, Cochrane and Embase for studies focused on MRA treatment in HFpEF and/or HFmrEF. Eight randomized controlled trials enrolling adults with HFpEF or HFmrEF (LVEF ≥40%) were analyzed in a fixed-effects Bayesian NMA. Risk ratios (RRs) with 95% credible intervals (CrIs) were estimated for hospitalization for HF, cardiovascular death, and hyperkalemia. Heterogenicity was accessed using I2. Across a network comprising 10,644 patients, mean age 70.2; 48% women; mean LVEF 54.9%, finerenone reduced hospitalization for HF versus placebo (RR 0.84; 95% CrI 0.75-0.93), whereas spironolactone (RR 0.86; 95% CrI 0.73-1.01) and eplerenone (RR 0.86; 95% CrI 0.59-1.26) showed nonsignificant effects. None of the MRAs achieved a statistically significant reduction in cardiovascular mortality versus placebo: finerenone (RR 0.93; 95% CrI 0.78-1.10), spironolactone (RR 0.93; 95% CrI 0.76-1.14), and eplerenone (RR 1.10; 95% CrI 0.29-5.69). All MRAs increased hyperkalemia versus placebo: finerenone (RR 2.06; 95% CrI 1.77-2.41), spironolactone (RR 2.13; 95% CrI 1.81-2.53), and eplerenone (RR 2.17; 95% CrI 0.75-7.97). CONCLUSION In HFpEF/HFmrEF, finerenone was the only MRA to significantly reduce hospitalization for HF, while no agent significantly reduced cardiovascular mortality and hyperkalemia risk increased across therapies. Overall, finerenone may offer the most favorable efficacy-safety balance among MRAs, pending confirmation in larger dedicated trials.

Abstract A decline in mortality due to heart failure (HF) with reduced ejection fraction (HFrEF) has been attributed to effective guideline-directed medical therapies. But few effective therapies are available for HF with preserved ejection fraction (HFpEF), despite a high burden of HF events, or for HF with mildly reduced ejection fraction (HFmrEF). Novel therapies are needed for these HF subtypes. Clinical trials have demonstrated the efficacy of sodium–glucose cotransporter 2 inhibitors for improving outcomes in HFpEF and HFmrEF. While renin–angiotensin system inhibitors, angiotensin receptor/neprilysin inhibitors, and steroidal mineralocorticoid receptor antagonists for HFpEF or HFmrEF have not demonstrated effects on primary trial outcomes, sub-analyses from large HF trials suggest they may reduce the risk of hospitalization for HF or mortality. Beta blockers may be beneficial for HFmrEF. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduced HF events and cardiovascular deaths in participants with HF and ejection fraction ≥40% in the FINEARTS-HF trial, and is under evaluation for HFpEF and HFmrEF in the REDEFINE-HF and CONFIRMATION-HF trials. As treatment for HFpEF and HFmrEF may be impacted by comorbidities, novel treatments could be tailored to specific phenotypes such as obesity and chronic kidney disease. Trials of glucagon-like peptide-1 receptor agonist (GLP-1 RA), semaglutide, and dual glucose-dependent insulinotropic polypeptide receptor agonist/GLP-1 RA, tirzepatide, for HFpEF with obesity, observed an impact on HF hospitalization events and quality of life. Trials of selective mineralocorticoid modulator, balcinrenone, and aldosterone synthase inhibitor, vicadrostat, will address key evidence gaps and help improve outcomes for patients with HFpEF and HFmrEF.

Heart failure (HF) management is well-defined for reduced ejection fraction (HFrEF) but less so for mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). This meta-analysis evaluates the impact of Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, on cardiovascular and renal outcomes in these patient populations. A systematic search in PubMed and Embase identified randomized controlled trials (RCTs) on Finerenone’s cardiovascular and renal effects. Three RCTs were included—FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF—encompassing 19,027 participants. Primary outcomes included cardiovascular death, HF hospitalization, and renal failure. Secondary outcomes focused on safety and adverse events like acute kidney injury and hyperkalemia. Meta-analyses were performed using hazard ratios (HR), confidence intervals (CI), and Relative Risk (RR). Finerenone was associated with a 20% reduction in HF hospitalization risk (HR 0.80, 95% CI: 0.72–0.90) and a 14% reduction in all-cause mortality (RR 0.86, 95% CI: 0.77–0.97). Finerenone did not significantly reduce cardiovascular death (HR 0.91, 95% CI: 0.82–1.01, p = 0.06). Renal failure rates were similar between Finerenone and placebo (RR 1.05, 95% CI: 0.65–1.68). Hyperkalemia incidence was significantly higher with Finerenone, with a RR of 2.31 (95% CI: 1.98–2.69). This meta-analysis shows that Finerenone significantly reduces HF hospitalizations and all-cause mortality in patients with chronic kidney disease and heart failure. Further studies are needed to clarify its effects on cardiovascular death and renal failure.

Abstract Mineralcorticoid receptor (MR) blockade is a mainstay of treatment for heart failure with reduced ejection fraction (HFrEF); however, the benefit is less well established in heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF). The TOPCAT study failed to demonstrate a reduction in cardiovascular mortality and heart failure (HF) hospitalizations in this population but suggested potential benefits of mineralocorticoid receptor antagonists (MRAs) in specific patients subgroups. The FINEARTS-HF study, which evaluated the non-steroidal MRA finerenone in patients with HFmrEF or HFpEF, demonstrated a significant reduction in the primary composite endpoint of cardiovascular death and events related to worsening of heart failure (WHF), primarily driven by a decrease in total WHF events. Moreover, the FINEARTS-HF study demonstrated consistent efficacy across the entire left ventricular ejection fraction (LVEF) spectrum, regardless of sodium–glucose cotransporter 2 inhibitors use, sex, or age, with an early onset of benefit and a favourable safety and tolerability profile. Finerenone is currently indicated in class I in diabetic patients with chronic kidney disease to reduce the risk of HF; in light of the FINEARTS-HF results, it could become a new pillar of therapy for patients with HFpEF and HFmrEF.

The non-steroidal MRA finerenone reduces clinical events in heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) but the frequency and implications of treatment-related hypotension are not known. FINEARTS-HF was a randomized, placebo-controlled trial of finerenone in symptomatic patients with chronic HF (LVEF ≥ 40%). Two treatment-emergent definitions of hypotension were included: i) systolic blood pressure (SBP) < 100 mmHg measured at any study visit, regardless of symptoms (main analysis); ii) investigator-reported adverse event with no specific SBP threshold. Independent predictors of hypotension were identified using multivariable Cox models. The associations between hypotension, treatment, and subsequent clinical risk were evaluated using time-updated Cox models with adjustment for a propensity score representing the probability to develop post-treatment hypotension. The primary outcome was a composite of total HF events and CV death. Finerenone results in an early and sustained SBP lowering by -3.4 mmHg (-2.6 to 4.2) by 6 months. Over a median follow-up of 32 months of treatment, 899 of the 5815 (15.5%) patients with available data experienced hypotension (SBP<100 mmHg), more frequently with finerenone (18.5% vs 12.4%, p<0.001). The cumulative incidence of post-randomization hypotension gradually accrued over time and relatively fewer participants experienced symptomatic hypotension reported as an adverse event (7.7% with finerenone vs 4.8% with placebo, p<0.001). Participants experiencing hypotension (SBP < 100 mmHg definition) had lower baseline SBP, were older, were more likely to be Asian or Black, had higher levels of NT-proBNP, history cigarette smoking, and without concomitant diabetes (Panel A). Following hypotension, participants experienced an excess mortality risk in the overall population (adj HR 1.38; 95% CI 1.13-1.68; p=0.001; Panel B). Finerenone benefits on the primary endpoint appeared to be consistent irrespective of hypotension occurrence (Pinteraction = 0.33). In this post-hoc analysis of the FINEARTS-HF trial, the occurrence of hypotension was associated with a markedly increased subsequent risk of death. The treatment benefits of finerenone on the primary outcome were consistent irrespective of hypotension occurrence.

Although a higher high-sensitivity cardiac troponin T (hsTnT) level is associated with worse outcomes in patients with heart failure (HF) and reduced ejection fraction, little is known about the relationship between troponin, and serial changes in hsTnT, and subsequent outcomes in patients with HF and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Additionally, the benefits of mineralocorticoid receptor antagonist (MRA) according to hsTnT levels and the effect of MRA on hsTnT levels have not been investigated in previous large-scale HF trials. To assess the prognostic value of hsTnT in HFmrEF/HFpEF, the effect of the non-steroidal MRA finerenone on outcomes according to baseline hsTnT levels, and the effect of finerenone on hsTnT levels. FINEARTS-HF was a randomized, double-blind, multicentre, and event-driven trial in patients with HF and a left ventricular ejection fraction ≥40%, investigating the efficacy and safety of finerenone compared to placebo. Patients were divided into tertiles based on baseline hsTnT levels: <13.3 ng/L, 13.3-<23.9 ng/L, and ≥23.9 ng/L (a 99th percentile upper reference limit of the assay was 14.0 ng/L for women and 22.0 ng/L for men). The primary outcome of total HF events and cardiovascular deaths was compared across these three hsTnT groups. The effects of finerenone compared to placebo on outcomes and hsTnT levels were also examined. Overall, 5,812 patients who had a baseline hsTnT measurement were included in this study, with the following distribution: 1,934 (<13.3 ng/L), 1,940 (13.3-<23.9 ng/L), and 1,938 (≥23.9 ng/L). Patients with higher hsTnT were older, more often male, and had more impaired renal function at baseline. Higher hsTnT was associated with a greater adjusted risk of the primary outcome: the rate ratio (95% confidence interval [CI]) was 1.43 (1.16-1.78) for hsTnT >13.3-<23.9 ng/L, and 2.26 (1.80-2.84) for ≥23.9 ng/L, compared to <13.3 ng/L as the reference. The benefits of finerenone compared to placebo on the primary outcome were consistent across hsTnT categories (Pinteraction=0.75) and levels as a continuous variable (Pinteraction=0.33) (Figure 1). Finerenone did not reduce hsTnT from baseline to 1 year (P=0.66) (Figure 2). Elevated hsTnT, possibly reflecting myocardial injury, was associated with worse cardiovascular outcomes in patients with HFmrEF/HFpEF. Despite its benefits on total HF events and cardiovascular death, finerenone did not reduce hsTnT compared to placebo. Reduction in chronic myocardial injury may not be the primary mechanism by which finerenone reduces cardiovascular events in HFmrEF/HFpEF.Figure 1 and 2

Finerenone improved heart failure (HF) outcomes in patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Clinical decision‐making around initiation of mineralocorticoid receptor antagonists often relies on measures of kidney function and serum potassium (K+) levels. The aim of this study was to evaluate the efficacy and safety of finerenone across categories of serum K+ and estimated glomerular filtration rate (eGFR).

The efficacy and safety of the non‐steroidal mineralocorticoid receptor antagonist, finerenone, have not been examined in patients without diabetes. We examined the efficacy and safety of finerenone, compared with placebo, according to glycaemic status in FINEARTS‐HF.

While patients with severe heart failure (HF) were historically considered to have reduced left ventricular ejection fraction (LVEF), it is increasingly recognized that severe HF occurs across the full spectrum of LVEF. The aim of this study was to assess prevalence, cardiovascular (CV) outcome risk, and treatment response to the non‐steroidal mineralocorticoid receptor antagonist finerenone among patients with severe HF in FINEARTS‐HF.

Albuminuria reduction accounted for a modest proportion of the effect of finerenone in reducing adverse cardiovascular outcomes among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Whether this is similar among patients with heart failure (HF) is not clear. We performed a post hoc mediation analysis of 5,086 participants with available data from the FINEARTS-HF trial, which randomized patients with heart failure with mildly reduced or preserved ejection fraction to finerenone or placebo. Using accelerated failure time models, we explored the proportion of risk reduction mediated by a change in urine albumin/creatinine ratio (UACR; log-transformed and >30% decline) between baseline and 3 months on the subsequent risk of: (1) the composite of cardiovascular death or first HF event; (2) first HF event. A bootstrap approach (with 500 replications) was used to estimate the 95% confidence intervals. At baseline, the median UACR was 17 [6, 59] mg/g. Finerenone lowered UACR by 26% at 3 months, compared with placebo. When analyzed continuously, the reduction in UACR was estimated to mediate 34% (95% CI 16, 132) and 29% (95% CI 14, 82) of the treatment effect on the composite outcome and first HF event, respectively. When analyzed categorically, a reduction in UACR >30% was estimated to mediate 15% (95% CI 5, 68) and 11% (95% CI 3, 39) of the treatment effect on the composite outcome and first HF event, respectively (Fig. 1). Among participants of FINEARTS-HF, despite relatively low levels of baseline albuminuria, early changes in UACR accounted for a modest proportion of the effect of finerenone on reducing cardiovascular outcomes.

Finerenone did not modify the risk of kidney outcomes or eGFR decline among patients with heart failure (HF) in the FINEARTS-HF trial, who were generally at low risk for kidney disease progression. However, whether the effect of finerenone on eGFR slope differs according to baseline urine albumin:creatinine ratio (UACR) is not clear. FINEARTS-HF was a global, randomized clinical trial of finerenone vs. placebo among patients with HF with mildly reduced or preserved ejection fraction (N = 6,001). In this post-hoc analysis, we used mixed models repeated measures approaches to explore treatment effects on changes in eGFR slope from baseline to month 3, (acute slope), month 3 to end of follow-up (chronic slope), and baseline to end of follow-up (total slope) according to categories of baseline UACR (<30, 30–<300, ≥300 mg/g). Among 5,797 participants with available data, the mean baseline eGFR was 62 ± 20mL/min/1.73 m2 and median UACR was 18 [7, 67] mg/g (UACR <30mg/g: 61%; 30–<300mg/g: 30%; and ≥300mg/g: 10%). Finerenone caused a greater initial decline in eGFR (acute slope) than placebo across all categories of UACR (P-interaction = 0.26). Although there was no clear heterogeneity of treatment effects (P-interaction = 0.09), finerenone appeared to lead to a slower decline in chronic eGFR slope than placebo among those with UACR ≥300 mg/g (difference 1.2; 95% CI 0.1, 2.2 mL/min/1.73 m2/year). Among patients with HF and macroalbuminuria (at higher risk of kidney disease progression), finerenone slowed the decline in chronic eGFR slope to a clinically relevant greater extent than placebo.

BACKGROUND Finerenone did not modify the risk of kidney outcomes or estimated glomerular filtration rate (eGFR) decline among patients with heart failure (HF) in the FINEARTS-HF trial, who were generally at low risk for kidney disease progression. However, whether the effect of finerenone on eGFR slope differs according to baseline urine albumin to creatinine ratio (UACR) or eGFR is not clear. METHODS FINEARTS-HF was a global, randomized clinical trial of finerenone vs. placebo among patients with HF with mildly reduced or preserved ejection fraction (N=6,001). In this post-hoc analysis, we used mixed models repeated measures approaches to explore treatment effects on changes in eGFR slope from baseline to month 3, (acute slope), month 3 to end of follow-up (chronic slope), and baseline to end of follow-up (total slope) according to categories of baseline UACR (<30, 30-<300, ≥300 mg/g) and eGFR (<45, 45-<60, ≥60 mL/min/1.73 m2). RESULTS Among 5,797 participants with available data, the mean baseline eGFR was 62±20mL/min/1.73m2 and median UACR was 18 [7, 67] mg/g (UACR<30mg/g: 61%; 30-<300 mg/g: 30%; and ≥300 mg/g: 10%). Finerenone caused a greater initial decline in eGFR (acute slope) than placebo across all categories of baseline UACR and eGFR. Although there was no clear heterogeneity of treatment effects (P-interaction=0.09), finerenone appeared to slow the decline in chronic eGFR slope more than placebo among those with UACR ≥300 mg/g (difference 1.2; 95%CI 0.1, 2.2 mL/min/1.73 m2 per year). The association of finerenone vs. placebo on chronic eGFR slope was consistent across baseline eGFR categories (P-interaction=0.48). CONCLUSIONS Among patients with HF and macroalbuminuria (a subgroup of patients at higher risk of kidney disease progression), finerenone was associated with slower decline in chronic eGFR slope to a clinically relevant greater extent than placebo.

BACKGROUND: Finerenone improves outcomes in patients with heart failure and mildly reduced or preserved ejection fraction. It is important to understand the efficacy and safety of finerenone in these patients according to age. METHODS: The aim of this analysis was to evaluate the interaction between age and the efficacy and safety of finerenone in the FINEARTS-HF trial (Finerenone Trial to Investigate Efficacy and Safety Compared to Placebo in Patients With Heart Failure). A total of 6001 patients aged 40 to 97 years were stratified by quartile (Q1–Q4) of baseline age: Q1, 40 to 66 years (n=1581); Q2, 67 to 73 years (n=1587); Q3, 74 to 79 years (n=1421); and Q4, ≥80 years (n=1412). FINEARTS-HF evaluated the impact of age on the efficacy of finerenone with respect to the primary composite outcome of cardiovascular death and total (first and recurrent) heart failure events, including heart failure hospitalization or urgent heart failure event, along with secondary efficacy and safety outcomes. RESULTS: The incidence of primary outcomes increased with age. Finerenone reduced the risk of the primary outcome consistently across all age categories: rate ratio in Q1, 0.70 (95% CI, 0.53–0.92); Q2, 0.83 (95% CI, 0.64–1.07); Q3, 0.98 (95% CI, 0.76–1.26); and Q4, 0.85 (95% CI, 0.67–1.07); Pinteraction=0.27. Similarly, a consistent effect was observed for the components of the primary outcome. The mean increase in Kansas City Cardiomyopathy Questionnaire-total symptom score from baseline to 12 months was greater with finerenone than placebo, with a consistent effect across all age categories: mean placebo-corrected change in Q1, 2.87 (95% CI, 1.09–4.66); Q2, 1.24 (95% CI, −0.59 to 3.07); Q3, 0.94 (−0.98 to 2.86); and Q4, 1.24 (−0.90 to 3.38); Pinteraction=0.50. Adverse events were similar across all age categories. The odds of experiencing hypotension, elevated creatinine, or hyperkalemia (increased) or hypokalemia (decreased) related to finerenone did not differ by age. CONCLUSIONS: In the FINEARTS-HF trial, finerenone reduced the primary outcome and components of the primary outcome and improved symptoms across a wide age spectrum. In addition, finerenone was safe and well-tolerated, irrespective of age. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04435626 and EudraCT 2020-000306-29.

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Importance Sex is associated with the clinical presentation, outcomes, and response to treatment in patients with heart failure (HF). However, little is known about the safety and efficacy of treatment with finerenone according to sex. Objective To estimate the efficacy and safety of finerenone compared with placebo in both women and men. Design, Setting, and Participants Prespecified analyses were conducted in the phase 3 randomized clinical trial Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF). The trial was conducted across 653 sites in 37 countries. Participants were adults aged 40 years and older with symptomatic HF and left ventricular ejection fraction (LVEF) of 40% or greater randomized between September 2020 and January 2023. Intervention Finerenone (titrated to 20 mg or 40 mg) or placebo. Main Outcomes and Measures The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events (unplanned HF hospitalizations or urgent HF visits). Results A total of 6001 patients were randomized in FINEARTS-HF, of whom 2732 were women (45.5%), with a mean (SD) age of 73.6 (9.1) years. Women had higher rates of any obesity, higher LVEF (54.6 [7.6%] vs 50.9 [7.6] for men), lower mean (SD) estimated glomerular filtration rate than men (59.7 [19.1] vs 64.1 [20.0] for men; P<.001) , worse New York Heart Association functional class, and lower Kansas City Cardiomyopathy Questionnaire-Total Symptom Scores (KCCQ-TSS) (mean [SD] 62.3 [24.0] vs 71.0 [23.1]). The incident rate of the primary outcome was slightly lower in women (15.7; 95% CI, 14.3-17.3) than in men (16.8; 95% CI, 15.4-18.3) per 100 person-years. Compared with placebo, finerenone reduced the risk of the primary end point similarly in women and men: rate ratio 0.78 (95% CI, 0.65-0.95) in women and 0.88 (95% CI, 0.74-1.04) in men (P = .41 for interaction). Consistent effects were observed for the components of the primary outcome and all-cause mortality. The mean increase (improvement) in KCCQ-TSS from baseline to 12 months was greater with finerenone, regardless of sex (P = .73 for interaction). Finerenone had similar tolerability in women and men. Conclusions and Relevance In FINEARTS-HF, finerenone reduced the risk of the primary end point similarly in women and men with heart failure with mildly reduced or preserved ejection fraction. Finerenone had similar tolerability in women and men. Trial Registration ClinicalTrials.gov Identifier: NCT04435626.

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Purpose of review Obesity is an important risk factor for heart failure with preserved ejection fraction (HFpEF). In patients who already have HFpEF, obesity contributes to high symptom burden and increased risk for heart failure (HF) hospitalization. This review examines the latest clinical trials assessing the efficacy of pharmacological interventions in the treatment of obesity-related HFpEF. Recent findings Recent results from randomized clinical trials (RCTs) suggest that incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (e.g., semaglutide) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs (e.g., tirzepatide), can improve quality of life, exercise tolerance, and markers of HF severity while promoting weight loss in patients with obesity and HFpEF. Some evidence also suggests that these therapies may reduce risk for HF hospitalizations. Additionally, exploratory analyses of the nonsteroidal mineralocorticoid receptor antagonist finerenone has been associated with reduced cardiovascular mortality and total worsening HF events across all body mass index (BMI) levels, with greater benefits observed in patients with higher BMIs. Summary Antiobesity medications such as semaglutide and tirzepatide may represent important treatment options for patients with obesity-related HFpEF. Additional evidence suggests that certain other HF medications may have increased efficacy in patients with obesity.

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist approved by the U.S. Food and Drug Administration for treating heart failure (HF) with mildly reduced ejection fraction and HF with preserved ejection fraction reduces morbidity and mortality by mitigating inflammation and fibrosis. The FINEARTS-HF (Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction) trial demonstrated significant benefits, particularly after recent HF events, with ongoing studies evaluating broader applications across the cardio–kidney–metabolic spectrum.

Sodium–glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist (nsMRA) finerenone have each been shown to individually improve heart failure events among patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Moreover, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan has been shown to improve outcomes in patients with HFmrEF/HFpEF with a left ventricular ejection fraction (LVEF) below normal (<60%). However, the expected benefits of the combined use of these agents with long-term administration are not well defined. Here, in this cross-trial analysis of DELIVER, FINEARTS-HF and PARAGON-HF, combined use of SGLT2i and nsMRA therapies was estimated to reduce the risk of cardiovascular death or first worsening heart failure event by 31% in the overall population (hazard ratio 0.69; 95% confidence interval 0.59–0.81), while combined use of SGLT2i, nsMRA and ARNI therapies was estimated to reduce risk by 39% in patients with HFmrEF/HFpEF and an LVEF <60% (hazard ratio 0.61; 95% confidence interval 0.48–0.77). With long-term use, combined SGLT2i and nsMRA therapies in a 65-year-old patient with HFmrEF/HFpEF, or combined SGLT2i, nsMRA and ARNI therapies in a 65-year-old patient with an LVEF <60%, were projected to afford 3.6 (2.0–5.2) or 4.9 (2.5–7.3) additional years free from cardiovascular death or a heart failure event, respectively. Combined therapy was estimated to result in meaningful gains in event-free survival across a broad age range, from 55 to 85 years. Among patients with HFmrEF and HFpEF, the potential aggregated long-term treatment effects of early combination medical therapy with SGLT2i and nsMRA (and ARNI in selected individuals) are projected to be substantial. In a cross-trial analysis, combined treatment with medications that have individually shown to improve cardiovascular outcomes in heart failure with mildly reduced or preserved ejection fraction demonstrates substantial benefit, including for event-free survival.

Importance Treatment with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improved outcomes in patients with heart failure with mildly reduced or preserved ejection fraction in FINEARTS-HF, but was associated with increased levels of serum potassium in follow-up. Objective To investigate the frequency and predictors of serum potassium level greater than 5.5 mmol/L and less than 3.5 mmol/L and examine the treatment effect associated with finerenone, relative to placebo, on clinical outcomes based on postrandomization potassium levels. Design, Setting, and Participants Secondary analysis of the FINEARTS-HF multicenter, randomized clinical trial, performed between September 14, 2020, and January 10, 2023, with a median follow-up of 32 months (final date of follow-up: June 14, 2024). Patients with heart failure and left ventricular ejection fraction greater than or equal to 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides were included. Intervention Participants received finerenone or placebo. Main Outcomes and Measures The primary outcome was a composite of total worsening heart failure events or cardiovascular death. Results A total of 6001 participants were included (3003 randomized to receive finerenone and 2998 randomized to receive placebo). The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up. Finerenone increased the risks of potassium level increasing to greater than 5.5 mmol/L (hazard ratio [HR], 2.16 [95% CI, 1.83-2.56]; P < .001) and decreased the risks for potassium level decreasing to less than 3.5 mmol/L (HR, 0.46 [95% CI, 0.38-0.56]; P < .001). Both low (< 3.5 mmol/L; HR, 2.49 [95% CI, 1.8-3.43]) and high (>5.5 mmol/L; HR, 1.64 [95% CI, 1.04-2.58]) potassium levels were associated with higher subsequent risks of the primary outcome in both treatment groups. Nevertheless, the risk of the primary outcome was generally lower in patients treated with finerenone compared with placebo, even in those whose potassium level increased to greater than 5.5 mmol/L. Conclusions and Relevance In patients with heart failure with mildly reduced or preserved ejection fraction, finerenone resulted in more frequent hyperkalemia and less frequent hypokalemia. However, with protocol-directed surveillance and dose adjustment, clinical benefit associated with finerenone relative to placebo was maintained even in those whose potassium level increased to greater than 5.5 mmol/L. Trial Registration ClinicalTrials.gov Identifier: NCT04435626.

This prespecified analysis of the Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial investigates the long-term effects of treatment with the nonsteroidal mineralocorticoid receptor antagonist, finerenone, in patients with heart failure with mildly reduced or preserved ejection fraction.

BACKGROUND The prevalence and prognostic significance of liver biomarkers in heart failure (HF) with mildly reduced or preserved ejection fraction are uncertain, with both potential hemodynamic and metabolic contributions to liver dysfunction in these patients. We evaluated the prevalence and prognostic value of liver biomarkers and assessed the effects of the nonsteroidal mineralocorticoid receptor antagonist finerenone on these biomarkers and clinical outcomes, in FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure). METHODS FINEARTS-HF was a randomized, double-blind, placebo-controlled trial that enrolled 6001 patients with left ventricular ejection fraction ≥40%, evidence of structural heart disease, and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Liver biomarkers examined were total bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. RESULTS Among 5873 patients with available baseline bilirubin measurements, 11.9% had elevated levels (>1.0 mg/dL). Higher bilirubin levels were associated with a greater risk of total worsening HF events and cardiovascular death. Compared with placebo, finerenone rapidly reduced bilirubin and alkaline phosphatase levels (but not transaminase levels), with effects sustained over time. Finerenone reduced the risk of total worsening HF events and cardiovascular death across all bilirubin tertiles (T1 [<0.4 mg/dL], rate ratio 0.94 [95% CI, 0.75-1.17]; T2 [0.5-0.6 mg/dL], 0.83 [0.66-1.05]; T3 [≥0.7 mg/dL], 0.77 [0.62-0.97]), with no significant interaction by bilirubin level (Pinteraction=0.43). Consistent effects were observed for the components of the primary outcome, all-cause death, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score. CONCLUSIONS Baseline bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of finerenone on morbidity and mortality in HF with mildly reduced or preserved ejection fraction. Finerenone reduced bilirubin and alkaline phosphatase, suggesting a possible decongestive effect in HF with mildly reduced or preserved ejection fraction. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.

Supplemental Digital Content is available in the text. Background: Chronic kidney disease and type 2 diabetes are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials, finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type 2 diabetes. These prespecified analyses from FIGARO-DKD assessed the effect of finerenone on clinically important HF outcomes. Methods: Patients with type 2 diabetes and albuminuric chronic kidney disease (urine albumin-to-creatinine ratio ≥30 to <300 mg/g and estimated glomerular filtration rate ≥25 to ≤90 mL per min per 1.73 m2, or urine albumin-to-creatinine ratio ≥300 to ≤5000 mg/g and estimated glomerular filtration rate ≥60 mL per min per 1.73 m2), without symptomatic HF with reduced ejection fraction, were randomized to finerenone or placebo. Time-to-first-event outcomes included new-onset HF (first hospitalization for HF [HHF] in patients without a history of HF at baseline); cardiovascular death or first HHF; HF-related death or first HHF; first HHF; cardiovascular death or total (first or recurrent) HHF; HF-related death or total HHF; and total HHF. Outcomes were evaluated in the overall population and in prespecified subgroups categorized by baseline HF history (as reported by the investigators). Results: Overall, 7352 patients were included in these analyses; 571 (7.8%) had a history of HF at baseline. New-onset HF was significantly reduced with finerenone versus placebo (1.9% versus 2.8%; hazard ratio [HR], 0.68 [95% CI, 0.50–0.93]; P=0.0162). In the overall population, the incidences of all HF outcomes analyzed were significantly lower with finerenone than placebo, including an 18% lower risk of cardiovascular death or first HHF (HR, 0.82 [95% CI, 0.70–0.95]; P=0.011), a 29% lower risk of first HHF (HR, 0.71 [95% CI, 0.56–0.90]; P=0.0043) and a 30% lower rate of total HHF (rate ratio, 0.70 [95% CI, 0.52–0.94]). The effects of finerenone on improving HF outcomes were not modified by a history of HF. The incidence of treatment-emergent adverse events was balanced between treatment groups. Conclusions: The results from these FIGARO-DKD analyses demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02545049.

BACKGROUND In patients with type 2 diabetes (T2D), risks of cardiovascular mortality and heart failure (HF) increase with decreasing kidney function (estimated glomerular filtration rate [eGFR]) and increasing albuminuria (urine albumin-to-creatinine ratio [UACR]). Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and T2D in FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis). OBJECTIVES This study sought to evaluate the effects of finerenone on HF outcomes by eGFR and/or UACR categories. METHODS FIDELITY included 13,026 patients with T2D and CKD (UACR 30-5,000 mg/g and eGFR ≥25 mL/min/1.73 m2) randomized to finerenone or placebo. Time-to-event outcomes were first hospitalization for heart failure (HHF), cardiovascular death or first HHF, recurrent HHF, and cardiovascular death or recurrent HHF, analyzed in subgroups by baseline eGFR (<60 and ≥60 mL/min/1.73 m2) and/or UACR (<300 and ≥300 mg/g). RESULTS Compared with placebo, finerenone significantly reduced risk of first HHF (HR: 0.78 [95% CI: 0.66-0.92]; P = 0.003), cardiovascular death or first HHF (HR: 0.83 [95% CI: 0.74-0.93]; P = 0.002), recurrent HHF (HR: 0.79 [95% CI: 0.64-0.96]; P = 0.021), and cardiovascular death or recurrent HHF (HR: 0.82 [95% CI: 0.72-0.95]; P = 0.006). The risk of outcomes increased across baseline eGFR and UACR categories; lowest incidences were seen in patients with an eGFR ≥60 mL/min/1.73 m2 and a UACR <300 mg/g. Finerenone improved HF outcomes irrespective of baseline eGFR and/or UACR categories (all P interaction values >0.10). CONCLUSIONS Compared with placebo, finerenone improved HF-related outcomes in patients with CKD and T2D, with consistent benefits across eGFR and/or UACR categories. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Chronic Kidney Disease [FIGARO-DKD], NCT02545049).

BACKGROUND Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. METHODSANDRESULTS ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups. CONCLUSIONS Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

ABSTRACT Introduction To evaluate the cardiorenal protective effects of finerenone in patients with diabetes and heart failure through a meta-analysis of randomized controlled trials (RCTs). Methods This meta-analysis included 12 RCTs (total n = 65,226) assessing finerenone versus placebo. Primary outcomes included cardiovascular composite endpoints (major adverse cardiovascular events [MACE]) and kidney composite outcomes (sustained eGFR decline, end-stage kidney disease, or renal mortality). Secondary outcomes encompassed total worsening heart failure events and cardiovascular mortality. Random-effects models were applied to pool hazard ratios (HRs) with 95% confidence intervals (CIs). Heterogeneity was quantified using Cochran’s Q and I² statistics. Sensitivity analyses and publication bias assessments (Egger’s/Begg’s tests, funnel plots) were performed. Results Finerenone significantly reduced major adverse cardiovascular events (9 RCTs, n = 21,542; hazard ratio [HR] 0.858, 95% CI: 0.786–0.937; p = 0.001) and kidney composite outcomes (n = 23,109; HR 0.827, 95% CI: 0.760–0.901; p < 0.001), despite substantial heterogeneity (I² = 78.2% and 64.4%, respectively). Sensitivity analyses confirmed robustness, with consistent effects after sequential trial exclusion. Finerenone also reduced worsening heart failure events (n = 12,874; HR 0.790, 95% CI: 0.700–0.891; p < 0.001; I² = 4.7%), though cardiovascular mortality reduction was nonsignificant (HR 0.914, 95% CI: 0.831–1.005; p = 0.063). No publication bias was detected for primary outcomes. Conclusion Finerenone demonstrates consistent cardiorenal protection in patients with diabetes and heart failure, significantly reducing cardiovascular and kidney complications.

The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone was shown in 2 trials (FIDELIO-DKD and FIAGARO-DKD) to significantly decrease cardiovascular (CV) events and slow progression of kidney function in patients with type 2 diabetes and chronic kidney diseases (CKD). The only medications recommended as first line therapy for patients with heart failure and mildly reduced ejection fraction and preserved ejection fraction (HFmrEF/HFpEF) are the sodium-glucose co-transporters type 2 inhibitors (SGLT-2i). Recently, finerenone was evaluated in patients with HFmr/HFpEF in a trial called the FINEARTS-HF. The latter was a randomized, double-blind, placebo-controlled international trial with the primary composite outcome consisting of first and recurrent (i.e. total) worsening heart failure (HF) events and death from CV causes. Patients included were 40 years or older with left ventricular ejection fraction (LVEF) ≥40%, New York Heart Association (NYHA) functional status, mostly II and III, elevated natriuretic peptides, and evidence of structural heart disease. After a median follow-up of 32 months, 14.9 and 17.7 primary outcome events per 100 patient-year occurred in the finerenone and placebo group, respectively, rate ratio (RR) 0.84 (95% CI, 0.74 to 0.95; P 0.007). The significant reduction in the primary outcome was mainly driven by the reduction in total worsening HF events (RR 0.82; 95% CI 0.71 to 0.94), whereas reduction in CV death did not reach statistical significance RR 0.93 (95% CI, 0.78 to 1.11). Results of secondary outcomes of the FINEART-HF trial showed a trend towards reduction in all-cause death [hazard ratio (HR) 0.93, 95% CI, 0.83 to 1.06)] and worsening of kidney composite outcome HR 1.33 (95% CI, 0.94 to 1.89). There was no heterogeneity in results in different patient subgroups classified by diabetes status, baseline EF, and use of sodium-glucose co-transporters type 2 inhibitors (SGLT-2is). The most common adverse effects of finerenone were hyperkalemia (serum potassium > 5.5 mmol/L) occurring in 14.3% and 6.9% of patients in the finerenone and placebo, groups, respectively. In summary, finerenone is a useful agent for treatment of HFmr/HFpEF that can be added to SGLT2i. Its main limitations are hyperkalemia and possibly worsening kidney function in patients with (HFmr/HFpEF). Long-term studies are required to evaluate the safety of finerenone in patients with (HFmr/HFpEF).

To describe the baseline characteristics of participants in the FINEARTS‐HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS‐HF trial is comparing the effects of the non‐steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF.

Background Mineralocorticoid receptor antagonists (MRAs) reduce mortality and hospitalization in patients with heart failure (HF). Finerenone, a selective nonsteroidal MRA, has recently demonstrated clinical benefits in patients with HF. However, real‐world evidence comparing nonsteroidal and steroidal MRAs in HF is lacking. Methods We conducted a retrospective, propensity score–matched cohort study using the TriNetX database. Adult patients diagnosed with HF from January 2021 to February 2025 who initiated nonsteroidal or a steroidal MRA were included. The primary outcome was a composite of all‐cause mortality, all‐cause hospitalization, and worsening HF at 1 year. Secondary outcomes included each component individually and safety events. Subgroup and sensitivity analyses were performed, including Kaplan–Meier survival, E‐value estimation, and landmark analysis. Results After matching, 1619 patients were included in each group. The incidence of the primary composite outcome was significantly lower in the nonsteroidal MRAs group (hazard ratio [HR], 0.79 [95% CI, 0.70–0.90]; P<0.001). Nonsteroidal MRAs were also associated with lower risks of all‐cause mortality (HR, 0.49), hospitalization (HR, 0.80), and worsening HF (HR, 0.76). Subgroup analyses showed consistent benefit. No significant differences in safety outcomes were observed. Conclusions In this large real‐world cohort, nonsteroidal MRAs use was associated with improved 1‐year clinical outcomes compared with steroidal MRAs in patients with HF. These findings support the potential clinical utility of nonsteroidal MRAs across HF phenotypes and highlight the need for further randomized studies to validate these results.

This study aimed to validate the health economic model for finerenone in the treatment of patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40% in the United Kingdom. A Markov model informed by the pivotal FINEARTS-HF trial compared finerenone + standard of care (SoC) to SoC alone. Cross-validation was performed on the results (life years [LYs] and quality adjusted life years [QALYs]) for the SoC arm against three models in HF with LVEF >40%. External validation compared cardiovascular (CV) mortality and the number of total HF events (hospitalisation for heart failure [HFF] and urgent heart failure visit [UHFV]) against FINEARTS-HF. The model estimated similar discounted outcomes to other models in HF (6.47 vs. 6.63–7.91 LYs and 4.78 vs. 4.63–5.27 QALYs). CV deaths (22 vs. 27) and UHFV events (60 vs. 61) avoided with finerenone were similar between the model and FINEARTS-HF. The broad estimated range of avoided HHF events (205–303 vs. 219 in FINEARTS-HF) was largely driven by baseline patient age. This comprehensive validation exercise demonstrated that the finerenone model accurately estimated observed clinical data and was well aligned in its projections with previous models assessing similar populations.

Canada’s Drug Agency (CDA-AMC) recommends that Kerendia be reimbursed by public drug plans as an add-on “to standard of care in adults with heart failure with left ventricular ejection fraction (LVEF) ≥ 40% to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits,” if certain conditions are met. Evidence from 1 clinical trial showed that adding Kerendia to standard of care (SOC) therapy, improved outcomes, including reduced cardiovascular (CV) deaths, total heart failure (HF) events, and hospitalizations for HF and/or urgent visits, compared to placebo plus SOC therapy in adult patients with HF with LVEF of 40% or more. The Canadian Drug Expert Committee (CDEC) determined that adding Kerendia to SOC therapy provides acceptable clinical value compared with SOC therapy alone for these patients and addresses the needs identified by both patients and clinicians, such as reducing mortality and lowering the risk of initial and recurrent hospitalizations. This determination was enough for CDEC to recommend that Kerendia be reimbursed. Given that Kerendia is expected to be used in addition to SOC therapy, acceptable clinical value refers to added value of Kerendia in combination with SOC therapy versus SOC therapy alone. Kerendia should only be covered when initiated as an add-on to SOC therapy in adults with HF (New York Heart Association [NYHA] class II to IV) with mildly reduced or preserved ejection fraction (LVEF ≥ 40%). Treatment should not be initiated in patients with serum or plasma potassium levels of greater than 5.0 mmol/L (i.e., severe hyperkalemia) or with an estimated glomerular filtration rate (eGFR) of less than 25 mL/min/1.73 m2. Kerendia should only be reimbursed when prescribed by a clinician who has expertise in managing HF and the cost of Kerendia is reduced. Treatment should be discontinued if the patient develops renal failure or hyperkalemia that cannot be adequately managed. Important budget impact considerations must be addressed for health systems to be able to adopt Kerendia.

Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved EF (HFpEF) show substantial heterogeneity in prognosis. To evaluate the performance of biomarker-driven prognostic models derived from the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) Trial in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to examine whether baseline risk modified the therapeutic effect of finerenone. This is a prespecified secondary analysis of the FINEARTS-HF trial, which was conducted across 653 sites in 37 countries among adults aged 40 years and older with symptomatic HF and left ventricular EF (LVEF) of 40% or greater. Patients were randomized between September 2020 and January 2023, and data analysis for this study was conducted from September to October 2025. The median (IQR) follow-up period was 32 (23-37) months. Finerenone (titrated to 20 mg or 40 mg) or placebo. EMPEROR-Preserved risk scores for the outcomes of first HF hospitalization or cardiovascular death, cardiovascular death, and all-cause death were calculated in FINEARTS-HF using models incorporating N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, New York Heart Association functional class, history of chronic obstructive pulmonary disease and diabetes, insulin use, and—depending on outcome—age, hemoglobin and albumin levels, HF duration, time from prior HF hospitalization, and sodium-glucose transporter 2 inhibitor use. Estimated risks were compared with observed event rates, and model performance was assessed using Harrell C statistic. Treatment effects were evaluated across risk quintiles (Q1 to Q5) and across the continuous risk distribution. Among 6001 patients (mean [SD] age, 72.0 [9.6] years; 2732 [45.5%] women; 3003 randomized to finerenone and 2998 randomized to placebo), the EMPEROR-Preserved risk model estimated risk of outcomes, with Q5 vs Q1 hazard ratios (HRs) of 10.49 (95% CI, 8.14-13.52) for the composite of HF hospitalization or cardiovascular death and 13.47 (95% CI, 8.79-20.64) for cardiovascular death. The model demonstrated good discrimination. The treatment effect of finerenone was consistent across risk quintiles for first HF hospitalization or cardiovascular death (Q1: HR, 0.93 [95% CI, 0.58-1.49]; Q2: HR, 1.04 [95% CI, 0.76-1.43]; Q3: HR, 0.82 [95% CI, 0.62-1.07]; Q4: HR, 0.81 [95% CI, 0.65-1.01]; and Q5: HR, 0.88 [95% CI, 0.74-1.05]; P for interaction = .68) and remained uniform across the continuous risk spectrum. The EMPEROR-Preserved risk models demonstrated good performance in FINEARTS-HF. Baseline risk did not modify the relative treatment effect of finerenone. ClinicalTrials.gov Identifier: NCT04435626

Heart failure with nonreduced ejection fraction (HFnrEF), defined as signs and symptoms of heart failure (HF) with a left ventricular ejection fraction (LVEF) of > 40%, continues to increase in prevalence with significant effects to patients, their care givers, and the health care system broadly. Historically, this population has been divided into HF with mildly reduced (HFmrEF) or HF with preserved ejection fraction (HFpEF). However, contemporary evidence indicates that patients across the spectrum of LVEF > 40% experience similar clinical outcomes and, importantly, respond consistently to several key pharmacotherapies. Adoption of the term HFnrEF provides a practical and unified framework for clinical decision-making, reducing ambiguity and promoting consistent application of evidence-based therapies. To support clinicians in translating evidence into practice, the Canadian Cardiovascular Society (CCS) and the Canadian Heart Failure Society (CHFS) present this guideline, which is focused on pharmacological management of symptomatic heart failure with nonreduced ejection fraction (HFnrEF). Underpinned by Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology and meta-analyses, outcomes of interest include pharmacotherapies shown to reduce the risk of HF hospitalization (HFH) and improve patient well-being in this population. The guideline offers concise recommendations for 4 key classes of pharmacological therapies: sodium-glucose cotransporter-2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), and evidence-based drugs with glucagon-like peptide-1 (GLP-1) receptor agonist activity. Recommendations are complemented by practical tips to guide the initiation, titration, and maintenance of these foundational treatments. By emphasizing therapeutic consistency across the > 40% LVEF spectrum, this guideline aims to streamline care pathways and enhance the delivery of guideline-directed medical therapy for patients with symptomatic HFnrEF in real-world settings.

Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in patients with chronic kidney disease associated with type 2 diabetes. It is rapidly and completely absorbed and undergoes first-pass metabolism in the gut wall and liver resulting in a bioavailability of 43.5%. Finerenone can be taken with or without food. The pharmacokinetics of finerenone are linear and its half-life is 2 to 3 h in the dose range of up to 20 mg. Cytochrome P450 (CYP) 3A4 (90%) and CYP2C8 (10%) are involved in the extensive biotransformation of finerenone to pharmacologically inactive metabolites, which are excreted via both renal (80%) and biliary (20%) routes. Moderate or severe renal impairment, or moderate hepatic impairment result in area-under-the-curve increases of finerenone (< 40%), which do not require a dose adjustment per se, as the starting dose is based on estimated glomerular filtration rate (eGFR) and titrated according to serum potassium levels and eGFR decline. No relevant effects of age, sex, body size or ethnicity on systemic finerenone exposure were identified. Modulators of CYP3A4 activity were found to affect finerenone exposure, consistent with its classification as a sensitive CYP3A4 substrate. Serum potassium should be monitored during drug initiation or dosage adjustment of either a moderate or weak CYP3A4 inhibitor or finerenone, and the dose of finerenone should be adjusted as appropriate. Its use with strong inhibitors is contraindicated and strong or moderate inducers of CYP3A4 should be avoided. Finerenone has no potential to affect relevant CYP enzymes and drug transporters. Finerenone is a drug that is used to treat patients with chronic kidney disease and type 2 diabetes. Many of these patients take several medicines to treat other conditions. This review summarizes several studies showing the suitability of finerenone for these patients. Taken as a daily tablet, the dose circulates in the body before being quickly removed. The age, sex, body weight, and ethnicity of a patient do not affect dosing. As finerenone can cause an increase of serum potassium levels, potassium levels and kidney function should be measured before a patient starts treatment. The starting dose will depend on a patient’s kidney function, with the dose changed according to potassium levels and changes in kidney function. A protein called cytochrome P450 3A4 (CYP3A4) is key to removing finerenone from the body. Anyone taking medicines that strongly inhibit CYP3A4 should not take finerenone. Serum potassium levels should be measured before starting finerenone or changing the dose of either finerenone or ‘moderate’ or ‘weak’ CYP3A4 inhibitors, with the dose of finerenone adjusted as appropriate. Finerenone should not be taken alongside drugs that result in ‘moderate’ or ‘strong’ increases in CYP3A4 activity. In patients with moderate hepatic impairment, potassium should be monitored and finerenone doses be adjusted as appropriate. Finerenone is not expected to affect other drugs. Finerenone slows decline in kidney function, a treatment effect associated with reducing urine albumin. Potassium level-guided starting dose and dose changes support finerenone being effectively used and well tolerated in patients.

Finerenone is a novel non-steroidal mineralocorticoid receptor antagonist (MRA) that has been shown to improve renal outcomes in patients with diabetic kidney disease (DKD), as demonstrated in FIGARO and FIDELIO-DKD trials. Our purpose is to describe finerenone used, compare with FIDELITY pooled patients (FIGARO + FIDELIO-DKD), and analyze the impact of finerenone in a short follow-up. A descriptive, observational, prospective study including patients with DKD who initiated finerenone between May 2024 and January 2025. Demographic data, clinical characteristics, laboratory parameters, echocardiographic findings, and treatment history were analyzed. A subanalysis was conducted to evaluate the impact of finerenone in patients with at least four months of follow-up. A total of 66 patients were included. The mean age was 68.2 ± 9.2 years, and 22.7% were female. In Table 1A, the data from our registry vs FIDELITY is shown. Our registry included older patients with a higher percentage of heart failure (HF) (42.4%). Among HF patients, 16.7% had reduced left ventricular ejection fraction (LVEF < 40%), 7.6% had mid-range ejection fraction (LVEF 41%–49%), and 18.2% had preserved ejection fraction (LVEF ≥ 50%). Two patients in our cohort were kidney transplant recipients. Regarding baseline analytical data we observed a lower estimated glomerular filtration rate (eGFR) (57.5 vs. 47.5 ml/min/1.73 m², P < 0.001) and higher serum potassium levels (4.35 vs. 4.54 mEq/L, P < 0.001), without difference in albumin-to-creatinine ratio (UACR). The median 24-hour proteinuria was 1.28 g/24 h. Most patients (87.9%) initiated finerenone at a dose of 10 mg, while 12.1% started at 20 mg. Regarding baseline treatment, our registry showed a higher use of GLP-1 receptor agonists, SGLT2 inhibitors, and potassium binders compared to FIDELITY, with no differences in RAAS inhibitor use. Thirty-one patients (46.9%) had at least four months of follow-up. Finerenone could be titrate in seven patients (22.6%). A significant reduction in UACR was observed, especially in patients without MRA before finerenone started. No significant worsening renal function was detected (38 vs. 36.5 ml/min/1.73 m², P = 0.103). Twelve patients (36.4%) had mild hyperkalemia, with no significant clinical impact. No patients discontinued the drug, and no adverse effects were reported. During follow-up, one patient was HF admission, and one died from a non-cardiovascular cause. Due to high prevalence of DKD, understanding the real-world impact of finerenone is essential. Despite the small sample size, our registry includes older patients with lower eGFR and similar levels of UACR. We observed a significant decrease in albuminuria in patients without previous MRA, but higher incidence of hyperkalemia. Longer follow-up and larger patient recruitment are needed to further assess the efficacy and safety of finerenone in real-world.

Introduction FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) investigated the nonsteroidal, selective mineralocorticoid receptor (MR) antagonist finerenone in patients with CKD and type 2 diabetes (T2D). This analysis explores the impact of use of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) on the treatment effect of finerenone. Methods Patients (N = 5674) with T2D, urine albumin-to-creatinine ratio (UACR) of 30 to 5000 mg/g and estimated glomerular filtration rate (eGFR) of 25 to <75 ml/min per 1.73 m2 receiving optimized renin-angiotensin system (RAS) blockade were randomized to finerenone or placebo. Endpoints were change in UACR and a composite kidney outcome (time to kidney failure, sustained decrease in eGFR ≥40% from baseline, or renal death) and key secondary cardiovascular outcomes (time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) (ClinicalTrials.gov, NCT02540993). Results Of 5674 patients, 259 (4.6%) received an SGLT-2i at baseline. Reduction in UACR with finerenone was found with or without use of SGLT-2i at baseline, with ratio of least-squares means of 0.69 (95% CI = 0.66–0.71) and 0.75 (95% CI -= 0.62–0.90), respectively (Pinteraction = 0.31). Finerenone also significantly reduced the kidney and key secondary cardiovascular outcomes versus placebo; there was no clear difference in the results by SGLT-2i use at baseline (Pinteraction = 0.21 and 0.46, respectively) or at any time during the trial. Safety was balanced with or without SGLT-2i use at baseline, with fewer hyperkalemia events with finerenone in the SGLT-2i group (8.1% vs. 18.7% without). Conclusion UACR improvement was observed with finerenone in patients with CKD and T2D already receiving SGLT-2is at baseline, and benefits on kidney and cardiovascular outcomes appear consistent irrespective of use of SGLT-2i.

BACKGROUND Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear. METHODS In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m2 of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m2 (stage 1 or 2 CKD). Patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events. RESULTS A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%). CONCLUSIONS Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).

BACKGROUND Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of atrial fibrillation or flutter (AFF) due to cardiac remodeling and kidney complications. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, inhibited cardiac remodeling in preclinical models. OBJECTIVES To examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in FIDELIO-DKD. METHODS Patients with CKD and T2D were randomized (1:1) to finerenone or placebo. Eligible patients had a urine albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g, an estimated glomerular filtration rate (eGFR) ≥25 to <75 ml/min/1.73 m2 and received optimized doses of renin-angiotensin system blockade. Effect on new-onset AFF was evaluated as a prespecified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death) and key secondary outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) were analyzed by history of AFF. RESULTS Of 5,674 patients, 461 (8.1%) had a history of AFF. New-onset AFF occurred in 82 (3.2%) patients on finerenone and 117 (4.5%) on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53 to 0.94; p = 0.016). The effect of finerenone on primary and key secondary kidney and cardiovascular outcomes was not significantly impacted by baseline AFF (interaction p value: 0.16 and 0.85, respectively). CONCLUSIONS In patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. The risk of kidney or cardiovascular events was reduced irrespective of history of AFF at baseline.

BACKGROUND Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. However, its long-term effects on kidney and cardiovascular outcomes are unknown. METHODS In this double-blind trial, we randomly assigned 5734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300, an estimated glomerular filtration rate (eGFR) of 25 to less than 60 ml per minute per 1.73 m2 of body-surface area, and diabetic retinopathy, or they had a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of 25 to less than 75 ml per minute per 1.73 m2. All the patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. The key secondary composite outcome, also assessed in a time-to-event analysis, was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. RESULTS During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P = 0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P = 0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively). CONCLUSIONS In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993.).

OBJECTIVE Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. We explored whether baseline HbA1c level and insulin treatment influenced outcomes. RESEARCH DESIGN AND METHODS Patients with T2D, urine albumin-to-creatinine ratio (UACR) of 30–5,000 mg/g, estimated glomerular filtration rate (eGFR) of 25 to <75 mL/min/1.73 m2, and treated with optimized renin–angiotensin system blockade were randomly assigned to receive finerenone or placebo. Efficacy outcomes included kidney (kidney failure, sustained decrease ≥40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite endpoints. Patients were analyzed by baseline insulin use and by baseline HbA1c <7.5% (58 mmol/mol) or ≥7.5%. RESULTS Of 5,674 patients, 3,637 (64.1%) received insulin at baseline. Overall, 5,663 patients were included in the analysis for HbA1c; 2,794 (49.3%) had baseline HbA1c <7.5% (58 mmol/mol). Finerenone significantly reduced risk of the kidney composite outcome independent of baseline HbA1c level and insulin use (Pinteraction = 0.41 and 0.56, respectively). Cardiovascular composite outcome incidence was reduced with finerenone irrespective of baseline HbA1c level and insulin use (Pinteraction = 0.70 and 0.33, respectively). Although baseline HbA1c level did not affect kidney event risk, cardiovascular risk increased with higher HbA1c level. UACR reduction was consistent across subgroups. Adverse events were similar between groups regardless of baseline HbA1c level and insulin use; few finerenone-treated patients discontinued treatment because of hyperkalemia. CONCLUSIONS Finerenone reduces kidney and cardiovascular outcome risk in patients with CKD and T2D, and risks appear consistent irrespective of HbA1c levels or insulin use.

ABSTRACT Background In FIGARO-DKD, finerenone reduced the risk of cardiovascular events in patients with type 2 diabetes (T2D) and stage 1–4 chronic kidney disease (CKD). In FIDELIO-DKD, finerenone improved kidney and cardiovascular outcomes in patients with advanced CKD. This analysis further explores kidney outcomes in FIGARO-DKD. Methods FIGARO-DKD (NCT02545049) included patients with urine albumin-to-creatinine ratio (UACR) 30–<300 mg/g and estimated glomerular filtration rate (eGFR) 25–90 mL/min/1.73 m2 or UACR 300–5000 mg/g and eGFR ≥60 mL/min/1.73 m2. Outcomes included two composite kidney endpoints, a composite of ≥40% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death, and a composite of ≥57% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death. Changes in albuminuria and eGFR slope were also analyzed. Kidney and CV outcomes were evaluated by baseline UACR. Results A lower incidence rate for the eGFR ≥40% kidney composite endpoint was observed with finerenone compared with placebo, but the between-group difference was not significant [hazard ratio (HR) = 0.87; 95% confidence interval (CI): 0.76–1.01; P = .069]. A greater treatment effect was observed on the eGFR ≥57% kidney composite endpoint (HR = 0.77; 95% CI: 0.60–0.99; P = 0.041) with a 36% relative risk reduction for end-stage kidney disease. A larger magnitude of effect on kidney outcomes was observed with finerenone versus placebo for patients with severely increased albuminuria than with moderately increased albuminuria. Improvements in UACR, eGFR slope and cardiovascular risk were evident in both subgroups with finerenone. Conclusions The present analyses suggest that finerenone protects against kidney disease progression and cardiovascular events in patients with T2D and early- or late-stage CKD.

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BACKGROUND The non-steroidal mineralocorticoid receptor agonist (MRA) finerenone, reduced heart failure events and cardiovascular death in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) in a frequentist analysis of the FINEARTS-HF trial. We applied Bayesian methods including prior information to provide probabilistic estimates of efficacy and safety. OBJECTIVE To estimate the probability of different magnitudes of treatment benefit with finerenone versus placebo using Bayesian analysis of FINEARTS-HF. METHODS In this pre-specified Bayesian analysis, we estimated treatment efficacy incorporating prior information in a robust meta-analytic predictive (MAP) prior using data from two finerenone trials (FIDELIO-DKD and FIGARO-DKD) and a steroidal MRA spironolactone (TOPCAT). We compared results using vague priors and informative MAP priors. The primary outcome was cardiovascular death and total heart failure events. RESULTS Among 6,001 patients, Bayesian analysis with vague priors confirmed the frequentist results of a reduction in the rate of the primary outcome (RR 0.83; 95% credible interval (CrI) 0.74-0.94). Incorporating prior evidence increased the posterior probability of a ≥10% reduction in the primary event rate from 90% to 92%. The probability that finerenone reduced cardiovascular death was 80% (HR 0.93, 95% CrI: 0.79-1.10), and all-cause mortality was 85% (HR 0.94, 95% CrI: 0.83-1.06). Finerenone increased the probability of hyperkalaemia and decreased the probability of hypokalaemia. CONCLUSION The non-steroidal MRA finerenone reduced the rate of cardiovascular death and total heart failure events under both frequentist and Bayesian inference methods. The probability of benefit exceeded 80% for both cardiovascular and all-cause mortality with finerenone. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04435626.

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BACKGROUND Mapping clinical, biomarker, and diuretic dosing trajectories before adverse clinical outcomes in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) may inform population monitoring approaches. OBJECTIVES We assessed temporal patterns of 2 biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and estimated glomerular filtration rate [eGFR]), physician assigned functional status (NYHA functional class), a patient-reported outcome (Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and diuretic dosing leading up to a clinical event. METHODS FINEARTS-HF was a double-blind, randomized clinical trial testing finerenone vs placebo in 6,001 patients with symptomatic HF and a left ventricular ejection fraction of ≥40%. Key variables including NT-proBNP, eGFR, NYHA functional class, KCCQ-TSS, and diuretic dosing (expressed as furosemide equivalents) were serially assessed until the occurrence of cardiovascular death, first HF event, or the end of the follow-up period. Each variable was plotted relative to the number of months before an event or the end of follow-up. Patients who experienced a clinical event were compared with a control population who remained alive and free of hospitalization during follow-up. RESULTS Over a median 2.7-year follow-up period, 1,343 cardiovascular deaths or first HF events occurred. At baseline, the participants who experienced a clinical event had higher NT-proBNP values, lower eGFR, higher NYHA functional class, lower KCCQ-TSS, and higher diuretic doses compared with the control population. The eGFR declined by about 5 mL/min/1.73 m2 (from a mean of ∼57 to ∼52 mL/min/1.73 m2), and the NT-proBNP level increased by approximately 70% to 80%, in the 12 to 18 months leading up to an event; these markers remained relatively stable in the control group. NYHA functional class showed a sharp deterioration in the 6 to 9 months before an event, and KCCQ-TSS declined by approximately 6 points (from a mean of ∼68 to ∼62) during this period, reflecting worsening functional class and patient-reported symptoms, respectively. Finally, diuretic doses increased in the 6 months preceding the event, from ∼50 to ∼60 mg/day of furosemide equivalents. CONCLUSIONS In a large HFmrEF/HFpEF trial population, clinically meaningful changes in readily available biomarkers, functional status, and patient-reported health status were observed in the months leading up to a clinical event. Monitoring these parameters may help identify patients at high risk for near-term adverse clinical events. (Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure [FINEARTS-HF]; NCT04435626).

To assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs. We searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). In total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79–0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83–0.92; P < 0.001). For both drug classes, the effect on lowering the risk of MACE was restricted to approximately 14% in patients with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.82–0.90; P < 0.001), whereas no effect was observed in patients without established atherosclerotic cardiovascular disease (HR, 0.93; 95% CI, 0.85–1.02; P = 0.12). GLP1-RA reduced myocardial infarction, stroke and cardiovascular death more than finerenone (which appeared to have no effect). Only finerenone was beneficial for reducing the risk of HHF (HR, 0.78; 95% CI, 0.66–0.92; P = 0.003). Both finerenone (HR, 0.84; 95% CI, 0.77–0.92; P < 0.001) and GLP1-RA (HR, 0.81; 95% CI, 0.76–0.86; P < 0.001) reduced the risk of kidney disease progression, including macroalbuminuria, and finerenone was superior to GLP1-RA in delaying deterioration of kidney function. Finerenone and GLP1-RA lead to a risk reduction in MACE to a similar degree in patients with established atherosclerotic cardiovascular disease. For both drug classes, the effect on lowering the risk of progression of kidney disease was also in a similar magnitude in patients with T2DM, whereas only finerenone had a significant protective effect against HHF. Treatment decisions for patients with T2DM should consider the clinical benefit profiles of each drug.

Background: Mineralocorticoid receptor antagonists (MRAs) mechanistically reduce inflammation, oxidative stress and endothelial dysfunction. There is growing interest in understanding the composite cardiovascular (CV) protection afforded by therapies like the nonsteroidal MRA finerenone with systemic actions in patients with cardio-kidney-metabolic (CKM) syndrome. Methods: In this participant-level pre-specified pooled analysis from three large phase 3 clinical trials (FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF), we assessed the association between various nonfatal CV events (myocardial infarction, stroke, and heart failure hospitalization) and rates of subsequent mortality using time-updated models. We then examined the treatment effects of finerenone vs. placebo on major adverse cardiovascular events (MACE, a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization), which was a prespecified secondary endpoint in the FINE-HEART pooled analysis, using Cox regression models stratified by trial and region. Results: During a median of 2.9 years of follow-up, among the 18,991 participants, 1,544 (8.1%) experienced heart failure hospitalization, 500 (2.6%) nonfatal myocardial infarction, 570 (3.0%) nonfatal stroke, and 892 (4.7%) CV death. Patients with incident myocardial infarction, stroke, and heart failure hospitalization consistently experienced markedly higher subsequent risks of mortality ( Figure 1 ). Mortality was highest after heart failure hospitalization (incidence rate 23.4 [21.4-25.8] per 100py compared with 3.2 [3.1-3.4] per 100py for individuals without nonfatal CV events). Finerenone reduced the composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization (HR 0.91; 95% CI, 0.85–0.98; P = 0.010, Figure 2). Results were essentially unchanged in a sensitivity analysis including undetermined deaths as CV deaths (HR 0.90; 95% CI, 0.84–0.96; P = 0.002). The treatment effect on MACE was consistent across FINEARTS-HF (HR 0.95; 95% CI 0.86–1.05), FIDELIO-DKD (HR 0.88; 95% CI 0.76–1.02), and FIGARO-DKD (HR 0.87; 95% CI 0.76–1.00); P int =0.55. Risk reductions did not differ by the number of CKM conditions ( P int =0.98). Conclusion: Among patients with cardio-kidney-metabolic syndrome, major adverse cardiovascular events were frequent, prognostically meaningful, and reduced with the non-steroidal MRA finerenone.

BACKGROUND Mineralocorticoid receptor antagonists (MRA) modulate cardiac and systemic pathways such as fibrosis and inflammation, which may contribute to the onset of atrial fibrillation (AF) or atrial flutter (AFL). OBJECTIVES In this participant-level pooled analysis of 3 large clinical trials, the authors evaluated the effect of the nonsteroidal MRA finerenone on incident AF/AFL across the cardio-kidney-metabolic (CKM) spectrum. METHODS In this prespecified analysis, we pooled participants from 2 trials of chronic kidney disease and type 2 diabetes (FIDELIO-DKD and FIGARO-DKD) and a trial of heart failure (HF) with mildly reduced or preserved ejection fraction (FINEARTS-HF). Patients were randomized 1:1 to finerenone or placebo. New-onset AF/AFL was prospectively adjudicated in all trials by blinded clinical event committees. The risk of new-onset AF/AFL was evaluated using Cox regression models stratified by region and trial. RESULTS Among 14,581 patients who were free of AF/AFL at trial enrollment, 631 (4.3%) experienced new-onset AF/AFL during follow-up. Predictors of new-onset AF/AFL included older age, history of HF, higher body mass index, geographic region, and higher levels of urine albumin-to-creatinine ratio. During 2.9 years of median follow-up, new-onset AF/AFL occurred in 286 (3.9%) participants receiving finerenone and 345 (4.7%) assigned to placebo (HR: 0.83; 95% CI: 0.71-0.97; P = 0.019). Risk reductions were consistent irrespective of number of CKM conditions (Pinteraction = 0.87) and by trial (Pinteraction = 0.57). Participants with new-onset AF/AFL were at significantly higher subsequent risk of cardiovascular death, HF hospitalization, and adverse kidney outcomes. CONCLUSIONS The nonsteroidal MRA finerenone reduced the risk of new-onset AF/AFL across the CKM spectrum.

ABSTRACT Background Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes in two phase 3 outcome trials. The Finerenone, in addition to standard of care, on the progression of kidney disease in patients with Non-Diabetic Chronic Kidney Disease (FIND-CKD) study investigates the effect of finerenone in adults with CKD without diabetes. Methods FIND-CKD (NCT05047263 and EU CT 2023-506897-11-00) is a randomized, double-blind, placebo-controlled phase 3 trial in patients with CKD of non-diabetic aetiology. Adults with a urinary albumin:creatinine ratio (UACR) ≥200–≤3500 mg/g and an estimated glomerular filtration rate (eGFR) ≥25–<90 ml/min/1.73 m2 receiving a maximum tolerated dose of a renin–angiotensin system inhibitor were randomized 1:1 to once-daily placebo or finerenone 10 or 20 mg depending on eGFR >60 or <60 ml/min/1.73 m2. The primary efficacy outcome is total eGFR slope, defined as the mean annual rate of change in eGFR from baseline to month 32. Secondary efficacy outcomes include a combined cardiorenal composite outcome comprising time to kidney failure, sustained ≥57% decrease in eGFR, hospitalization for heart failure or cardiovascular death, as well as separate kidney and cardiovascular composite outcomes. Adverse events are recorded to assess tolerability and safety. Results Across 24 countries, 3231 patients were screened and 1584 were randomized to study treatment. The most common causes of CKD were chronic glomerulonephritis (57.0%) and hypertensive/ischaemic nephropathy (29.0%). Immunoglobulin A nephropathy was the most common glomerulonephritis (26.3% of the total population). At baseline, mean eGFR and median UACR were 46.7 ml/min/1.73 m2 and 818.9 mg/g, respectively. Diuretics were used by 282 participants (17.8%), statins by 851 (53.7%) and calcium channel blockers by 794 (50.1%). Sodium–glucose co-transporter 2 (SGLT2) inhibitors were used in 16.9% of patients; these individuals had a similar mean eGFR (45.6 versus 46.8 ml/min/1.73 m2) and a slightly higher median UACR (871.9 versus 808.3 mg/g) compared with those not using SGLT2 inhibitors at baseline. Conclusions FIND-CKD is the first phase 3 trial of finerenone in patients with CKD of non-diabetic aetiology.

ABSTRACT Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and finerenone each improve kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD). This study compares the association between combined therapy versus monotherapy with SGLT2i or finerenone and the kidney, cardiovascular and mortality outcomes in CKD patients. Methods This retrospective cohort study included adults ≥18 years with CKD between 9 July 2021, and 30 November 2023 from multiple centers in the USA, utilizing the TriNetX database. Exposures included treatment with finerenone, SGLT2i or a combination of both. The primary outcome was major adverse kidney events (MAKE). Secondary outcomes included all-cause mortality, major adverse cardiac events (MACE) and end-stage renal disease (ESRD). Results A total of 853 patients were included in the combined group [mean (±standard deviation) age, 66.7 ± 11.4 years; 34.9% female], 942 in the finerenone group (mean age, 68.2 ± 11.4 years; 45.8% female) and 45 948 in the SGLT2i group (mean age, 70.2 ± 11.8 years; 41.4% female). After matching, the combined group had less MAKE compared with finerenone monotherapy [adjusted hazard ratio (aHR) 0.20; 95% confidence interval (CI) 0.09–0.45] or SGLT2i monotherapy (aHR 0.44; 95% CI 0.22–0.89). The hazards of all-cause mortality and ESRD were also lower in the combined group compared with either finerenone or SGLT2i alone, while hazard of MACE was similar between the combined and monotherapy groups. The combined group had higher risk of hyperkalemia compared with SGLT2i monotherapy (aHR = 1.36; 95% CI 1.08–1.71). Conclusion Combined therapy with finerenone and SGLT2i is associated with less MAKE and all-cause mortality in CKD patients compared with monotherapy. However, the risk of hyperkalemia with finerenone warrants caution.