Browsing by Subject "Mineralocorticoid receptor antagonist"

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    Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment: A subgroup analysis from the FIDELIO-DKD trial
    (Wiley, 2022) Rossing, Peter; Agarwal, Rajiv; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Ruilope, Luis M.; Amod, Aslam; Marre, Michel; Joseph, Amer; Lage, Andrea; Scott, Charlie; Bakris, George L.; FIDELIO-DKD Investigators; Medicine, School of Medicine
    Aims: Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease and type 2 diabetes in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone. Materials and methods: Patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate 25-<75 ml/min per 1.73 m2 receiving optimized renin-angiotensin system blockade were randomized to finerenone or placebo. Results: Of the 5674 patients analysed, overall, 394 (6.9%) received GLP-1RAs at baseline. A reduction in UACR with finerenone was observed with or without baseline GLP-1RA use; ratio of least-squares means 0.63 (95% confidence interval 0.56, 0.70) with GLP-1RA use and 0.69 (95% confidence interval 0.67, 0.72) without GLP-1RA use (p value for interaction .20). Finerenone also significantly reduced the primary kidney (time to kidney failure, sustained decrease in estimated glomerular filtration rate ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) versus placebo, with no clear difference because of GLP-1RA use at baseline (p value for interaction .15 and .51 respectively) or any time during the trial. The safety profile of finerenone was similar between subgroups. Conclusions: This exploratory subgroup analysis suggests that finerenone reduces UACR in patients with or without GLP-1RA use at baseline, and the effects on kidney and CV outcomes are consistent irrespective of GLP-1RA use.
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    Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes
    (Elsevier, 2022) Filippatos, Gerasimos; Anker, Stefan D.; Pitt, Bertram; Rossing, Peter; Joseph, Amer; Kolkhof, Peter; Lambelet, Marc; Lawatscheck, Robert; Bakris, George L.; Ruilope, Luis M.; Agarwal, Rajiv; Medicine, School of Medicine
    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).
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    Finerenone efficacy in patients with chronic kidney disease, type 2 diabetes and atherosclerotic cardiovascular disease
    (Oxford University Press, 2022) Filippatos, Gerasimos; Anker, Stefan D.; Pitt, Bertram; McGuire, Darren K.; Rossing, Peter; Ruilope, Luis M.; Butler, Javed; Jankowska, Ewa A.; Michos, Erin D.; Farmakis, Dimitrios; Farjat, Alfredo E.; Kolkhof, Peter; Scalise, Andrea; Joseph, Amer; Bakris, George L.; Agarwal, Rajiv; Medicine, School of Medicine
    Aims: Finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, improves cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). This subgroup analysis of FIDELITY, a pre-specified, pooled, individual patient-data analysis of FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049), compared finerenone vs. placebo in patients with and without baseline history of atherosclerotic CV disease (ASCVD). Methods and results: Outcomes included a composite CV outcome [CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF)]; CV death or HHF; a composite kidney outcome (kidney failure, sustained estimated glomerular filtration rate decrease ≥57%, or kidney-related death); all-cause mortality; and safety by baseline history of ASCVD.Of 13 026 patients, 5935 (45.6%) had a history of ASCVD. The incidence of the composite CV outcome, CV death or HHF, and all-cause mortality was higher in patients with ASCVD vs. those without, with no difference between groups in the composite kidney outcome. Finerenone consistently reduced outcomes vs. placebo in patients with and without ASCVD (P-interaction for the composite CV outcome, CV death or HHF, the composite kidney outcome, and all-cause mortality 0.38, 0.68, 0.33, and 0.38, respectively). Investigator-reported treatment-emergent adverse events were consistent between treatment arms across ASCVD subgroups. Conclusion: Finerenone reduced the risk of CV and kidney outcomes consistently across the spectrum of CKD in patients with T2D, irrespective of prevalent ASCVD.
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    Finerenone Reduces New-Onset Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes
    (Elsevier, 2021) Filippatos, Gerasimos; Bakris, George L.; Pitt, Bertram; Agarwal, Rajiv; Rossing, Peter; Ruilope, Luis M.; Butler, Javed; Lam, Carolyn S. P.; Kolkhof, Peter; Roberts, Luke; Tasto, Christoph; Joseph, Amer; Anker, Stefan D.; FIDELIO-DKD Investigators; Medicine, School of Medicine
    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: This work aims to examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study. 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 pre-specified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) and key secondary outcome (time to first onset of 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%) patients on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53-0.94; 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. (EudraCT 2015-000990-11 [A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease]; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD]; NCT02540993).
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    Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses From the FIGARO-DKD Trial
    (Wolters Kluwer, 2022) Filippatos, Gerasimos; Anker, Stefan D.; Agarwal, Rajiv; Ruilope, Luis M.; Rossing, Peter; Bakris, George L.; Tasto, Christoph; Joseph, Amer; Kolkhof, Peter; Lage, Andrea; Pitt, Bertram; FIGARO-DKD Investigators; Medicine, School of Medicine
    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.
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    Hyperkalemia Risk with Finerenone: Results from the FIDELIO-DKD Trial
    (Wolters Kluwer, 2022) Agarwal, Rajiv; Joseph, Amer; Anker, Stefan D.; Filippatos, Gerasimos; Rossing, Peter; Ruilope, Luis M.; Pitt, Bertram; Kolkhof, Peter; Scott, Charlie; Lawatscheck, Robert; Wilson, Daniel J.; Bakris, George L.; FIDELIO-DKD Investigators; Medicine, School of Medicine
    Background: Finerenone reduced risk of cardiorenal outcomes in patients with CKD and type 2 diabetes in the FIDELIO-DKD trial. We report incidences and risk factors for hyperkalemia with finerenone and placebo in FIDELIO-DKD. Methods: This post hoc safety analysis defined hyperkalemia as ≥mild or ≥moderate based on serum potassium concentrations of >5.5 or >6.0 mmol/L, respectively, assessed at all regular visits. Cumulative incidences of hyperkalemia were based on the Aalen-Johansen estimator using death as competing risk. A multivariate Cox proportional hazards model identified significant independent predictors of hyperkalemia. Restricted cubic splines assessed relationships between short-term post-baseline changes in serum potassium or eGFR and subsequent hyperkalemia risk. During the study, serum potassium levels guided drug dosing. Patients in either group who experienced ≥mild hyperkalemia had the study drug withheld until serum potassium was ≤5.0 mmol/L; then the drug was restarted at the 10 mg daily dose. Placebo-treated patients underwent sham treatment interruption and downtitration. Results: Over 2.6 years' median follow-up, 597 of 2785 (21.4%) and 256 of 2775 (9.2%) patients treated with finerenone and placebo, respectively, experienced treatment-emergent ≥mild hyperkalemia; 126 of 2802 (4.5%) and 38 of 2796 (1.4%) patients, respectively, experienced moderate hyperkalemia. Independent risk factors for ≥mild hyperkalemia were higher serum potassium, lower eGFR, increased urine albumin-creatinine ratio, younger age, female sex, β-blocker use, and finerenone assignment. Diuretic or sodium-glucose cotransporter-2 inhibitor use reduced risk. In both groups, short-term increases in serum potassium and decreases in eGFR were associated with subsequent hyperkalemia. At month 4, the magnitude of increased hyperkalemia risk for any change from baseline was smaller with finerenone than with placebo. Conclusions: Finerenone was independently associated with hyperkalemia. However, routine potassium monitoring and hyperkalemia management strategies employed in FIDELIO-DKD minimized the impact of hyperkalemia, providing a basis for clinical use of finerenone.
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    Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone
    (Oxford University Press, 2022) Agarwal, Rajiv; Anker, Stefan D.; Bakris, George; Filippatos, Gerasimos; Pitt, Bertram; Rossing, Peter; Ruilope, Luis; Gebel, Martin; Kolkhof, Peter; Nowack, Christina; Joseph, Amer; Medicine, School of Medicine
    Despite the standard of care, patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) progress to dialysis, are hospitalized for heart failure and die prematurely. Overactivation of the mineralocorticoid receptor (MR) causes inflammation and fibrosis that damages the kidney and heart. Finerenone, a nonsteroidal, selective MR antagonist, confers kidney and heart protection in both animal models and Phase II clinical studies; the effects on serum potassium and kidney function are minimal. Comprising the largest CKD outcomes program to date, 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) are Phase III trials investigating the efficacy and safety of finerenone on kidney failure and cardiovascular outcomes from early to advanced CKD in T2D. By including echocardiograms and biomarkers, they extend our understanding of pathophysiology; by including quality of life measurements, they provide patient-centered outcomes; and by including understudied yet high-risk cardiorenal subpopulations, they have the potential to widen the scope of therapy in T2D with CKD.