ObjectivesThis study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or ...sex.DesignFIDELITY post hoc analysis; median follow-up of 3 years.SettingFIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials.ParticipantsAdults with type 2 diabetes and chronic kidney disease receiving optimised renin–angiotensin system inhibitors (N=13 026).InterventionsRandomised 1:1; finerenone or placebo.Primary and secondary outcome measuresCardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes.ResultsMean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65–74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65–74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); Pinteraction=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); Pinteraction=0.99). Effects on HHF reduction were not modified by age (Pinteraction=0.70) but appeared more pronounced in males (Pinteraction=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65–74 but not ≥75; no heterogeneity in treatment effect was observed (Pinteraction=0.51). In sex subgroups, finerenone consistently reduced kidney events (Pinteraction=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups.ConclusionsFinerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups.Trial registration numbersNCT02540993, NCT02545049.
Kidney Disease
Left ventricular hypertrophy (LVH) is a predictor of cardiovascular (CV) disease and associated morbidity and mortality. Patients with chronic kidney disease (CKD), type 2 diabetes ...(T2D) have a higher prevalence of LVH. In this exploratory analysis we investigated the effect of baseline LVH on cardiovascular and renal outcomes from FIDELITY, a pooled dataset from two phase III multicentre, double-blind trials of patients with CKD and T2D (FIDELIO-DKD and FIGARO-DKD).
Patients in FIDELITY were treated with the maximum tolerated labelled dose of a renin–angiotensin system inhibitor (RASi) and randomized 1:1 to finerenone or placebo. LVH at baseline was determined based on coded electrocardiogram findings. Efficacy outcomes included a composite of CV death, non-fatal myocardial infarction (MI), non-fatal stroke, or hospitalization for heart failure (HFF), and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Safety was also assessed.
Notable differences in demographics and baseline characteristics included higher systolic blood pressure and urine albumin-to-creatinine ratio in patients with LVH vs those without. Finerenone consistently reduced the relative risk of the CV composite outcome in patients with and without LVH (reduction of 28% vs 11%, respectively; p-value for interaction 0.11; Figure). The relative risk of HHF was reduced in both patient subgroups (66% reduction in patients with LVH vs 14% without LVH), with the effect of finerenone being significantly greater in patients with LVH (p-value for interaction 0.0024). Overall safety was similar between subgroups. The incidence of hyperkalaemia was higher with finerenone vs placebo irrespective of baseline LVH status, however discontinuation due to hyperkalaemia remained low in both groups.
In this exploratory analysis, finerenone, in addition to standard of care with a RASi, reduced the overall risk of CV and kidney outcomes in patients with CKD and T2D with or without LVH at baseline. Furthermore, the effect of finerenone in reducing the incidence of HHF appeared to be more pronounced in patients with LVH than in those without.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In FIDELITY, finerenone improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). This analysis explored the efficacy and safety of finerenone in Black ...patients.
Subanalysis of randomized controlled trials.
Patients with T2D and CKD.
Finerenone or placebo.
Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; composite of kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline from baseline maintained for ≥4 weeks, or renal death.
Of 13,026 patients, 522 (4.0%) self-identified as Black. Finerenone demonstrated similar effects on the cardiovascular composite outcome in Black (hazard ratio HR, 0.79 95% confidence interval (CI), 0.51-1.24) and non-Black patients (HR, 0.87 95% CI, 0.79-0.96; P = 0.5 for interaction). Kidney composite outcomes were consistent in Black (HR, 0.71 95% CI, 0.43-1.16) and non-Black patients (HR, 0.76 95% CI, 0.66-0.88; P = 0.9 for interaction). Finerenone reduced urine albumin-to-creatinine ratio by 40% at month 4 (least-squares mean treatment ratio, 0.60 95% CI, 0.52-0.69; P < 0.001) in Black patients and 32% at month 4 (least-squares mean treatment ratio, 0.68 95% CI, 0.66-0.70; P < 0.001) in non-Black patients, versus placebo. Chronic eGFR decline (month 4 to end of study) was slowed in Black and non-Black patients treated with finerenone versus placebo (between-group difference, 1.4 mL/min/1.73 m2 per year 95% CI, 0.33-2.44; P = 0.01 and 1.1 mL/min/1.73 m2 per year 95% CI, 0.89-1.28; P < 0.001, respectively). Safety outcomes were similar between subgroups.
Small number of Black patients; analysis was not originally powered to determine an interaction effect based on Black race.
The efficacy and safety of finerenone appear consistent in Black and non-Black patients with CKD and T2D.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing ...cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate. The MRA mode of action increases potassium.
Methods
Nonlinear mixed-effects population pharmacokinetic/pharmacodynamic models were used to analyze the finerenone dose–exposure–response relationship for potassium in FIDELIO-DKD. Individual time-varying exposures from pharmacokinetic analyses were related to the potassium response via a maximal effect, indirect-response model informed by 148,384 serum potassium measurements.
Results
Although observed potassium levels decreased with increasing dose (i.e., inverse relation), model-based simulations for a fixed-dose setting (i.e., no dose titration) revealed the intrinsic finerenone dose–exposure–potassium response, with potassium levels increasing in a dose- and exposure-dependent manner, thus explaining the apparent conflict. The potassium limit for inclusion and uptitration from finerenone 10 to 20 mg in FIDELIO-DKD was ≤ 4.8 mmol/L. Modified limits of ≤ 5.0 mmol/L were simulated, resulting in higher hyperkalemia frequencies for both the finerenone and the placebo arms, whereas the relative hyperkalemia risk of a finerenone treatment compared with placebo did not increase.
Conclusions
The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone was found to improve cardiorenal outcomes in patients with type 2 diabetes, a urine ...albumin-to-creatinine ratio of 30–5000 mg/g, an estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2 or more and also receiving optimized renin-angiotensin system blockade treatment. This present analysis focused on the efficacy and safety of finerenone on kidney outcomes. Among 13,026 patients with a median follow-up of three years, finerenone significantly reduced the hazard of a kidney composite outcome (time to kidney failure, sustained 57% or more decrease in eGFR from baseline, or kidney death) by 23% versus placebo (hazard ratio, 0.77; 95% confidence interval, 0.67–0.88), with a three-year absolute between-group difference of 1.7% (95% confidence interval, 0.7–2.6). Hazard ratios were directionally consistent for a prespecified baseline eGFR and urine albumin-to-creatinine ratio categories (Pinteraction = 0.62 and Pinteraction = 0.67, respectively), although there was a high degree of uncertainty in the 30–300 mg/g subgroup. Finerenone significantly reduced the hazard of end-stage kidney disease (ESKD) by 20% versus placebo (0.80; 0.64–0.99). Adverse events were similar between treatment arms, although hyperkalemia leading to treatment discontinuation occurred significantly more frequently with finerenone versus placebo (2.4% vs 0.8% and 0.6% vs 0.3% in patients with eGFR less than 60 vs. greater than or equal to 60 ml/min per 1.73 m2, respectively). Thus, finerenone improved kidney outcomes, reduced the hazard of ESKD, and is well tolerated in patients with chronic kidney disease and type 2 diabetes.
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Abstract Background and Aims The Chronic Kidney Disease Prognosis Consortium (CKD-PC) recently developed risk models to predict the 3-year risk of a ≥40% decrease in estimated glomerular filtration ...rate (eGFR) or to predict kidney failure in the general population. Unlike the kidney failure risk equation, the CKD-PC model is valid for all levels of eGFR (above and below 60 mL/min/1.73 m2) and includes chronic kidney disease (CKD) progression risk factors besides age, sex, eGFR and albuminuria; namely: systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, body mass index, glycated hemoglobin, insulin use, and oral diabetes medication use 1. We evaluated whether the CKD-PC model, developed using electronic health record data, is valid for use in a contemporary clinical population using the FIDELITY pooled dataset from international randomized clinical trials of finerenone 2. Additionally, to inform clinical practice, we evaluated the efficacy of finerenone using categories of 3-year CKD progression risk as predicted by the model. Method FIDELITY was an individual, patient-level, prespecified, pooled efficacy and safety analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials of patients with CKD and type 2 diabetes (T2D), randomized 1:1 to finerenone or placebo. The 3-year CKD progression risk of these patients was predicted and the validity of the CKD-PC model was evaluated using area under the curve (AUC) score (with higher scores indicating better risk prediction), Brier score (lower scores indicating better prediction), and by calibration plots of observed versus predicted risk by deciles of 3-year CKD progression risk. To evaluate the efficacy of finerenone, 3-year risk was categorized in quartiles and the effect of finerenone versus placebo on a kidney composite outcome, defined as kidney failure, a sustained ≥40% decrease in eGFR from baseline over ≥4 weeks, or renal death, was assessed. Results The FIDELITY population comprised 13,026 individuals with a mean eGFR of 58 mL/min/1.73 m2 and urine albumin-to-creatinine ratio of 515 mg/g. The median follow-up was 3 years and there were 1849 total kidney outcome events. Of 12,968 patients analyzed, the median 3-year risk of kidney failure was 15% (Q1–Q3: 9–24%). Overall, the model demonstrated good discrimination to predict a ≥40% kidney composite outcome for patients with CKD and T2D in FIDELITY: AUC score 0.726 (95% confidence interval CI 0.712–0.739) and Brier score 0.100 (95% CI 0.097–0.103). The predicted 3-year risk was generally slightly higher than the observed risk (Fig. 1). Finerenone was effective in preventing CKD progression across the risk quartiles (p-interaction = 0.094) with a trend towards greater efficacy in the higher risk quartiles (3-year risk of CKD progression ≥10%) (Fig. 2). All risk groups showed benefit with finerenone compared to placebo regarding eGFR decline in the chronic phase. Conclusion The CKD-PC risk model for CKD progression performed well in a large global clinical trial population of patients with CKD and T2D. Finerenone was effective across the range of baseline risk of CKD progression.
Background and Objective
Finerenone reduces the risk of kidney failure in patients with chronic kidney disease and type 2 diabetes. Changes in the urine albumin-to-creatinine ratio (UACR) and ...estimated glomerular filtration rate (eGFR) are surrogates for kidney failure. We performed dose–exposure–response analyses to determine the effects of finerenone on these surrogates in the presence and absence of sodium glucose co-transporter-2 inhibitors (SGLT2is) using individual patient data from the FIDELIO-DKD study.
Methods
Non-linear mixed-effects population pharmacokinetic/pharmacodynamic models were used to quantify disease progression in terms of UACR and eGFR during standard of care and pharmacodynamic effects of finerenone in the presence and absence of SGLT2i use.
Results
The population pharmacokinetic/pharmacodynamic models adequately described effects of finerenone exposure in reducing UACR and slowing eGFR decline over time. The reduction in UACR achieved with finerenone during the first year predicted its subsequent effect in slowing progressive eGFR decline. SGLT2i use did not modify the effects of finerenone. The population pharmacokinetic/pharmacodynamic model demonstrated with 97.5% confidence that finerenone was at least 94.1% as efficacious in reducing UACR in patients using an SGLT2i compared with patients not using an SGLT2i based on the 95% confidence interval of the SGLT2i-finerenone interaction from 94.1 to 122%. The 95% confidence interval of the SGLT2i-finerenone interaction for the UACR-mediated effect on chronic eGFR decline was 9.5–144%.
Conclusions
We developed a model that accurately describes the finerenone dose–exposure–response relationship for UACR and eGFR. The model demonstrated that the early UACR effect of finerenone predicted its long-term effect on eGFR decline. These effects were independent of concomitant SGLT2i use.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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