In this double-blind trial, patients with chronic kidney disease and type 2 diabetes were randomly assigned to receive the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone or ...placebo. Treatment with finerenone resulted in lower risks of chronic kidney disease outcomes and cardiovascular outcomes than placebo.
In this double-blind trial, patients with stage 1 to 4 chronic kidney disease and type 2 diabetes were randomly assigned to receive finerenone or placebo. Finerenone treatment was superior with ...regard to the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
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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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist with a short half-life. Its effects on cardiorenal outcomes were thought to be mediated primarily via nonhemodynamic ...pathways, but office blood pressure (BP) measurements were insufficient to fully assess hemodynamic effects. This analysis assessed the effects of finerenone on 24-h ambulatory BP in patients with chronic kidney disease and type 2 diabetes.
ARTS-DN (NCT01874431) was a phase 2b trial that randomized 823 patients with type 2 diabetes and chronic kidney disease, with urine albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate of 30-90 ml/min per 1.73 m2 to placebo or finerenone (1.25-20 mg once daily in the morning) administered over 90 days. Ambulatory BP monitoring (ABPM) over 24 h was performed in a subset of 240 patients at screening, Day 60, and Day 90.
Placebo-adjusted change in 24-h ABPM systolic BP (SBP) at Day 90 was -8.3 mmHg (95% confidence interval CI, -16.6 to 0.1) for finerenone 10 mg (n = 27), -11.2 mmHg (95% CI, -18.8 to -3.6) for finerenone 15 mg (n = 34), and -9.9 mmHg (95% CI, -17.7 to -2.0) for finerenone 20 mg (n = 31). Mean daytime and night-time SBP recordings were similarly reduced and finerenone did not increase the incidence of SBP dipping. Finerenone produced a persistent reduction in SBP over the entire 24-h interval.
Finerenone reduced 24-h, daytime, and night-time SBP. Despite a short half-life, changes in BP were persistent over 24 h with once-daily dosing in the morning.
Aims
To explore the modifying effect of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and ...type 2 diabetes (T2D) in the pooled analysis of FIDELIO‐DKD and FIGARO‐DKD.
Materials and methods
Patients with T2D and CKD treated with optimized renin‐angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate eGFR decline, or renal death), change in urine albumin‐to‐creatinine ratio (UACR), and safety were analysed by GLP‐1RA use.
Results
Of 13 026 patients, 944 (7.2%) used GLP‐1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio HR 0.76, 95% confidence interval CI 0.52–1.11 with GLP‐1RA; HR 0.87, 95% CI 0.79–0.96 without GLP‐1RA; P‐interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45–1.48 with GLP‐1RA; HR 0.77, 95% CI 0.67–0.89 without GLP‐1RA; P‐interaction = 0.79) irrespective of baseline GLP‐1RA use. Reduction in UACR with finerenone at Month 4 was –38% in patients with baseline GLP‐1RA use compared with –31% in those without GLP‐1RA use (P‐interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP‐1RA use.
Conclusions
The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP‐1RA use. Subsequent studies are needed to investigate any potential benefit of this combination.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that significantly reduces risk of kidney and CV outcomes in patients with CKD and T2D. GLP-1RAs have also been shown to improve CV ...outcomes in patients with T2D. Mechanisms of action of finerenone and GLP-1RAs are largely independent but their combined effects are unknown. We report outcomes from the FIDELIO-DKD trial in patients by GLP-1RA treatment.
FIDELIO-DKD (NCT02540993) randomized 5734 patients with T2D (UACR 30–5000mg/g; eGFR 25–<75mL/min/1.73 m2; treated with optimized RAS blockade) to finerenone or placebo. Primary outcome was time to kidney failure, sustained eGFR decline ≥40% from baseline, or renal death. Secondary outcomes included time to CV death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure, and change in UACR from baseline to month 4.
Of 5674 patients analyzed, 394 (6.9%) were treated with a GLP-1RA at baseline. There was no between-group interaction for primary kidney (HR 1.17, 95%CI 0.71–1.90 with GLP-1RA; HR 0.80, 95%CI 0.71–0.91 without GLP-1RA; P-interaction 0.15) or secondary CV outcomes (HR 1.02, 95%CI 0.60–1.74 with GLP-1RA; HR 0.85, 95%CI 0.73–0.98 without GLP-1RA; P-interaction 0.51). Reduction in UACR was independent of GLP-1RA use (ratio of LS-means 0.63, 95%CI 0.56–0.70 with GLP-1RA; 0.69, 95%CI 0.67–0.72 without GLP-1RA; P-interaction 0.20). Incidences of hyperkalemia events were similar in patients with and without GLP-1RA use.
Effects of finerenone on kidney and CV outcomes appear consistent irrespective of GLP-1RA use, with a potential additive benefit for UACR reduction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aim
To evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, diabetes duration and baseline insulin use on cardiorenal outcomes and diabetes progression.
Materials and Methods
...Composite efficacy outcomes included cardiovascular (cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke or hospitalization for heart failure), kidney (kidney failure, sustained ≥ 57% estimated glomerular filtration rate decline or renal death) and diabetes progression (new insulin initiation, increase in antidiabetic medication, 1.0% increase in HbA1c from baseline, new diabetic ketoacidosis diagnosis or uncontrolled diabetes).
Results
In 13 026 participants, risk reductions in the cardiovascular and kidney composite outcomes with finerenone versus placebo were consistent across HbA1c quartiles (P interaction .52 and .09, respectively), HbA1c variability (P interaction .48 and .10), diabetes duration (P interaction .12 and .75) and insulin use (P interaction .16 and .52). HbA1c variability in the first year of treatment was associated with a higher risk of cardiovascular and kidney events (hazard ratio HR 1.20; 95% confidence interval CI 1.07‐1.35; P = .0016 and HR 1.36; 95% CI 1.21‐1.52; P < .0001, respectively). There was no effect on diabetes progression with finerenone or placebo (HR 1.00; 95% CI 0.95‐1.04). Finerenone was well‐tolerated across subgroups; discontinuation and hospitalization because of hyperkalaemia were low.
Conclusions
Finerenone efficacy was not modified by baseline HbA1c, HbA1c variability, diabetes duration or baseline insulin use. Greater HbA1c variability appeared to be associated with an increased risk of cardiorenal outcomes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Patients with chronic kidney disease (CKD), type 2 diabetes (T2D), and heart failure (HF) have a very high risk of adverse cardiorenal events. FIDELITY (prespecified pooled analysis of FIDELIO-DKD ...NCT02540993 and FIGARO-DKD NCT02545049) evaluated finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist in patients with CKD and T2D. This FIDELITY substudy analyzed the effects of finerenone in patients with and without a history of HF at baseline. Eligible patients had T2D and either a urine albumin-to-creatinine ratio (UACR mg/g)≥30–<300 and estimated glomerular filtration rate (eGFR mL/min/1.73m2)≥25–≤90, or UACR≥300–≤5000 and eGFR≥25, and received optimized renin–angiotensin system blockade. Key exclusion criteria included symptomatic chronic HF with reduced ejection fraction or recent HF hospitalization (HHF). Patients were randomized to finerenone or placebo. Outcomes included a cardiovascular outcome (time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or HHF) and a kidney outcome (kidney failure, sustained eGFR decrease≥57%, or kidney death). Investigator-reported adverse events were assessed. 1007/13,026 eligible patients had a history of HF at baseline. Primary results of the FIDELITY analysis were presented at the European Cardiology Society Congress 2021. This abstract will present detailed HF outcomes, including new onset and recurrent HF events in the total population and cardiovascular and kidney efficacy and safety results by history of HF at baseline. In FIDELITY, finerenone improved CV and kidney outcomes in patients with CKD and T2D versus placebo. The proposed analysis will provide further insights into the effects of finerenone on HF outcomes across a broad spectrum of CKD severity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of cardiovascular complications. FIDELITY (prespecified pooled analysis of FIDELIO-DKD NCT02540993 and FIGARO-DKD ...NCT02545049) evaluated finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) in patients with CKD and T2D. Cardiovascular and kidney outcomes were compared in primary and secondary prevention populations. Patients with T2D, and either urine albumin-to-creatinine ratio (UACR mg/g)≥30–<300 and estimated glomerular filtration rate (eGFR mL/min/1.73m2)≥25–≤90, or UACR≥300–≤5,000 and eGFR≥25, treated with optimized renin–angiotensin system blockade, were randomized to finerenone or placebo. Cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or heart failure hospitalization) and kidney outcomes (kidney failure, sustained eGFR decrease≥57% or kidney death) were categorized by prior atherosclerotic cardiovascular disease (CVD). Investigator-reported adverse events (AEs) were assessed. 5,935/13,026 of eligible patients had a history of CVD. Finerenone lowered the risk of the cardiovascular outcome vs placebo (HR=0.86; 95%CI=0.78-0.95; 3.0-year median follow-up), with no treatment modification by CVD history (HR=0.83 95%CI=0.74-0.94 in patients with CVD; HR=0.91 95%CI=0.78-1.06 in patients without CVD; Pinteraction=0.375). The effect of finerenone on the kidney outcome (HR=0.77; 95%CI=0.67-0.88) was not modified by CVD (HR=0.71 95%CI=0.57-0.88 and HR=0.81 95%CI=0.68-0.97 in patients with and without CVD history, respectively; Pinteraction=0.325). AEs did not differ between CVD subgroups, with a low incidence of hyperkalemia-related treatment discontinuation that was more frequent in the finerenone group but similar between CVD subgroups. Finerenone reduced the risk of cardiovascular and kidney outcomes in patients with CKD and T2D vs placebo, irrespective of CVD history.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent trials investigating novel therapies in chronic kidney disease (CKD) and type 2 diabetes (T2D) include the randomized, placebo-controlled phase III FIDELIO-DKD and CREDENCE studies of ...finerenone (selective, nonsteroidal mineralocorticoid receptor antagonist) and canagliflozin (sodium-glucose co-transporter-2 inhibitor), respectively. This analysis investigated how differences in trial design between FIDELIO-DKD and CREDENCE influence the treatment effects of the two drugs.
This was a post hoc analysis of FIDELIO-DKD that included patients meeting the CKD inclusion criteria of the CREDENCE study (urine albumin-to-creatinine ratio >300–5000 mg/g and estimated glomerular filtration rate eGFR 30–<90 mL/min/1.73 m2 at screening). The cardiorenal composite endpoint comprised kidney failure, eGFR decrease of ≥57% from baseline sustained for ≥4 weeks, or renal or cardiovascular death (equivalent to the CREDENCE primary endpoint).
Overall, 81.4% (4619/5674) of patients were eligible for this analysis; 2291 (49.6%) received finerenone and 2328 (50.4%) received placebo. The cardiorenal composite endpoint risk was significantly reduced by 26% with finerenone versus placebo (hazard ratio 0.74, 95% confidence interval 0.63–0.87; p=0.0003); after adjusting for history of heart failure, the risk was reduced by 28%. In CREDENCE, the cardiorenal endpoint risk reduction was 30% with canagliflozin versus placebo (see Figure for all results).
The results of this analysis highlight the pitfalls of direct comparisons between trials, and how subtle differences in patient eligibility criteria and endpoint definitions can lead to meaningful differences in outcomes. Both the FIDELIO-DKD and CREDENCE studies demonstrate cardiorenal benefits of a similar magnitude when these differences are considered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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