Part1: Cardiovascular And Kidney Outcomes With Finerenone in Patients With Type2 Diabetes And Chronic Kidney Disease: The FIDELITY Pooled Analysis
May 26, 2022
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Aims
The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease(CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of the safety and efficacy of finerenone compared with placebo
Methods and results
For this prespecified analysis, two-phase, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained >57% decrease in estimated glomerular filtration rate from baseline over >4 weeks. or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3-3.8 years), the composite cardiovascular outcome occurred in 825(12.7%) patients receiving finerenone and 939(14.4%) receiving placebo Hazard ratio(HR), 0.86:95% confidence interval(C), 0.78-0.95: P=0.0018]. The composite kidney outcome occurred in 360(5.5%) patients receiving finerenone and 465(7.1%)receiving placebo (HR, 0.77;95%Cl, 0.67-0.88;P=0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%).
Conclusion
Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes.
Key Question
Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerate renin-angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney diseases in patients with type 2 diabetes?
Key Finding
In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of>60 mLmin/1.73mthey were identified solely based on albuminuria.
Take-Home Message
Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates the reduction of both cardiovascular and kidney disease burdens.
Keywords
Cardiorenal outcomes · Chronic kidney disease ·Finerenone ·Hospitalization for heart failure ●Hyperkalaemia ·Type 2 diabetes
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Introduction
Patients with chronic kidney disease(CKD) and type 2 diabetes have high residual cardiorenal morbidity and mortality, despite current therapies, and the risks of progression towards kidney failure and cardiovascular events increase with the severity and stage of CKD. Compared with patients with advanced kidney disease, who are more likely to progress to dialysis, patients with better preserved estimated glomerular filtration rate (eGFR) have a greater lifetime risk of cardiovascular morbidities such as heart failure, myocardial infarction (M), stroke, or death from cardiovascular causes.
Evidence suggests that overactivation of the mineralocorticoid receptor (MR) leads to inflammation and fibrosis in the heart, kidneys, and vasculature where the MR is extensively expressed that can drive CKD and cardiovascular disease progression. Finerenone is a novel, selective, nonsteroidal MR antagonist (MRA) that blocks MR-mediated sodium reabsorption and MR overactivation and has demonstrated anti-inflammatory and anti-fibrotic effects in the preclinical kidney and cardiovascular disease models.89 The FInerenone in reducing kiDnEy failure and disease prOgression in Diabetic Kidney Disease(FIDELIO-DKD) and FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease(FIGARO-DKD)phase ll trials are complementary due to features such as their similar designs and endpoints. Together, they form the largest cardiorenal outcomes programme in CKD in type 2 diabetes to date. They investigated the efficacy and safety of finerenone, on top of maximum tolerated renin-angiotensin system inhibition, on kid-ney and cardiovascular outcomes in patients with mild-to-severe CKD in type 2 diabetes (Supplementary material online, Figure S1). In FIDELIO-DKD, finerenone significantly reduced the risk of the primary kidney composite outcome and the key secondary cardio-vascular composite outcome in patients with predominantly stage 3-4 CKD with severely increased albuminuria and type 2 diabetes. In FIGARO-DKD, finerenone significantly reduced the primary cardiovascular composite outcome risk in a broader patient population than studied in FIDELIO-DKD(patients with stage 2-4 CKD and moderately increased albuminuria or stage 1-2 CKD with severely increased albuminuria).710
The FIDELIO-DKD trial was designed to detect a treatment effect of finerenone on kidney failure endpoints, whereas the FIGARO-DKD trial aimed to detect an effect on a cardiovascular composite primary endpoint.710 To improve the ability to detect a treatment effect on the kidney failure outcome, patients with a higher urine albumin-to-creatinine ratio (UACR) were preferentially selected in the FIDELIO-DKD trial. To provide a greater kidney failure-free interval to detect a treatment effect on cardiovascular events, in FIGARO-DKD, a population with moderate UACR and a wider eGFR range was selected. Thus, the two trials complemented each other with a slight overlap in the populations studied, and their similar designs and overlapping research sites allowed for the comparison and pooling of their results.
The efficacy and safety of finerenone, however, have not been fully evaluated across the spectrum of CKD in type 2 diabetes. The Fnerenone in chronic kidney disease and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analYsis(FIDELITY) pools these complementary studies with similar designs, assessments, and conduct. The FIDELITY prespecified pooled analysis aimed to provide more robust estimates of finerenone efficacy and safety across the spectrum of patients with CKD and type 2 diabetes, to provide reassurance regarding outcomes in a wide range of patients with a degree of precision that was not possible to obtain by considering the two trials separately.
Methods
Study design
This prespecified pooled efficacy and safety analysis, which was prespecified in a formal statistical analysis plan, combines data from FIDELIO-DKD (NCT02540993) and FIGARO-DKD(NCTO2545049), two-phase III, randomized, double-blind, placebo-controlled, multicentre clinical trials (Table 1 and Supplementary material online, Figure S2). Trial design and study protocol details have been published previously.11 Patients
Eligible patients were adults(aged ≥18years) with type 2 diabetes and CKD treated with a maximum tolerated labelled dose of an angiotensin-converting enzyme inhibitor(ACEi)or angiotensin receptor blocker (ARB).
Chronic kidney disease in FIDELIO-DKD
CKD in FIDELIO-DKD was defined as either:(i) persistent(demonstrated at both the run-in and screening visits, which took place between a minimum of 4 to a maximum of 16 weeks apart), moderately increased albuminuria (UACR≥30-<300mg/g) with an eGFR of ≥25-<60mL/min/1.73 m² and the presence of diabetic retinopathy， or（i） persistent， severely increased albuminuria(UACR≥300<5000mg/g)and an eGFR of ≥25-<75mL/min/1.73 m²2.
Chronic kidney disease in FIGARO-DKD
CKD in FIGARO-DKD was defined as either:(i) persistent, moderately increased albuminuria (UACR >30-<300mg/g) with an eGFR of ≥25-<90mL/min/1.73 m²， or （i） persistent， severely increased albuminuria （UACR ≥300-<5000mg/g）and an eGFR ≥60mL/min/1.73 m². Patients in both trials had to have serum potassium≤4.8mmol/L at both the run-in and screening visits. Other key exclusion criteria included a clinical diagnosis of symptomatic chronic heart failure with reduced ejection fraction (ie., a Class IA recommendation for MRA treatment). Inclusion and exclusion criteria are listed in the Supplementary material online, Appendix.
Procedures
The procedures for the FIDELIO-DKD and FIGARO-DKD studies have been described previously. Briefly, eligible patients were randomized 1:1 to receive oral finerenone(10 or 20mg) or a placebo. Both studies consisted of run-in, screening, double-blind treatment, and safety follow-up periods (Supplementary material online, Figure S2).10 The run-in period required ACEi or ARB therapy to be adjusted to a maximum tolerated labelled dose that did not lead to unacceptable side effects. The study drug was withheld if potassium concentrations exceeded 5.5 mmol/L and restarted when potassium levels fell to <5.0mmol/L. Further details are found in the Supplementary material online, Appendix.
Outcomes
The outcome definitions for FIDELIO-DKD and FIGARO-DKD have been described previously.10 The efficacy outcomes selected for this analysis were either a primary or a secondary outcome or those prespecified in the hierarchical outcomes in the complementary studies. The eff-cacy outcomes of interest for this pooled analysis were a composite cardiovascular outcome of time to cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure(HHF), and a composite kidney outcome of time to the first onset of kidney failure, sustained >57% decrease in eGFR from baseline over ≥4weeks, or renal death. In
the composite kidney outcome, kidney failure was defined as end-stage kidney disease (ESKD) or a sustained decrease in eGFR to<15 mL/min/1.73 m2, and ESKD was defined as the initiation of chronic dialysis(for >90days) or kidney transplantation. Other prespecified outcomes included: a second composite kidney outcome of time to the first occurrence of kidney failure, sustained >40% decrease in eGFR from baseline over >4 weeks, or renal death; time to all-cause mortality; time to all-cause hospitalization; and change in UACR from baseline to Month 4.
The eGFR ≥40% composite kidney outcome was the primary or secondary outcome in the complimentary trials.10 However, a sustained >57% decrease in eGFR(equivalent to doubling of serum creatinine)was selected in FIDELITY because it is a classic outcome in diabetic nephropathy studies.12-14and is a more robust kidney failure surrogate outcome than a ≥40% decrease in eGFR, particularly when initial changes in eGFR occur.415 This outcome was selected before data pooling and analysis. Furthermore, the eGFR>57% outcome was a predefined outcome in the complimentary trials.
In the safety analyses, adverse events were considered treatment-emergent if they started or worsened during study drug intake or up to 3 days after any temporary or permanent interruption. The hyper-kalaemia management procedure has been described previously.
Statistical analyses
Statistical analyses were prespecified exploratory evaluations rather than hypothesis confirming. Statistical tests where P-values are provided were exploratory; therefore, no adjustment for multiplicity was performed.
The full analysis set comprised all randomized patients [except those with critical Good Clinical Practice(GCP)violations, who were prospect-very excluded from all analyses]. Safety analyses were performed in the safety analysis set, defined as all randomized patients without critical GCP violations who took≥1 dose of the study drug. Study outcomes were analysed using stratified Cox proportional hazards models fitted using the stratification factors: study, region (North America, Latin America, Europe, Asia, and others),eGFR category at screening (25-<45,45-<60, and ≥60mLmin/1.73 m), albuminuria category (moderately increased and severely increased) at screening, and a history of cardiovascular dis-ease (present or absent; see Supplementary material online, Appendix, for further details).P-values for the comparison of treatment groups are presented based on a stratified log-rank test Treatment effects are expressed as hazard ratios(HRs) with corresponding 95% confidence intervals(Cls) from the stratified Cox proportional hazards models. Events were counted from randomization up to the end-of-study visit and patients without an event were censored at the date of their last contact with complete information on all components of the respective outcome. The time-to-event analysis reporting included first events only. Events based on a sustained decrease in eGFR were considered in the analysis from randomization up until 5 months after the last eGFR was recorded at a clinic visit. For subgroup analyses, HRs were derived from stratified Cox proportional hazards models, including a treatment sub-group and a subgroup by treatment interaction term as fixed effects.
Cumulative incidences based on Aalen-Johansen accounting for mortality as competing risk and corresponding numbers needed to treat were calculated in 6-month intervals for the composite cardiovascular outcome and the key composite kidney outcome. Cumulative incidences based on Kaplan-Meier were calculated for all-cause mortality. An on-treatment sensitivity analysis was performed for outcomes considering only events occurring up until 30days after study drug cessation in the full analysis set.
The sponsor, Bayer, conducted the statistical analyses, and all authors had access to the data and participated in its interpretation. All analyses were performed using SAS software, version 9.4(SAS Institute, Cary, NC, USA). Additional statistical methods are found in the Supplementary material online, Appendix.
