Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis

Abstract

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 safety and efficacy of finerenone compared with placebo. Methods and results For this prespecified analysis, two phase III, 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 (CI), 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% CI, 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 tolerated renin–angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease 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 mL/min/1.73m2 they were identified solely on the basis of 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 reduction of both cardiovascular and kidney disease burden.

A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors, Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics

“…Indeed, MRA such as eplerenone and spironolactone reduce the eGFR in the acute phase; however, they also exert a nephroprotective effect on the long-run [ 74 ]. This has also been demonstrated for finerenone [ 75 , 76 , 77 , 78 ].…”

Efficacy and Safety of Finerenone in Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

“…The direct antifibrotic properties of finerenone resulted in reduced myofibroblast and collagen deposition accompanied by a decrease in kidney plasminogen activator inhibitor (PAI)-1 and naked cuticle 2 (NKD2) expression in mouse models of progressive kidney fibrosis (Droebner et al, 2021). Our data showing that the relative risk of a sustained ≥40% decrease in the eGFR was reduced by 15%, ESKD by 20%, and FIDELITY analysis showed the relative risk of a sustained ≥57% decrease in the eGFR was reduced by 30% (Agarwal et al, 2021a). These results indicate that finerenone may have long-term renal benefits for CKD patients.…”

“…However, Randomized Aldactone Evaluation Study (RALES) cautions us about what also might come following the publication of impactful results from controlled trials (Moura-Neto and Ronco, 2021). Therefore, routine potassium monitoring and hyperkalemia management strategies [finerenone treatment interruption and dose reduction or adding other therapies (such as diuretics or potassium binders)] are essential, which will minimize the impact of hyperkalemia and enable sustained clinical use of finerenone (Clase et al, 2020;Agarwal et al, 2021a;Epstein et al, 2021;Moura-Neto and Ronco, 2021). Notably, AEs are not all related to the trial regimen, although our meta-analysis showed a comparable incidence of AEs between the finerenone and placebo groups.…”

“…These studies' results are consistent with the findings of our meta-analysis. It should be noted that screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden (Agarwal et al, 2021a).…”

Perspective on Nonsteroidal Mineralocorticoid Receptor Antagonism in Diabetic Kidney Disease

“…For this pooled analysis population (n = 13,026) with median follow up of 3 years, there was a 14% decrease in the CV outcome and a 23% decrease in a composite kidney disease outcome (time to kidney failure, ≥57% sustained decline in eGFR or kidney related death). 8 As a result of these clinical trials, finerenone received United States Food and Drug Administration (US FDA) approval for reducing CKD progression, CV events, and HF hospitalizations in those with CKD due to T2DM.…”