Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial

Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial (1)

Aldosterone binds to the mineralocorticoid receptor (MR), leading to sodium absorption and potassium excretion, thereby controlling fluid and electrolyte status as well as blood pressure (2,3)

• the dihydropyridine finerenone is a nonsteroidal, selective antagonist of the MR has:
  • showed in preclinical models, more potent anti-inflammatory and antifibrotic effects than steroidal MRAs (4)
  • in patients with T2DM and CKD treated with finerenone
    • reduced albumin-to-creatinine ratio compared to those treated with a RAS blocker and smaller effects on serum potassium levels compared to those treated with spironolactone (5)

The phase 3 Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial was a double-blind, placebo-controlled, randomized (1:1), multicenter trial. Patients (n=5674, >=18 years) diagnosed with type 2 diabetes and CKD receiving an ACE-inhibitor or ARB medication at maximum tolerable dose were included in the study and randomized to finerenone or placebo

• assessed the long-term efficacy and safety of finerenone on kidney and CV oucomes in patients with advanced CKD and T2DM (1)
• primary outcome was a composite of kidney failure defined as end-stage kidney disease (dialysis >=90 days or kidney transplantation) or an eGFR <15mL/min/1.73m², sustained decrease of >=40% of eGFR in >=4 weeks, or renal death
• secondary CV outcome was a composite of CV death, non-fatal MI, non-fatal stroke, or HF hospitalization. Other secondary outcomes were all-cause death, change in UACR from baseline to 4 months and a composite of kidney failure, sustained decrease of >=57% of eGFR from baseline for a minimum of 4 weeks or renal death. Median follow-up was 2.6 years
• study results:
  • incidence of the primary outcome was significantly lower in patients receiving finerenone (17.8%) compared to patients in the placebo group (21.1%). This resulted in an HR of 0.82 (95% CI:0.73-0.93, P=0.001).
  • The number of patients needed to treat (NNT) with finerenone to prevent one primary outcome event was 29 (95% CI: 16-166).
  • Patients treated with finerenone had a 13% lower risk of the composite of CV death, non-fatal MI, nonfatal stroke, or hospitalization due to HF compared to 14.5% of patients receiving placebo (HR 0.86, 95% CI:0.75-0.99, P=0.03).
  • The NNT with finerenone was 42 (95% CI: 22-397) for the secondary CV composite outcome. All-cause death was not different between the finerenone and placebo groups.
  • serious adverse events were well balanced between the two groups (31.9% in the finerenone group vs. 34.3% in the placebo group)
• study authors concluded that patients with T2DM and CKD, who received finerenone had a significant lower risk of a primary kidney event compared to patients treated with placebo
  • also a composite of CV events was reduced by finerenone in these patients when compared to placebo

Finerenone And New Onset Of Atrial Fibrillation Or Flutter In Patients With Chronic Kidney Disease And Type 2 Diabetes

• subanalysis of the FIDELIO-DKD trial, treatment with finerenone in optimally treated patients with T2DM and CKD resulted in a reduction of new-onset atrial fibrillation or flutter compared to placebo (7)
  • risk of kidney or cardiovascular events was reduced irrespective of history of atrial fibrillation or flutter at baseline

Summation of results of FIDELIO-DKD and FIGARO-CKD

An analysis (2 RCTs; n=12,512) found early albuminuria reduction accounted for large proportion of treatment effect (TE) vs CKD progression & modest proportion of TE vs CV (cardiovascular) outcomes (reduction in urine albumin:creatinine ratio mediated 84% & 37% of TE on these outcomes, respectively) (8).

Reference:

• Bakris GL, Agarwal R, Anker SD, et al.Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Eng J Med, 2020, DOI: 10.1056/NEJMoa2025845
• Barrera-Chimal J, Girerd S, Jaisser F.Kidney, et al. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. 2019;96:302-319.
• Currie G, Taylor AHM, Fujita T, et al. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. BMC Nephrol 2016; 17: 127.
• Grune J, Beyhoff N, Smeir E, et al. Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone’s antifibrotic activity. Hypertension 2018; 71:599-608.
• Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 2015; 314:884-94.
• Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel nonsteroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J 2013; 34:2453-63
• Filippatos G, Bakris GL, Pitt B, Agarwal R, Rossing P, Ruilope LM, Butler J, Lam CSP, Kolkhof P, Roberts L, Tasto C, Joseph A, Anker SD; FIDELIO-DKD Investigators. Finerenone Reduces Onset of Atrial Fibrillation in Patients with Chronic Kidney Disease and Type 2 Diabetes. J Am Coll Cardiol. 2021 May 4:S0735-1097(21)04966-4
• Pitt B, Filippatos G, Anker SD, Bakris GL; FIDELIO-DKD and FIGARO-DKD Investigators. Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes : A Mediation Analysis. Ann Intern Med. 2023 Dec 5. doi: 10.7326/M23-1023.