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

Sep 06, 2022
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bayer AG
Date Presented:
08/29/2022
Date Published:
11/22/2021
Date Updated:
09/06/2022
Original Posted Date:
11/16/2020
References

Contribution To Literature:

Highlighted text has been updated as of September 6, 2022.

The FIDELIO-DKD trial showed that finerenone has salutary effects on CV and renal outcomes among patients with T2DM and CKD, who were on a background of maximal RAS blockade therapy.

Description:

The goal of the trial was to assess the safety and efficacy of finerenone in reducing cardiovascular (CV) and renal events among patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).

Study Design

Eligible patients were randomized in a 1:1 fashion to either finerenone (n = 5,292) or placebo (n = 5,292). Patients with an estimated glomerular filtration rate (eGFR) of 25-60 at the screening visit received an initial dose of 10 mg once daily, and those with an eGFR of ≥60 at the screening visit received an initial dose of 20 mg once daily. An increase in the dose from 10 to 20 mg once daily was encouraged after 1 month, provided the serum potassium level was ≤4.8 mmol/L and the eGFR was stable.

  • Total screened: 13,911
  • Total number of enrollees: 5,674
  • Duration of follow-up: 2.6 years
  • Mean patient age: 66 years
  • Percentage female: 30%

Inclusion criteria:

  • Age ≥18 years
  • T2DM
  • eGFR between 25-60 ml/min/1.73 m2, moderately elevated albuminuria (urinary albumin-to-creatinine ratio [UACR] between 30-300 mg/g), and diabetic retinopathy, OR severe albuminuria (UACR 300-5000 mg/g) and eGFR between 25-75 ml/min/1.73 m2
  • Maximal tolerated renin-angiotensin system (RAS) blockers
  • Potassium ≤4.8 mmol/L

Exclusion criteria:

  • Heart failure (HF) with reduced ejection fraction and New York Heart Association class II-IV
  • Uncontrolled hypertension
  • Glycated hemoglobin (HbA1c) >12%
  • Other kidney disease

Other salient features:

  • Median HbA1c: 7.7%
  • Systolic blood pressure: 138 mm Hg
  • Mean eGFR: 44
  • Serum potassium: 4.3 mmol/L

Principal Findings:

The primary composite outcome (kidney failure, sustained decrease of 40% in the eGFR from baseline, or death from renal causes) for finerenone vs. placebo was 17.8% vs. 21.1% (hazard ratio 0.82, 95% confidence interval 0.73-0.93, p = 0.0014).

  • Kidney failure: 7.3% vs. 8.3%
  • End-stage kidney disease: 4.2% vs. 4.9%

Secondary outcomes for finerenone vs. placebo:

  • CV death, myocardial infarction (MI), stroke, hospitalization for HF (HHF): 13% vs. 14.8% (p = 0.03)
  • CV death: 4.5% vs. 5.3% (p > 0.05)
  • Nonfatal MI: 2.5% vs. 3.1%
  • HHF: 4.9% vs. 5.7%
  • Hyperkalemia: 15.8% vs. 7.8%

Patients with and without CV disease (CVD): Approximately 30% had a history of CVD at baseline. Reduction in CV death, MI, stroke, and HHF was similar for patients with and without CVD (p for interaction = 0.85); rates were higher in patients with a history of CVD.

Effect on atrial fibrillation (AF)/atrial flutter (AFL): New-onset AF or AFL over 2.6 years for finerenone vs. placebo: 3.2% vs. 4.5%, HR 0.71, 95% CI 0.53-0.94; p = 0.016. Baseline AF/AFL was present in 8.1%. No difference was noted for primary or key secondary renal or CV outcomes based on history of AF/AFL; CV events were higher among patients with AF/AFL compared to those without.

FIDELITY pooled analysis (n = 13,171): Included patients from FIDELIO-DKD and FIGARO-DKD.

  • CV death, MI, stroke, hospitalization for HF, for finerenone vs. placebo: 12.7% vs. 14.4% (HR 0.86, 95% CI 0.78-0.95, p = 0.0018)
  • Time to kidney failure, sustained ≥57% decrease in eGFR from baseline, or renal death, for finerenone vs. placebo: 5.5% vs. 7.1% (HR 0.77, 95% CI 0.67-0.88, p = 0.0002)
  • All-cause mortality: 8.5% vs. 9.4% (p = 0.051)
  • All-cause hospitalization: 43.5% vs. 45% (p = 0.087)
  • All-cause mortality: HR 0.89, 95% CI 0.79-1.00 (p = 0.05)
  • CV mortality: HR 0.88, 95% CI 0.76-1.02 (p = 0.09)
  • Sudden cardiac death: HR 0.75, 95% CI 0.57-1.00 (p = 0.05)

Patients with (n = 5,935) and without (n = 7,091) atherosclerotic cardiovascular disease (ASCVD) in FIDELITY: Patients with ASCVD have more comorbidities and a longer duration of diabetes.

  • Primary endpoint for finerenone vs. placebo: 17.2% vs. 20.1% with ASCVD; 8.9% vs. 9.7% without ASCVD (p for interaction = 0.38)
  • CV death or hospitalization for HF: 11.5% vs. 13.9% with ASCVD; 5.6% vs. 6.4% without ASCVD (p for interaction = 0.68)
  • Composite kidney outcome: 4.7% vs. 6.4% with ASCVD; 6.2% vs. 7.8% without ASCVD (p for interaction = 0.33)

Interpretation:

The results of this trial indicate that finerenone has salutary effects on CV and renal outcomes among patients with T2DM and CKD, who were on a background of maximal RAS blockade therapy. There was a higher risk of hyperkalemia with finerenone. There also appeared to be a reduction in incident atrial fibrillation or flutter with finerenone in this patient population. This is hypothesis generating, and will likely need to be further validated. A similar benefit has been reported with eplerenone but not with spironolactone (different patient populations, but all of them are mineralocorticoid receptor antagonists [MRAs]). The pooled FIDELITY analysis confirms a benefit in CV and renal outcomes with finerenone, irrespective of baseline ASCVD history. All-cause mortality was similar. Of note, patients with symptomatic HFrEF were excluded from both trials.

Finerenone is a novel, nonsteroidal, selective MRA with anti-inflammatory and antifibrotic effects. It is thought to have higher potency and less hyperkalemia than steroidal MRAs such as spironolactone and eplerenone. Similar efficacy has been reported with sodium-glucose luminal cotransporter-2 (SGLT2) inhibitors such as dapagliflozin, empagliflozin, canagliflozin, and sotagliflozin among patients with T2DM and CKD. It is unclear whether both therapies could be used together (only ~5% of patients in this trial were on SGLT2 inhibitors at baseline), or if one would be considered first line compared with the other.

References:

Presented by Dr. Gerasimos Filippatos at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 29, 2022.

Presented by Dr. Gerasimos S. Filippatos at the American College of Cardiology Annual Scientific Session (ACC 2022), Washington, DC, April 4, 2022.

Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022;43:474-84.

FIDELITY analysis: Presented by Dr. Gerasimos Filippatos at the European Society of Cardiology Virtual Congress, August 28, 2021.

Filippatos G, Bakris GL, Pitt B, et al., on behalf of the FIDELIO-DKD Investigators. Finerenone Reduces Onset of Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes. J Am Coll Cardiol 2021;78:142-52.

Presented by Dr. Gerasimos Filippatos at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 17, 2021.

Filippatos G, Anker SD, Agarwal R, et al., on behalf of the FIDELIO-DKD Investigators. Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes. Circulation 2020;143:540-52.

Presented by Dr. Gerasimos Filippatos at the American Heart Association Virtual Scientific Sessions, November 15, 2020.

Bakris GL, Agarwal R, Anker SD, et al., on behalf of the FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med 2020;383:2219-29.

Editorial: Ingelfinger JR, Rosen CJ. Finerenone — Halting Relative Hyperaldosteronism in Chronic Kidney Disease. N Engl J Med 2020;383:2285-6.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: ACC22, ACC21, ACC Annual Scientific Session, AHA20, AHA Annual Scientific Sessions, Atherosclerosis, ESC21, ESC22, ESC Congress, Albuminuria, Atrial Fibrillation, Atrial Flutter, Creatinine, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Hyperkalemia, Kidney Failure, Chronic, Metabolic Syndrome, Primary Prevention, Receptors, Mineralocorticoid, Renal Insufficiency, Chronic, Renin-Angiotensin System


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