Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease - FIGARO-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
Date Presented:
08/29/2022
Date Published:
11/22/2021
Date Updated:
09/06/2022
Original Posted Date:
08/28/2021
References

Contribution To Literature:

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

The FIGARO-DKD trial showed that finerenone has salutary effects on CV outcomes among patients with T2DM and CKD, who were on a background of maximal RAS blockade therapy, primarily due to a reduction in hospitalization for HF.

Description:

The goal of the trial was to assess the safety and efficacy of finerenone in reducing cardiovascular (CV) 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 = 3,686) or placebo (n = 3,666). Patients with an estimated glomerular filtration rate (eGFR) of 25-60 ml/min/1.73 m2 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: 19,381
  • Total number of enrollees: 7,352
  • Duration of follow-up: 3.4 years
  • Mean patient age: 64.1 years
  • Percentage female: 31%

Inclusion criteria:

  • Age ≥18 years
  • T2DM
  • eGFR between 25 and 90 ml/min/1.73 m2, moderately elevated albuminuria (urine albumin-to-creatinine ratio [UACR] between 30-300 mg/g); or severe albuminuria (UACR 300-5000 mg/g) an eGFR >60
  • Maximal tolerated renin–angiotensin system (RAS) blockers
  • Serum potassium ≤4.8 mmol/L

Exclusion criteria:

  • Heart failure with reduced ejection fraction (HFrEF) with New York Heart Association (NYHA) class II-IV
  • Uncontrolled hypertension

Other salient features/characteristics:

  • Median glycated hemoglobin (HbA1c): 7.7%
  • Mean systolic blood pressure: 136 mm Hg
  • Mean eGFR: 67.8 ml/min/1.73 m2
  • Mean serum potassium: 4.3 mmol/L
  • Diuretic: 48%, statin: 71%, SGLT2 inhibitor: 8%

Principal Findings:

The primary composite outcome of CV death, myocardial infarction (MI), stroke, hospitalization for HF, for finerenone vs. placebo, was 12.4% vs. 14.2% (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.76 -0.98, p = 0.03).

  • CV death: 5.3% vs. 5.8%
  • MI: 2.8% vs. 2.8%
  • Stroke: 2.9% vs. 3.0%
  • Hospitalization for HF: 3.2% vs. 4.4% (HR 0.71, 95% CI 0.56-0.90)

Secondary outcomes for finerenone vs. placebo:

  • Kidney failure (sustained decrease from baseline of ≥40% in GFR, or death from renal cause): 9.5% vs. 10.8% (HR 0.87, 95% CI 0.76-1.01)
  • End-stage kidney disease (ESKD): 0.9% vs. 1.3% (HR 0.64, 95% CI 0.41-0.995)
  • All-cause hospitalizations: 42.7% vs. 43.8%
  • All-cause mortality: 9% vs. 10.1% (HR 0.89, 95% CI 0.77-1.04)
  • Hyperkalemia: 10.8% vs. 5.3%

Impact on HF: 7.8% had HF at baseline. New-onset HF among patients without known HF was significantly reduced with finerenone versus placebo (1.9% vs. 2.8%; HR 0.68, 95% CI 0.50-0.93; p = 0.0162).

Time to hospitalization for HF or CV death: 7.9% vs. 9.6% (p = 0.011). There was no difference between patients with and without HF at baseline (p for interaction = 0.18). Event rates were higher among patients with HF.

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 outcomes among patients with T2DM and CKD, who were on a background of maximal RAS blockade therapy, primarily due to a reduction in hospitalization for HF. There was also a reduction in ESKD. New-onset HF was reduced among patients without HF at baseline. There was a higher risk of hyperkalemia with finerenone. These results extend findings from FIDELIO-DKD and included patients with less severe CKD, including CKD stages 1 and 2 with severe albuminuria. 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 mineralocorticoid receptor antagonist (MRA) with anti-inflammatory and antifibrotic effects. It is felt to have higher potency and less hyperkalemia than steroidal MRAs such as spironolactone and eplerenone. Similar efficacy has been reported with 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 ~8% 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.

Filippatos G, Anker SD, Agarwal R, et al., on behalf of the FIGARO-DKD Investigators. Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses From the FIGARO-DKD Trial. Circulation 2022;145:437-47.

Presented by Dr. Gerasimos Filippatos at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 13, 2021.

Pitt B, Filippatos G, Agarwal R, et al., on behalf of the FIGARO-DKD Investigators. Cardiovascular Events With Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med 2021;385:2252-63.

Presented by Dr. Bertram Pitt at the European Society of Cardiology Virtual Congress, August 28, 2021.

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

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: ACC22, ACC Annual Scientific Session, AHA21, AHA Annual Scientific Sessions, ESC Congress, ESC21, ESC22, Diabetes Mellitus, Type 2, Heart Failure, Glomerular Filtration Rate, Kidney Failure, Chronic, Metabolic Syndrome, Myocardial Infarction, Primary Prevention, Renal Insufficiency, Chronic, Renin-Angiotensin System, Stroke


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