FIDELIO-DKD

Published

Bakris GL, et al. "Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes". The New England Journal of Medicine. 2020. 383(23):2219-2229.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with type 2 diabetes and chronic kidney disease (CKD) who are already treated with an ACE or ARB, does the addition of a selective mineralocorticoid receptor antagonist reduce the progression of chronic kidney disease?

Bottom Line

Selective mineralocorticoid antagonism reduces progression of chronic kidney disease, and as a secondary outcome, reduces cardiovascular events.

Major Points

Renin-angiotensin-aldosterone system antagonism has been shown to be beneficial in several trials of ACE-inhibitors and angiotensin receptor blockers in heart failure and chronic kidney disease. Aldosterone represents a downstream target of this system. Use of steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone in CKD are limited by hyperkalemia and off-target effects (e.g. gynecomastia, dysmenorrhea, and erectile dysfunction). Non-steroidal MRAs ("ns-MRA", such as finerenone) hold promise for targeting elevated aldosteronism in CKD with less risk of hyperkalemia compared to steroidal MRAs.

Published in 2020, the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) randomized 5,674 adults with diabetic nephropathy to finerenone or placebo. This medication was associated with a significant reduction in the primary endpoint of kidney failure, ↓ in baseline eGFR by ≥40%, or renal mortality (17.8% vs 21.1%; P=0.001; NNT=30). Notably few patients were on SGLT2 inhibitors, which have been shown to improve outcomes in CKD (CREDENCE, DAPA-CKD) and may have attenuated the effects of the treatment.

The related 2021 FIGARO-DKD study trial found that finerenone was associated with fewer CVD events when compared to placebo in a population that was similar to FIDELIO-DKD.

Guidelines

ADA and KDIGO consensus report on diabetes management in CKD (2022, adapted)

• If T2DM, eGFR ≥25 mL/min/1.74m², normal serum K, and albumin/creatinine ratio ≥30 mg/g, on maximum tolerated ACE-i or ARB, recommend addition of a non-steroidal MRA.

Design

• Multicenter, double-blind, parallel-group, randomized, controlled trial
• N=5674
  • Finerenone (n=2833)
  • Placebo (n=2841)
• Setting: 48 countries
• Enrollment: 2015-2018
• Median follow-up: 2.6 years
• Analysis: Intention-to-treat
• Primary outcome: Kidney failure, ↓ in baseline eGFR by ≥40%, or renal mortality

Population

Inclusion Criteria

• Adult aged ≥18 years with T2DM meeting ADA 2010 DM definition
• CKD, defined by 1 of the following:
  • Persistent albuminuria 30 to <300 mg/g, eGFR 25-59 mL/min/1.73 m², and known diabetic retinopathy
  • Persistent albuminuria 300-5000 mg/g and eGFR 25-74 mL/min/1.73 m²
• Maximum dose ACE-inhibitor or/ARB, with run-in details on pg 14 of the supplementary appendix
• Serum potassium ≤4.8 mmol/L
• Not pregnant and on ≥2 contraceptives if child-bearing age

Exclusion Criteria

• Diagnosed with non-diabetic kidney disease
• HgbA1c >12%
• Uncontrolled Hypertension ≥170/110 mm Hg at run-in visit or ≥160/100 mm Hg at screening visit
• Stroke, TIA, or acute coronary syndrome in the prior 30 days
• Chronic heart failure, NYHA class II-VI (indication for MRA)
• Prior or recent kidney transplant
• Addison's disease
• Child-Pugh C liver disease

Baseline Characteristics

• Demographics: Age 66 years, female sex 29.8%, White race 63.3%, Black race 4.7%, Asian race 25.4%
• Mean HbA1c: 7.7%
• Duration of DM: 16.6 years
• Labs: eGFR 44.3, Urinary albumin/creatinine 852 mg/g, serum potassium 4.37 mmol/L
• Medications
  • ACE inhibitor: 34.2 %
  • ARB: 65.7%
  • Anti-hyperglycemics
    • Insulin: 64.1%
    • GLP-1 receptor agonist: 6.9%
    • SGLT2i: 4.6%

Interventions

• After a 4-week run-in period with ACEi/ARB dose maximized as tolerated, participants were randomized to an arm:
  • Finerenone - 20 mg daily for eGFR >60 and 10 mg daily for eGFR 25-60, with increase in dose to 20 mg encouraged after 1 month if K and eGFR remained in acceptable ranges.
  • Placebo

Outcomes

Comparisons are finerenone vs. placebo.

Primary Outcomes

Components of the primary outcome are shown here for simplicity.

Kidney failure, ↓ in baseline eGFR by ≥40%, or renal mortality

Kidney failure was end-stage kidney disease or an eGFR <15 mL/min/1.73 m². Initiation of ≥90 days of HD or kidney transplantation.

17.8% vs 21.1% (HR 0.82; 95% CI 0.73-0.93; P=0.001)

Kidney failure: 7.3% vs. 8.3% (HR 0.87; 0.72-1.05)

ESRD: 4.2% vs. 4.9% (HR 0.86; 0.67-1.10)

eGFR sustained at <15 mL/min/1,73 m²: 5.9% vs. 7.0% (HR 0.82; 0.76-1.01)

↓ in baseline eGFR by ≥40%: 16.9% vs. 20.3% (HR 0.81; 0.72-0.92)

Renal mortality: <0.1% vs. <0.1%

Secondary Outcomes

CV mortality, nonfatal MI, nonfatal stroke, or HF hospitalization

13.0% vs 14.8% (HR 0.86; 95% CI 0.75-0.99; P=0.03)

CV mortality: 4.5% vs. 5.3% (HR 0.86; 0.68-1.08)

Nonfatal MI: 2.5% vs. 3.1% (HR 0.80; 0.57-1.09)

Nonfatal stroke: 3.2% vs. 3.1% (HR 1.03; 0.76-1.38)

HF hospitalization: 4.9% vs. 5.7% (HR 0.86; 0.68-1.08)

All-cause mortality

7.7% vs 8.6% (HR 0.90; 95% CI 0.75-1.07)

Any hospitalization

44.6% vs. 46.5% (HR 0.95; 0.88-1.02)

↓ in baseline eGFR by ≥57%

5.9% vs 8.6% (HR 0.68; 0.55-0.82)

Subgroup Analysis

There was evidence of treatment heterogeneity by baseline BMI, whereby persons without obesity had substantial treatment effect (HR 0.68, 95% CI 0.58-0.81) vs. those with BMI ≥30 (HR 0.98, 95% CI 0.83-1.17). There was also a trend towards treatment heterogeneity by history of CV disease, more treatment effect seen in patients with a history of CVD.

No evidence of treatment effect by age, sex, race, region, baseline potassium, or baseline HbA1c.

Adverse Events

See a full list of adverse events in Table 2 on page 2227.

Serious adverse events

31.9% vs 34.3%

Investigator-reported hyperkalemia

18.3% vs. 9.0%

Acute kidney injury

4.6% vs 4.8%

Criticisms

• Low use of SGLT2 inhibitors known to improve renal and cardiovascular outcomes in CKD.
• Of 13,911 patients screened, only 5734 underwent randomization.
• One site excluded for Good Clinical Practice violations.
• Bayer, study sponsor, was involved in designing, conducting, and analyzing results of the trial.
• It seems that there were bottle errors and some patients actually received some duration of the agent for the opposite arm. The analysis plan was adjusted so that these bottle errors were accounted for, but no additional description about the frequency of these bottle errors were presented. See details in the trial protocol, PDF page 239, protocol page 133.

Funding

Funded by Bayer, the maker of finerenone (brand name Kerendia), who also helped design, conduct, and analyze the trial.