Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes.

N Eng J Med. 2020;383:2219-2229.

Background
• Management guidelines for chronic kidney disease (CKD) in individuals with type 2 diabetes include controlling
hypertension, and hyperglycemia, along with using treatments that affect the renin-angiotensin system (RAS), like ACE
inhibitors or ARBs.1,2
• Previous studies suggest that overactivation of the mineralocorticoid receptor may lead to inflammation and fibrosis,
resulting in progressive cardiovascular and kidney dysfunction.1,3
• Finerenone, a nonsteroidal mineralocorticoid receptor antagonist shown (MRA), was to delay the progression of kidney
and cardiovascular issues in preclinical models.1,3
• Despite available treatments diabetic kidney disease patients still face a risk of progressing to end-stage renal disease. 1
Objective
• This trial aimed to determine if finerenone slows the progression of CKD and reduces cardiovascular risks in patients
with advanced CKD and type 2 diabetes.
Study Design
• Randomized, double-blinded, placebo-controlled, parallel-group, multicenter, phase 3 study trial.
• Following a 4 to 16-week run-in period and up to 2 weeks screening period, patients from 650 study centers in 48
countries were stratified by geographic region, eGFR category, and albuminuria category and then randomized in a 1:1
ratio: 1. Finerenone starting at 10mg/day or 20mg/day oral dose depending on (eGFR) during the screening visit.
 Finerenone 10 mg, if eGFR at screening is 25 to < 60/ml/min1.73m2
 Finerenone 20 mg, if eGFR at screening is ≥ 60/ml/min1.73m2
2. Control - Placebo
Inclusion Criteria Exclusion Criteria
- Men or women ≥ 18 - Non-diabetic renal disease
- T2DM and CKD - Uncontrolled hypertension: ≥170/110 mmHg at
- Maximal tolerated dose of ACEI run-in visit or ≥160/100 mmHg at screening visit
or ARB for at least 4 weeks. - Patients with chronic heart failure with reduced
- Serum potassium ≤4.8 mmol/L. ejection fraction (HFrEF)
- Moderate Albuminuria (ACR of 30 - ACS, Stroke/TIA in the last 30 days prior to
to < 300) and eGFR of 25 to < screening
60/ml/min1.73m2 + diabetic - Dialysis for acute renal failure within 12 weeks
retinopathy of run-in visit
- or Severe Albuminuria; ACR of - Scheduled kidney transplant within the next 12
300 to 5000, and eGFR of 25 to < months
75/ml/min1.73m2 - HbA1c > 12%.

Outcomes
• Primary: A decrease of at least 40% in eGFR over 4 weeks from baseline, End-Stage kidney disease, kidney
failure, or death from renal causes.
• Key Secondary: Cardiovascular mortality, acute myocardial infarction, nonfatal stroke, or hospitalization due
to heart failure.
• Other secondary kidney outcomes: Death from any cause, hospitalization for any cause, and composite
kidney failure, a sustained decrease of at least 57 % in the eGFR from baseline maintained for at least 4 weeks,
(secondary composite kidney outcome).
Statistics
• Calculating a sample size of 1068 participants would provide 90% effective power to detect a 20% risk
reduction in the primary outcome when treated with finerenone compared to placebo.
• The study utilized a weighted Bonferroni-Holm procedure to account for multiple comparisons between the
primary and secondary outcomes.
• Stratified Log-rank tests were used for comparison between finerenone and placebo and Cox proportional
hazards model was used for relative risk and 95% CI calculations
• The analyses were conducted on the basis of intention to treat.
Results

• 650 sites enrolled patients: mean age 66 years, 70.2% male, 63.3% White.
• 13,911 patients were screened, 5734 were randomized, 2866 were assigned to finerenone, and 2868 were assigned to
placebo from September 2015 through June 2018.
 Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes.
N Eng J Med. 2020;383:2219-2229.

• 60 patients were dropped due to critical good clinical practice violations leaving 5674 patients in the full analysis
set.
• 29.0% of patients in the finerenone group and 28.2% in the placebo group discontinued the trial regimen.
• Mean finerenone dose =15.1 mg and mean placebo dose =16.5 mg, adherence 92.1% in the finerenone group, and
92.6% in the placebo group.
• After a median follow-up of 2.6 years, finerenone demonstrated substantial advantages in both primary and
secondary outcomes, consistently resulting in lower incidence rates for these outcomes compared to the placebo.
Finerenone Placebo Hazard Ratio p-value NNT
n = 2833 n = 2841 (95% CI)
Events(%) Events(%)
Primary composite 504 (17.8%) 600 (21.1%) 0.82 (0.73-0.93) 0.001 29
outcomes
Key secondary 367 (13.0%) 420 (14.8%) 0.86 (0.75-0.99) 0.03 42
composite outcomes
Other secondary 252 (8.9%) 326 (11.5%) 0.76 (0.65 – 0.90) - -
kidney outcomes

Discussion/Conclusion:
• Results of this trial are restricted to patients already taking a RAS blocker either ACEI or ARB for at least 4 weeks
prior to the screening visit.
• Finerenone, when combined with a single RAS blocker, resulted in a lower incidence of primary and secondary
outcomes, NNT=29 and 42 (respectively).
• No fatal hyperkalemia events were reported, and finerenone was well-tolerated with only minor effects on blood
pressure overall.
Strengths
• The study demonstrated fewer severe adverse effects when an MRA like finerenone was combined with a RAS
blocker, as opposed to dual RAS therapy.
• The inclusion of a run-in period in the finerenone trial allowed for the optimization of background treatments,
ensuring that patients received standardized care and enhancing the reliability of the study’s outcomes.
Weaknesses
• This study's results are limited to patients with type 2 diabetes-related advanced CKD, excluding non albuminureic
CKD patients, less advanced CKD, etc.
• Most participants were white, with only 4.7% identifying as black, which limits the study's generalizability and
external validity.
Clinical Implications
The results of the FIDELIO-DKD trial indicate that the addition of finerenone, along with an RAS blocker, for patients with
chronic kidney disease and type 2 diabetes can lead to a significant reduction in the risk of CKD progression, kidney failure,
and cardiovascular events.1 In the FIGARO-DKD trial, finerenone showed additional success in reducing the occurrence of
new-onset heart failure and enhancing heart failure outcomes in patients with both CKD and type 2 diabetes. 4 The KDIGO
2022 guideline for Diabetes Management in Chronic Kidney Disease recommends the use of MRAs like finerenone,
underlining the clinical significance of finerenone’s ability to slow the progression of both kidney and cardiovascular
dysfunction in patients with type 2 diabetes and CKD.5
References
1. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2
diabetes. N Engl J Med. 2020;383(23):2219-2229. doi:10.1056/nejmoa2025845
2. Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes,
2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for
the Study of Diabetes (EASD) [published correction appears in Diabetes Care. 2020 Jul;43(7):1670].
Diabetes Care. 2020;43(2):487-493. doi:10.2337/dci19-0066
3. Grune J, Beyhoff N, Smeir E, et al. Selective Mineralocorticoid Receptor Cofactor Modulation as
Molecular Basis for Finerenone's Antifibrotic Activity. Hypertension. 2018;71(4):599-608.
doi:10.1161/HYPERTENSIONAHA.117.10360
4. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular Events with Finerenone in Kidney Disease and Type
2 Diabetes. N Engl J Med. 2021;385(24):2252-2263. doi:10.1056/NEJMoa2110956
5. Kidney Disease: Improving Global Outcomes (KDIGO) Work Group. KDIGO 2022 Clinical Practice
Guideline for Diabetes Management in Chronic Kidney Disease. International Society of Nephrology;
2022. 102(5S):S1-S127. Accessed October 27, 2023. https://kdigo.org/guidelines/diabetes-ckd/