FIDELIO-DKD
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, with agents antagonizing aldosterone shown to be beneficial in heart failure patients. Use of existing 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 hold promise for targeting elevated aldosteronism in CKD with less risk of hyperkalemia compared to steroidal MRAs.
The FIDELIO-DKD study was the first phase 3 trial showing that selective, non-steroidal MR antagonism reduces the progression of kidney disease in diabetic CKD. A key secondary outcome was the risk of cardiovascular endpoints, with reduced risk in the finerenone group. The Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial, a study specifically investigating cardiovascular outcomes, is ongoing. 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.
Guidelines
As of April 2020, no guidelines have been published that reflect the results of this trial.
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[1]
- 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[2]
- 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
- Mean age: 66 years
- Female sex: 29.8%
- Race:
- White: 63.3%
- Black: 4.7%
- Asian: 25.4%
- Mean HbA1c: 7.7%
- Duration of DM: 16.6 years
- Mean eGFR: 44.3
- Median 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
- participants underwent 4-week run-in period with ACEi/ARB dose maximized as tolerated.
- Randomized 1:1 to finerenone vs placebo.
- finerenone dose started at 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.
- trial visits at month 1, month 4, then every 4 months
Outcomes
Comparisons are finerenone vs. placebo.
Primary Outcomes
- 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)
Secondary Outcomes
- Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke,or hospitalization for heart failure
- 13.0% vs 14.8% (HR 0.86; 95% CI 0.75-0.99; P=0.03)
- Death from any cause
- 7.7% vs 8.6% (HR 0.90; 95% CI 0.75-1.07; P=0.02)
Subgroup Analysis
There was evidence of treatment heterogeneity by baseline BMI. Participants with baseline BMI <30 kg/m2 were found to have a substantial treatment effect (HR 0.68, 95% CI 0.58-0.81) vs those with BMI >/= 30 (HR 0.98, 95% CI 0.83-0.1.17). There was also a trend towards treatment heterogeneity by history fo 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
- Serious adverse events
- 31.9% vs 34.3%
- Investigator-reported hyperkalemia
- 11.8% vs 4.8%
- 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.[3]
Funding
Funded by Bayer, the maker of finererone, who also helped design, conduct, and analyze the trial.