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Finerenone Across Cardiovascular-Kidney-Metabolic Syndrome Stages: Post Hoc Analysis of the FIDELITY Randomized
Kevin Bryan Lo1, John W Ostrominski1, Yasuhiro Hamatani1
1Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Importance:
Cardiovascular-kidney-metabolic (CKM) syndrome reflects the interplay of obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has improved outcomes in type 2 diabetes (T2D) and CKD.
Objective:
To evaluate the efficacy and safety of finerenone across CKM stages, and to examine the effects of finerenone on CKM syndrome progression and regression over time.
Design, Setting, And Participants:
This study is a post hoc pooled analysis of 2 randomized, double-blind, placebo-controlled, phase 3 multinational, multicenter clinical trials (FIDELITY) and was conducted across 48 countries. Patients with T2D and CKD with estimated glomerular filtration rate (eGFR) 25 mL/min/1.73 m2 or higher, serum potassium 4.8 mmol/L or less, and taking maximally tolerated renin angiotensin system inhibitor therapy were included and classified into CKM syndrome stages, using American Heart Association criteria. These data were analyzed from September 2025 and March 2026.
Intervention:
Participants in the pooled trials were randomly assigned to either finerenone or placebo.
Main Outcomes And Measures:
Cardiovascular composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization and a kidney composite outcome of kidney failure, a sustained 57% or more decrease in eGFR from baseline over 4 weeks or more, or death from kidney failure.
Results:
Among 12 990 participants (mean [SD] age, 64.8 [9.5] years; 3932 women [30%] and 9058 men [70%]) in FIDELITY, 3864 were classified as CKM stage 2 (30%), 3275 stage 3 (25%), and 5851 stage 4 (45%). After a median follow-up of 3 years, stage 4 was associated with a higher incidence of cardiovascular events (adjusted hazard ratio [aHR], 1.87; 95% CI, 1.56-2.24) and kidney events (aHR, 1.96; 95% CI, 1.43-2.69) when compared with stage 2. Finerenone consistently reduced cardiovascular (P for interaction = .86) and kidney (P for interaction = .65) events, irrespective of baseline CKM stage. Absolute rate reductions for the composite cardiovascular outcome were -1.1 per 100 person-years for stage 4 and -0.4 per 100 person-years for stage 2. After 3 years, participants randomized to finerenone were more likely to experience CKM syndrome regression (11.4% vs 7.4%; adjusted odds ratio [aOR], 1.66; 95% CI, 1.30-2.13; P < .001) and less likely to experience CKM syndrome progression (aOR, 0.89; 95% CI, 0.79, 1.00; P = .05) vs placebo.
Conclusions And Relevance:
Among patients with T2D and CKD in this study, finerenone reduced risks of cardiovascular and kidney events across CKM stages and led to greater CKM syndrome regression, and lesser CKM syndrome progression, over time.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02540993 and NCT02545049.
Insights
Finerenone, a treatment for type 2 diabetes and chronic kidney disease, reduced cardiovascular and kidney events across all stages of cardiovascular-kidney-metabolic syndrome. It also promoted syndrome regression and slowed progression.
Area of Science:
- Cardiovascular medicine
- Nephrology
- Endocrinology
Background:
- Cardiovascular-kidney-metabolic (CKM) syndrome links obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease.
- Finerenone, a mineralocorticoid receptor antagonist, shows promise in improving outcomes for type 2 diabetes (T2D) and CKD.
Purpose of the Study:
- Evaluate finerenone's efficacy and safety across CKM syndrome stages.
- Examine finerenone's impact on CKM syndrome progression and regression over time.
Main Methods:
- Post hoc pooled analysis of 2 multinational, double-blind, placebo-controlled phase 3 trials (FIDELITY).
- Included patients with T2D and CKD (eGFR ≥25 mL/min/1.73 m²), on maximally tolerated renin-angiotensin system inhibitors.
- Classified participants into CKM syndrome stages and analyzed cardiovascular and kidney composite outcomes.
Main Results:
- Finerenone consistently reduced cardiovascular and kidney events, irrespective of CKM stage.
- Stage 4 CKM was associated with higher cardiovascular and kidney event incidence compared to stage 2.
- Finerenone use led to greater CKM syndrome regression (11.4% vs 7.4%) and less progression (aOR, 0.89) versus placebo.
Conclusions:
- Finerenone effectively reduces cardiovascular and kidney event risks in patients with T2D and CKD across all CKM stages.
- The drug promotes CKM syndrome regression and mitigates progression over time.
- These findings support finerenone's role in managing CKM syndrome.
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