Finerenone Across Cardiovascular-Kidney-Metabolic Syndrome Stages

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.