Systolic blood pressure and albuminuria reduction mediate cardiovascular benefits of finerenone in T2 diabetes and CKD

Abstract Background and Hypothesis Finerenone reduces cardiovascular events in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The cardiovascular benefit emerges within months, before measurable kidney protection, but the early pathways carrying it are not comprehensively quantified. We hypothesized that early reductions in urine albumin-to-creatinine ratio (UACR) and systolic blood pressure (SBP) jointly mediate a substantial proportion of finerenone’s long-term cardiovascular benefit, whereas changes in body weight and serum potassium do not. Methods We performed causal mediation analysis using individual patient data from FIDELITY (pooled FIDELIO-DKD and FIGARO-DKD; n = 12,143). Mediators were change from baseline to month 4 in log urine albumin-to-creatinine ratio (UACR), systolic blood pressure (SBP), body weight, and serum potassium. The outcome was time from month 4 to first cardiovascular event (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization). Outcome models used parametric accelerated failure time regression with Weibull distribution. Joint mediation by UACR and SBP was estimated by bootstrapping. Results At month 4, finerenone reduced UACR by 32.2% (95% CI 30.3 to 34.2), SBP by 3.6 mmHg (3.1 to 4.1), and body weight by 0.23 kg (0.13 to 0.32), and increased serum potassium by 0.19 mEq/L (0.17 to 0.20). Although all four biomarkers changed significantly, only UACR and SBP mediated cardiovascular outcomes: UACR mediated 39% (95% CI 7 to 71) and SBP mediated 21% (3 to 40); body weight and potassium did not. Jointly, UACR and SBP mediated 50% (95% CI 21 to 100) of the cardiovascular benefit. Conclusions In T2D and CKD, early reductions in UACR and SBP jointly account for half of finerenone’s long-term cardiovascular benefit. Body weight and potassium changes do not mediate the benefit, supporting UACR and SBP as complementary indicators of cardiovascular efficacy.