FIVE-STAR: Mechanistic effects of finerenone in T2D plus CKD unravelled

A mechanistic study into the effects of finerenone indicated that the clinical benefits of this agent in patients with type 2 diabetes and chronic kidney disease (CKD) may be mainly derived from reducing intraglomerular pressure and not from changing vascular stiffness.

The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone has been demonstrated to decrease the risk for cardiovascular and kidney events in patients with type 2 diabetes and various degrees of CKD [1,2]. However, the underlying mechanisms responsible for the cardiorenal benefits of finerenone are not clearly determined. The FIVE-STAR study (NCT05887817) randomised 102 patients 1:1 to finerenone or placebo and evaluated the change in cardio-ankle vascular index (CAVI) from baseline to week 24, as the primary endpoint [3].

There was no significant difference in CAVI response between participants on finerenone and those on placebo (Δ-0.057; 95% CI -0.43 to +0.31; P=0.76), indicating that arterial stiffness is not a substantial factor explaining the cardiorenal effects of finerenone. “The pre-specified subgroup analysis suggested that patients with younger age (<70 years), those with lower glycosylated haemoglobin (HbA1c<6.8%), and patients with higher left ventricular ejection fraction (≥60%) were more likely to have an effect on CAVI following finerenone therapy,” said Prof. Atsushi Tanaka (Saga University, Japan). “The change in urine albumin-creatinine ratio (UACR), which was a key secondary endpoint of the trial, appeared to be in favour of the finerenone arm (OR 2.59; 95% CI 1.12–5.99; P=0.026). We also noticed reductions in systolic blood pressure and eGFR, and an increase in potassium in participants who were treated with finerenone.” The dip in eGFR was not associated with evidence of kidney injury, as was evaluated by several biomarkers.

Thus, the neutral vascular effects observed in the FIVE-STAR study may explain the fact that finerenone was not associated with a reduced risk for atherosclerotic cardiovascular disease in previous trials [1,2]. Instead, the changes in UACR may be responsible for the observed cardiorenal benefits that are seen with finerenone therapy in patients with type 2 diabetes and CKD. “This is in line with a recent study that showed that UACR was accountable for cardiorenal benefits with finerenone treatment [4],” expressed Prof. Tanaka.

1. Bakris GL, et al. N Engl J Med 2020;383:2219-2229.
2. Pitt B, et al. N Engl J Med 2021;385:2252-2253.
3. Tanaka A, et al. Finerenone on arterial stiffness and cardiorenal biomarkers in patients with type 2 diabetes and chronic kidney disease: the FIVE-STAR trial. Late-breaking clinical trials in chronic heart failure, Heart Failure 2025, 17–20 May, Belgrade, Serbia.
4. Agarwal R, et al. Ann Intern Med. 2023;176:1606-1616.

Medical writing support was provided by Robert van den Heuvel.
Copyright ©2025 Medicom Medical Publishers



Posted on 22 May 202517 July 2025