Finerenone Reduces Albuminuria via Hemodynamic Mechanisms Rather Than Improving Arterial Stiffness: Insights from the FIVE-STAR Trial

Highlight

The FIVE-STAR trial provides critical mechanistic insights into the clinical utility of finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA). The primary findings include:

1. Finerenone significantly reduced the urinary albumin-to-creatinine ratio (UACR) by approximately 29% compared to placebo over 24 weeks.
2. There was no significant impact on arterial stiffness, as measured by the cardio-ankle vascular index (CAVI), suggesting that systemic vascular compliance is not the primary driver of finerenone’s early cardiorenal benefits.
3. The observed early and sustained decline in estimated glomerular filtration rate (eGFR) occurred without an increase in urinary biomarkers of acute tubular injury, supporting a hemodynamic rather than a cytotoxic mechanism.
4. Exploratory proteomic analysis identified nominal changes in only 11 out of 181 circulating proteins, indicating a localized or specific rather than a broad systemic anti-inflammatory effect at the 24-week mark.

Background and Clinical Context

Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) remains a significant global health burden, often leading to end-stage kidney disease and heightened cardiovascular mortality. Overactivation of the mineralocorticoid receptor (MR) is a known driver of inflammation and fibrosis in both the heart and kidneys. Traditional steroidal MRAs, such as spironolactone and eplerenone, have been underutilized in CKD due to the high risk of hyperkalemia and limited evidence in this specific population.

Finerenone, a selective, non-steroidal MRA, has emerged as a cornerstone of therapy following the landmark FIDELIO-DKD and FIGARO-DKD trials, which demonstrated significant reductions in kidney failure progression and cardiovascular events. However, the precise physiological mechanisms—specifically whether finerenone’s benefits are mediated through improvements in systemic arterial stiffness or localized renal hemodynamics—have remained a subject of scientific debate. The FIVE-STAR trial (FInerenone on Vascular stiffnEss and cardiorenal biomarkers in patients with type 2 diabetes and chronic kidney disease) was designed to address this knowledge gap.

Study Design and Methodology

This investigator-initiated, multicenter, prospective, randomized, double-blind, placebo-controlled trial was conducted across 13 clinical sites in Japan. The study enrolled 102 patients with T2D and CKD, defined by an eGFR of 25 to < 90 mL/min/1.73 m2 and a UACR of 30 to < 3500 mg/g Cr.

Participants were randomized to receive either dose-adjusted finerenone (10 mg or 20 mg daily based on eGFR and potassium levels) or a matching placebo for 24 weeks. The primary endpoint was the change in the cardio-ankle vascular index (CAVI) from baseline to week 24. CAVI is a validated measure of arterial stiffness that is independent of blood pressure at the time of measurement, making it a robust tool for assessing vascular health.

Secondary endpoints included proportional changes in UACR and eGFR. Additionally, the researchers performed an exploratory analysis of 181 circulating proteins using the Olink Target 96 Cardiovascular III and Inflammation panels to detect changes in inflammatory and cardiovascular stress markers.

Key Findings: Arterial Stiffness and Albuminuria

Arterial Stiffness (CAVI)

At the conclusion of the 24-week treatment period, the change in CAVI was negligible in both groups. The finerenone group showed a mean change of -0.023 (95% CI, -0.299 to 0.254), while the placebo group showed a change of 0.011 (95% CI, -0.245 to 0.267). The group difference of -0.057 (P = 0.760) was not statistically significant. This suggests that finerenone does not exert a rapid or significant effect on large-artery stiffness in this patient population over a 6-month period.

Renal Outcomes (UACR and eGFR)

In contrast to the vascular findings, finerenone demonstrated a robust and rapid effect on renal biomarkers. Compared with placebo, finerenone led to a 29% reduction in UACR at both week 12 (group ratio 0.706; P = 0.043) and week 24 (group ratio 0.709; P = 0.046). Furthermore, the finerenone group experienced an early decline in eGFR, which stabilized over the 24 weeks. Critically, this eGFR ‘dip’ was not accompanied by increases in urinary biomarkers of tubular injury, such as N-acetyl-beta-D-glucosaminidase (NAG) or beta-2 microglobulin, confirming that the decline represents a reversible hemodynamic shift rather than structural damage.

Proteomic Insights and Mechanistic Plausibility

The exploratory proteomic analysis provided a window into the systemic effects of finerenone. Among the 181 proteins tested, only 11 showed nominal changes. These included proteins associated with cardiovascular remodeling and inflammation. However, the lack of widespread systemic protein modulation, combined with the significant UACR reduction and the eGFR dip, reinforces the hypothesis that finerenone’s immediate clinical benefits in CKD are primarily mediated through the reduction of intraglomerular pressure. By inhibiting MRs in the kidney, finerenone likely modulates the tubuloglomerular feedback mechanism and reduces the hyperfiltration that characterizes diabetic nephropathy.

Expert Commentary

The results of the FIVE-STAR trial are highly relevant for clinicians managing T2D and CKD. The dissociation between arterial stiffness and albuminuria reduction suggests that finerenone’s primary mode of action is distinct from agents that primarily target systemic vascular resistance.

One of the most important takeaways for the clinical community is the validation of the eGFR dip. Similar to the effects seen with SGLT2 inhibitors and ACE inhibitors, this initial decrease in filtration rate is a hallmark of successful nephroprotection. It indicates that the drug is successfully offloading the glomerular basement membrane. The lack of tubular injury markers in FIVE-STAR should reassure physicians that finerenone-induced eGFR changes are hemodynamically driven and do not signify acute kidney injury.

However, the study is not without limitations. The 24-week duration may be too short to observe structural changes in the arterial wall that could eventually manifest as improvements in CAVI. Additionally, the relatively small sample size may have limited the power to detect subtle proteomic shifts. Future research should investigate whether longer-term therapy (e.g., 2-3 years) might eventually lead to systemic vascular benefits.

Conclusion

The FIVE-STAR trial confirms that finerenone is a potent agent for reducing albuminuria in patients with T2D and CKD. While it does not appear to improve arterial stiffness in the short term, its ability to modulate renal hemodynamics and lower intraglomerular pressure is clearly demonstrated. For clinicians, these findings reinforce the role of finerenone as a targeted renal-protective therapy that works alongside other standard-of-care treatments to slow the progression of kidney disease.

Funding and Clinical Registration

This investigator-initiated trial was supported by Bayer Yakuhin, Ltd. The study is registered at ClinicalTrial.gov (NCT05887817) and the Japan Registry of Clinical Trials (jRCTs021230011).

References

1. Tanaka A, Vaduganathan M, et al. Effects of finerenone on arterial stiffness and cardiorenal biomarkers in patients with type 2 diabetes and chronic kidney disease: a randomised placebo-controlled mechanistic trial (FIVE-STAR). Cardiovasc Diabetol. 2025;24(1):454. doi:10.1186/s12933-025-03014-x.
2. Agarwal R, et al. Finerenone in Patients with Chronic Kidney Disease and Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229.
3. Pitt B, et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021;385(24):2252-2263.