Summary:
In patients with type 2 diabetes mellitus and chronic kidney disease, finerenone (a non-steroidal mineralocorticoid receptor antagonist) administered according to study protocol significantly reduced albuminuria but did not alter arterial stiffness as measured by pulse wave velocity compared to placebo control with standard care, though it was associated with potential hyperkalemia requiring monitoring, with renal benefits attributed to reduction in intraglomerular pressure rather than vascular effects.
| PICO | Description |
|---|---|
| Population | Patients with type 2 diabetes mellitus and chronic kidney disease, representing a high-risk population for both cardiovascular and renal disease progression. |
| Intervention | Finerenone, a non-steroidal selective mineralocorticoid receptor antagonist, administered at protocol-specified doses to assess mechanistic effects on vascular and renal biomarkers. |
| Comparison | Placebo control group receiving standard care without mineralocorticoid receptor antagonism. |
| Outcome | Finerenone significantly and sustainably reduced albuminuria but did not alter arterial stiffness (pulse wave velocity). Benefits are attributed to lowering intraglomerular pressure rather than vascular remodeling. Hyperkalemia remains a monitoring consideration. |
Clinical Context
The combination of type 2 diabetes and chronic kidney disease creates a particularly high-risk phenotype for cardiovascular morbidity and mortality. Mineralocorticoid receptor overactivation contributes to both conditions through mechanisms including inflammation, fibrosis, oxidative stress, and endothelial dysfunction. Finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), demonstrated significant cardiovascular and renal benefits in the FIDELIO-DKD and FIGARO-DKD trials, establishing its role in diabetic kidney disease management.
However, the mechanisms underlying finerenone’s clinical benefits remain incompletely understood. Arterial stiffness, measured by pulse wave velocity, represents both a consequence of and contributor to cardiorenal disease. Increased arterial stiffness promotes left ventricular hypertrophy, impairs coronary perfusion, and damages glomerular capillaries through transmission of pulsatile pressure. If finerenone reduced arterial stiffness, this could partially explain its cardiovascular benefits and suggest a vascular mechanism of action.
The FIVE-STAR trial was designed as a mechanistic study to specifically evaluate whether finerenone’s benefits involve vascular effects on arterial stiffness, or whether its renal and cardiovascular protection operates through other pathways. Understanding these mechanisms has implications for patient selection, monitoring strategies, and potential combination approaches with other vasoactive therapies.
Clinical Pearls
1. Renal Benefits Occur Independent of Vascular Stiffness Changes: The absence of arterial stiffness reduction despite robust albuminuria lowering suggests finerenone’s nephroprotective effects operate through hemodynamic mechanisms (reducing intraglomerular pressure) and/or anti-inflammatory/anti-fibrotic pathways rather than through vascular remodeling. This dissociation is mechanistically informative.
2. Albuminuria Reduction Confirms Mechanism: The significant and sustained albuminuria reduction replicates findings from larger trials and confirms that short-term treatment produces measurable renal effects. Albuminuria serves as both a therapeutic target and a biomarker of treatment response for finerenone.
3. Hyperkalemia Requires Ongoing Vigilance: As with all MRAs, potassium monitoring remains essential when initiating finerenone. The non-steroidal structure reduces but does not eliminate hyperkalemia risk compared to spironolactone or eplerenone. Baseline potassium, eGFR, and concomitant medications affecting potassium must be considered.
4. Mechanistic Studies Complement Outcomes Trials: While FIDELIO and FIGARO established clinical efficacy, mechanistic studies like FIVE-STAR refine understanding of how finerenone works. The lack of arterial stiffness effect suggests that other mechanisms—anti-inflammatory, anti-fibrotic, or hemodynamic—drive its cardiovascular and renal protection.
Practical Application
When prescribing finerenone for patients with T2DM and CKD, recognize that its benefits do not appear to depend on improving arterial stiffness. Patients with established arterial stiffness may still benefit through other mechanisms, and the absence of vascular effects should not discourage use in this population. Monitor albuminuria as a treatment response marker—reduction confirms pharmacodynamic effect.
Implement standard MRA monitoring protocols: check potassium and eGFR before initiation, within 4 weeks of starting, and periodically thereafter. Avoid initiation if potassium exceeds 5.0 mEq/L or eGFR is below threshold. Counsel patients about potassium-rich foods and review interacting medications including ACE inhibitors, ARBs, potassium supplements, and NSAIDs.
For patients with both CKD and significant arterial stiffness, combination with therapies that do improve vascular compliance (such as SGLT2 inhibitors, which have demonstrated arterial stiffness reduction) may provide complementary mechanisms of cardiorenal protection.
Broader Evidence Context
Finerenone now occupies an established position in diabetic kidney disease management alongside SGLT2 inhibitors, with guidelines recommending its addition when albuminuria persists despite ACE inhibitor/ARB and SGLT2 inhibitor therapy. The mechanistic insights from FIVE-STAR add to our understanding from the pivotal trials without changing clinical recommendations.
Other studies have examined arterial stiffness effects of various cardiometabolic therapies. SGLT2 inhibitors have shown more consistent arterial stiffness reduction, possibly through volume and metabolic effects. The differential vascular effects among drug classes may inform rational combination strategies targeting multiple pathophysiologic pathways.
Study Limitations
As a mechanistic study, sample size was designed for biomarker endpoints rather than clinical outcomes. Duration may have been insufficient to detect structural vascular remodeling that occurs over longer timeframes. Pulse wave velocity, while validated, represents one aspect of vascular function; other vascular parameters were not the primary focus. Population was Japanese, and ethnic differences in vascular properties and drug response exist.
Bottom Line
Finerenone significantly reduces albuminuria in patients with type 2 diabetes and chronic kidney disease but does not improve arterial stiffness, suggesting its cardiorenal benefits operate through hemodynamic and anti-fibrotic mechanisms rather than vascular remodeling.
Source: Atsushi Tanaka, 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).” Read article
