Finerenone and SGLT2 Inhibitors in Cardiorenal Disease: A Phenotype-Based Approach to Nephroprotection

Background/Objectives: Patients with chronic kidney disease (CKD), although treated with optimal renin–angiotensin–aldosterone system (RAAS) blockade, remain at substantial residual risk of disease progression and cardiovascular events. The recent arrival of sodium-glucose cotransporter-2 (SGLT2) inhibitors, and non-steroidal mineralocorticoid receptor antagonist finerenone, has expanded the therapeutic options with complementary mechanisms of action. In order to optimize treatment, this work proposes moving beyond a “one-size-fits-all” approach, toward a framework tailored to individual characteristics, disease drivers, and cardiovascular risk. Methods: A narrative review of pivotal clinical trials on SGLT2 inhibitors and finerenone, including mechanistic data and novel biomarkers, was conducted. Integrating evidence on combination therapy (CONFIDENCE trial) and kidney damage markers, a therapeutic algorithms and safety considerations were developed in accordance with the latest Kidney Disease: Improving Global Outcomes (KDIGO) 2024 and Italian SNLG/ISS guidelines. Results: SGLT2 inhibitors are established as a key component of chronic kidney disease treatment, regardless of diabetes status. Finerenone, added to RAAS blockade, provides significant renal and cardiovascular benefits in patients with diabetes, with recent trials suggesting similar benefits in non-diabetic populations. Given their complementary mechanisms and synergistic albuminuria reduction (CONFIDENCE trial), and considering the large compatibility of safety profiles, a phenotype-based procedure was proposed, integrating traditional and emerging biomarkers, in order to guide when to prioritize SGLT2, when to add finerenone, and when to initiate early combination therapy. Traditional criteria define the phenotype and treatment eligibility, while emerging biomarkers may help refine residual fibrotic risk within each phenotype and thereby orient the therapeutic decision. Conclusions: SGLT2 inhibitors and finerenone are complementary treatments for CKD, and a phenotype-based approach can be used to guides treatment selection and sequencing. This framework supports SGLT2 inhibitors as foundational therapy, with finerenone or early combination therapy for patients at higher residual risk, personalizing cardiorenal care.