Combination Kidney-Protective Therapy in Diabetic Kidney Disease: From RAAS Blockade to Multidrug Precision Nephrology

Abstract

Background Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. Although renin–angiotensin–aldosterone system (RAAS) blockade and newer disease-modifying therapies have improved outcomes, substantial residual kidney and cardiovascular risks remain because of the complex and multifactorial pathogenesis of DKD. Summary This review summarizes current and emerging evidence supporting combination kidney-protective therapy in DKD, including RAAS inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, finerenone, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), endothelin receptor antagonists, and aldosterone synthase inhibitors. RAAS inhibitors remain the cornerstone of kidney protection, while SGLT2 inhibitors, finerenone, and GLP-1 RAs provide complementary effects by targeting glomerular hyperfiltration, inflammation, fibrosis, metabolic abnormalities, and cardiovascular risk. Clinical trials and real-world evidence support the additive benefits of combining therapies with distinct mechanisms of action. The integration of these agents has established a multidrug approach centered on the four pillars of kidney protection: RAAS blockade, SGLT2 inhibition, mineralocorticoid receptor antagonism with finerenone, and GLP-1 receptor activation. Emerging therapies targeting endothelin and aldosterone pathways may further enhance individualized treatment strategies. Key Messages Multidrug therapy targeting complementary pathogenic pathways represents the current paradigm for DKD management. Phenotype-guided treatment selection may optimize kidney and cardiovascular protection, minimize residual risk, and advance precision nephrology approaches.