Convergent and complementary cardiorenal protective mechanisms of SGLT2 inhibitors, GLP-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists in diabetic kidney disease within the CKM framework

Diabetic kidney disease (DKD) is a major manifestation of cardiovascular-kidney-metabolic (CKM) syndrome and remains a leading cause of chronic kidney disease, kidney failure, heart failure, atherosclerotic cardiovascular disease, and premature mortality. Over the past decade, sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and the non-steroidal mineralocorticoid receptor antagonist (ns-MRAs), currently represented clinically by finerenone, have transformed the therapeutic landscape of DKD and related CKM phenotypes. Their benefits extend beyond glucose lowering and have been reproduced, to varying degrees, across populations with DKD, heart failure, obesity, and high cardiovascular risk. Although these drug classes act on distinct proximal targets, they appear to converge on several shared downstream mechanisms, including restoration of hemodynamic homeostasis, attenuation of inflammation and oxidative stress, preservation of mitochondrial and cellular metabolic integrity, and suppression of maladaptive fibrosis. At the same time, each class retains mechanistic strengths that may explain their partially distinct clinical profiles, with SGLT2is showing prominent benefits in heart failure and kidney disease progression, GLP-1RAs exerting stronger effects on weight reduction and atherosclerotic cardiovascular risk, and ns-MRAs such as finerenone targeting mineralocorticoid receptor-driven inflammatory and fibrotic injury. In this review, we synthesize current mechanistic and randomized clinical evidence supporting the convergent and complementary cardiorenal-metabolic effects of these three therapeutic pillars. We further discuss the biological rationale for dual- and triple-pathway combination strategies, the emerging role of phenotype-guided treatment selection, persistent residual risk, and unresolved questions regarding sequencing, safety, and implementation. A mechanistically integrated framework may help move DKD care within the broader CKM spectrum from conventional risk-factor management toward precision cardiorenal-metabolic medicine.