Cardiovascular-kidney-metabolic (CKM) syndrome describes the complex, bidirectional interplay among cardiovascular, renal, and metabolic dysfunctions, where impairment in one system accelerates decline in the others. This interconnected pathophysiology significantly elevates the risk and progression of heart disease, particularly heart failure, through mechanisms involving insulin resistance, systemic inflammation, neurohormonal activation, and endothelial dysfunction. In this context, therapeutic strategies targeting heart disease must address the multifaceted drivers of CKM. Recent advances highlight the need for an integrated, patient-centered approach that combines lifestyle interventions with pharmacological treatments tailored to individual cardiovascular risk. While foundational therapies such as RAAS inhibitors and statins remain essential, novel agents now offer additional prognostic and quality-of-life benefits. SGLT2 inhibitors have emerged as a cornerstone therapy, improving outcomes in heart failure with both preserved and reduced ejection fraction, independent of glycemic control. GLP-1 receptor agonists and dual GLP-1/GIP agonists like tirzepatide demonstrate cardiometabolic and renal protection, while finerenone shows promise in diabetic kidney disease and several heart failure phenotypes. These therapies not only target glycemic control but also reduce cardiovascular mortality, hospitalizations, and renal decline. Optimizing cardiovascular outcomes in CKM syndrome requires early, multifactorial therapeutic intervention, informed by evolving evidence and a deeper understanding of the heart–kidney–metabolism axis.
