Cardiovascular-kidney-metabolic (CKM) syndrome, formally defined by the American Heart Association in 2023, affects approximately 90% of US adults, who meet criteria for stage 1 or higher. The rapid convergence of multiple drug classes on CKM pathways-SGLT2 inhibitors, finerenone, GLP-1 receptor agonists, ARNI, and interleukin-directed therapies-has created an urgent need for pharmacologically grounded frameworks that guide drug selection, interpret biomarker responses, and monitor target engagement across interconnected organ systems. This review proposes a three-dimensional biomarker-guided approach to precision pharmacotherapy in CKM syndrome. In the organ-specific dimension, we map key biomarkers to their corresponding drug targets and elucidate the molecular mechanisms underlying drug-biomarker interactions: SGLT2 inhibitors attenuate myocardial injury through metabolic substrate shifting toward ketone body utilization and, based on preclinical evidence, NHE1 inhibition; neprilysin selectivity of sacubitril/valsartan explains the differential natriuretic peptide response; and tubuloglomerular feedback mediates the renoprotective hemodynamic effects of SGLT2 inhibitors. In the pathway-specific dimension, we identify cross-system biomarkers-hs-CRP, IL-6, galectin-3, GDF-15, and FGF21-that reveal shared druggable targets spanning the IL-1β/NLRP3 inflammasome axis (canakinumab, colchicine), IL-6 trans-signaling (ziltivekimab), and FGF21/β-klotho metabolic signaling. In the temporal dimension, we demonstrate how serial biomarker trajectories serve as pharmacodynamic readouts that distinguish therapeutic drug effects from disease progression, including the initial eGFR dip with SGLT2 inhibitors and natriuretic peptide changes during combination therapy. Central to this framework is the concept of "pharmacological phenotyping"-using multi-biomarker panels to define drug-responsive pathophysiological states that directly inform therapeutic selection, analogous to companion diagnostics in oncology. We further present a comprehensive drug-biomarker interaction matrix with pharmacological rationale and analyze the emerging drug development pipeline, including RNA-based Lp(a) therapeutics, FGF21 analogues, galectin-3 inhibitors, and in vivo CAR-T anti-fibrotic approaches. This framework provides a practical roadmap for biomarker-guided precision pharmacotherapy in CKM syndrome.
