AIMS: Adults with cardiovascular-kidney-metabolic (CKM) syndrome, characterized by interactions among metabolic, chronic kidney disease (CKD) and cardiovascular disease, face a high symptomatic burden, mortality risk and costs. Dapagliflozin has demonstrated significant benefits in adults with type 2 diabetes (T2D), heart failure (HF) and CKD. This modelling study aimed to estimate the clinical events and associated healthcare costs of dapagliflozin in adults with CKM syndrome from the Spanish National Health System (NHS) perspective over 3 years. METHODS AND RESULTS: A cost-offset model compared clinical events and their associated costs of 100,000 adults with CKM syndrome treated with dapagliflozin added to standard of care (SoC) and SoC alone. Clinical event rates were derived from dapagliflozin trials (DECLARE-TIMI 58, DAPA-HF, DAPA-CKD and DELIVER), and costs from national databases and literature. Robustness was assessed through scenario and subgroup analyses. The carbon dioxide (CO2) footprint impact associated with hospitalization for heart failure (HF), urgent HF visits and end-stage renal disease was assessed in an exploratory analysis. Over 3 years, dapagliflozin added to SoC prevented 10,151 clinical events (2,822 cardiovascular; 5,519 renal; 1,810 deaths) and saved €159.11 million per 100,000 adults compared to SoC, mainly by preventing end-stage renal disease (69%; -€110.32 million). Considering drug acquisition cost, the net cost saving was €52.47 million per 100,000 adults, representing a €1.49 return for every euro invested in dapagliflozin. Scenario analyses were consistent with the base case. Subgroup analyses showed greater benefits in adults with multiple comorbidities, especially those with all three conditions. The CO2 footprint reduction was 2,176 tons of CO2 per 100,000 adults. CONCLUSION: Dapagliflozin in adults with CKM syndrome reduced the incidence of clinical events, generating cost savings and improving the sustainability of the Spanish NHS.