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Background and Importance Cardio-renal-metabolic syndrome (CRM) is a multifactorial disorder linking cardiac, renal, and metabolic dysfunction, with high clinical burden and economic impact from hospitalisations, end-stage renal disease, and cardiovascular complications.Aim and Objectives To assess the cost-effectiveness of CRM therapies, focusing on sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and mineralocorticoid receptor antagonists (MRA).Material and Methods A systematic review (SR) was performed in PubMed, according to the PRISMA guidelines, for studies published between 8 August 2020, and 8 August 2025. Two search strategies combined cost-effectiveness terms with diabetes, heart failure (HF), chronic kidney disease (CKD), and CRM. Eligible outcomes included healthcare economic indicators such as the incremental cost-effectiveness ratio (ICER), quality-adjusted life years (QALY), life years gained, direct costs, and hospitalisations.Results The search identified 1920 articles, of which 381 were published in the last 5 years. A total of 57 full texts were assessed, and 17 were ultimately considered relevant. SGLT2i (dapagliflozin, empagliflozin, canagliflozin) produced incremental gains of 0.06-1.22 QALY per patient, with ICERs generally below willingness-to-pay thresholds. Dapagliflozin was cost saving in type 2 diabetes (T2D) in the United Kingdom (UK) and Spain, reducing HF hospitalisations and slowing renal decline; it was also cost-effective in CKD, with increased QALY and sub-threshold ICER in the UK, Germany, and Spain. In non-diabetic CKD in the United States (US), it yielded +2.0 life years and +1.3 QALY with an ICER≈60.000$/QALY (threshold 100.000-150.000$/QALY), while reducing renal replacement therapy. Empagliflozin added to standard therapy in CKD was dominant in Europe (France, UK, and the Netherlands), delaying renal progression and reducing HF hospitalisations and dialysis. GLP-1RA were not cost-effective as first-line therapies for T2D at current US prices. However, semaglutide was cost-effective in selected high-risk contexts (cardiovascular disease, obesity), with an ICER≈136.271$/QALY. MRA, particularly finerenone, reduced cardio-renal events and was cost-effective in patients with CKD and T2D: it was found dominant in the Netherlands and with ICERs below thresholds elsewhere (eg, 8.808£/QALY in England and Wales).Conclusion and Relevance Our analysis confirms that treatments, in the medium to long-term, may reduce costs related to hospitalisations, cardiovascular and renal complications, and loss of quality of life. These findings underscore the need for an integrated therapeutic approach to CRM management.Conflict of Interest No conflict of interest