Cardiovascular–Kidney–Metabolic Syndrome and Its Hepatic Dimension: A Narrative Review

Abstract

Metabolic syndrome came to the attention of the scientific community several decades ago, and its definition has undergone multiple changes over time. It is currently defined by the coexistence of hypertension, central obesity, dyslipidemia, and impaired glucose metabolism, with insulin resistance, chronic inflammation, and oxidative stress representing important underlying pathophysiological mechanisms. The latter two processes are major promoters of the onset and progression of atherosclerosis. In parallel, many individuals develop metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD). Growing evidence indicates that MASLD may interact bidirectionally with cardiovascular, renal, and metabolic dysfunction and may contribute to cardiometabolic risk. These observations have prompted proposals for a broader cardio–reno–hepato–metabolic axis. However, MASLD is not currently included in the established cardiovascular-kidney-metabolic (CKM) definition or staging system, and its incorporation remains an evolving conceptual extension. Prediabetes is a reversible condition characterized by abnormal glucose levels that do not meet the diagnostic criteria for diabetes. The American Diabetes Association defines prediabetes as glycated hemoglobin (HbA1c) = 5.7–6.4%, fasting plasma glucose = 100–125 mg/dL, or two-hour plasma glucose during an oral glucose tolerance test = 140–199 mg/dL. This comprehensive review examines traditional and genetic risk determinants, shared pathophysiological mechanisms, diagnostic strategies, clinical manifestations, emerging phenotypes, circulating microRNAs as non-invasive biomarkers, complications, and the principal therapeutic strategies, including diet, exercise, and pharmacotherapy. Particular attention is given to the recent approvals of resmetirom and semaglutide for metabolic dysfunction-associated steatohepatitis and to the expanding roles of sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and non-steroidal mineralocorticoid receptor antagonists. Cardiovascular, renal, metabolic, and hepatic disorders are frequently present in the same patient. Other individuals may develop this high-risk cluster over time. The aim of this article is to define the interplay between different metabolic conditions and to outline the best approach to diagnosis, monitoring, and effective integrated therapy.