The unified cardiometabolic disease continuum: mechanistic stages of a single pathophysiological process

Background: Type 2 diabetes mellitus (T2DM), atherosclerotic cardiovascular disease (ASCVD), heart failure with preserved ejection fraction (HFpEF), metabolic dysfunction-associated steatotic liver disease (MASLD), hypertension, and chronic kidney disease (CKD) share risk factors and may represent endpoints of a pathophysiological cardiometabolic continuum. We analyzed data suggesting these phenotypes arise along a unified cardiometabolic disease (UCD) continuum with distinct stages, biomarkers, and therapeutic targets. Methods: A structured narrative review was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Searches combined terms for mechanistic drivers (visceral adipose tissue, ceramides, lipotoxicity, NF-κB/NLRP3 signaling, gut microbiota, TMAO, adipokines, endothelial dysfunction, epicardial fat, metabolic flexibility) and clinical endpoints. Priority was given to peer-reviewed translational studies, major outcome trials, and consensus statements published between 2017-2026. Results: Current evidence supports a mechanistic framework in which visceral adipose tissue dysfunction and ectopic lipid accumulation, progressing through ceramide-mediated lipotoxicity, NF-κB/NLRP3-driven inflammation, gut microbiome-derived endotoxemia and TMAO, adipokine dysregulation, endothelial dysfunction, epicardial fat-mediated cardiac remodeling, impaired metabolic flexibility, and a cardiorenal amplification loop. Stage-specific mediators (e.g., ceramides, NLRP3, TMAO, leptin-adiponectin ratio) serve as biomarkers. The benefits of GLP-1 receptor agonists, SGLT2 inhibitors, and finerenone across T2DM, ASCVD, HFpEF, MASLD, and CKD reflect pharmacologic modulation of this continuum. Discussion: Data support a UCD model where T2DM, ASCVD, MASLD, HFpEF, hypertension, and CKD are manifestations of a progressive pathophysiological continuum. Framing these conditions as stages of a continuum informs risk stratification, biomarker development, and mechanism-guided therapy, providing a framework for designing trials targeting the continuum rather than individual endpoints.