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The unified cardiometabolic disease continuum: mechanistic stages of a single pathophysiological process
Luz María Quirino-Vela1, Miguel A Mayoral-Chávez1, Carlos A Matías-Cervantes1,2
1Laboratorio de Bioquímica, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca (UABJO), Oaxaca de Juárez, Oaxaca, Mexico.
Insights
Type 2 diabetes mellitus and related cardiometabolic diseases share risk factors and progress along a unified continuum. Understanding this continuum aids in risk stratification, biomarker discovery, and targeted therapies for better patient outcomes.
Area of Science:
- Cardiovascular Medicine
- Metabolic Diseases
- Nephrology
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 common risk factors.
- These conditions may represent interconnected endpoints within a broader cardiometabolic continuum.
- A unified cardiometabolic disease (UCD) continuum model proposes distinct stages, biomarkers, and therapeutic targets for these interrelated phenotypes.
Purpose of the Study:
- To analyze data supporting a unified cardiometabolic disease (UCD) continuum.
- To identify distinct stages, biomarkers, and therapeutic targets within this continuum.
- To provide a framework for understanding and treating interconnected cardiometabolic conditions.
Main Methods:
- A structured narrative review was conducted using major scientific databases (PubMed/MEDLINE, Scopus, Web of Science, Google Scholar).
- Searches combined mechanistic drivers (e.g., visceral adipose tissue, ceramides, inflammation, gut microbiota) with clinical endpoints.
- Priority was given to translational studies, major outcome trials, and consensus statements published between 2017-2026.
Main Results:
- Evidence supports a mechanistic framework involving visceral adipose tissue dysfunction, ectopic lipid accumulation, inflammation, gut microbiome alterations, and endothelial dysfunction.
- Stage-specific mediators like ceramides, NLRP3, TMAO, and the leptin-adiponectin ratio serve as potential biomarkers.
- Pharmacologic agents such as GLP-1 receptor agonists, SGLT2 inhibitors, and finerenone demonstrate benefits across multiple UCD phenotypes.
Conclusions:
- The unified cardiometabolic disease (UCD) model effectively describes T2DM, ASCVD, MASLD, HFpEF, hypertension, and CKD as stages of a progressive continuum.
- This continuum framework enhances risk stratification, biomarker development, and mechanism-guided therapeutic strategies.
- Future research and clinical trials can be designed to target the continuum rather than isolated endpoints for comprehensive management.
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.
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