Mechanism-based therapeutic strategies in cardiovascular-kidney-metabolic syndrome: integrating biological pathways with evidence from clinical trials
- 1Department of Cardiovascular Science and Metabolic Diseases, Livingstone Center for Prevention and Translational Science
- 2Department of Pathology and Microbiology, School of Medicine and Health Sciences, Mulungushi University
- 3Department of Medicine, Vanderbilt University Medical Center
Abstract
Cardiovascular-kidney-metabolic (CKM) syndrome describes the close relationship between metabolic dysfunction, chronic kidney disease, and cardiovascular disease, which share several biological pathways and frequently progress together. This review examines the mechanisms and clinical trial evidence supporting established and emerging therapies relevant to CKM syndrome. Sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and lipid-lowering therapies have shown cardiovascular, kidney, and metabolic benefits across several high-risk populations. However, most evidence comes from trials enrolling patients with individual conditions, such as type 2 diabetes, chronic kidney disease, heart failure, obesity, or atherosclerotic cardiovascular disease, rather than populations defined by CKM stage or phenotype. Evidence for the added clinical benefit of specific treatment combinations also remains limited. Newer therapies targeting aldosterone synthesis, endothelin signaling, inflammation, incretin pathways, and lipid-related pathways may broaden treatment options. In clinical practice, CKM stage and the predominant clinical phenotype may help identify treatment priorities while accounting for coexisting conditions, safety, treatment burden, cost, and access. This approach may provide a practical basis for selecting therapies across the CKM spectrum, although prospective studies are needed to determine whether phenotype-directed treatment improves clinical outcomes.
Related
- The Connection of Immune Response and cGAS-STING Pathway in Cardiovascular Disease: From Basic Mechanism to Therapeutic Implications
- Residual atherosclerotic cardiovascular disease risk in statin-treated patients: mechanisms, therapeutic strategies, and future directions—a scoping review
- Cancer-Associated Fibroblasts in Perineural Invasion: Biological Roles and Therapeutic Strategies
- Mechanism Analysis of Chronic Inflammation in Polycystic Ovary Syndrome and Targeted Therapeutic Strategies Based on Bioactive Constituents of Traditional Chinese Medicine.
- Acquired Chemoresistance in Colorectal Cancer: Therapy-Induced Signalling Adaptation, Cellular Plasticity and Mechanism-Guided Therapeutic Strategies.
BibTeX
@article{nzobokela2026mechanismbased,
title = {{Mechanism-based therapeutic strategies in cardiovascular-kidney-metabolic syndrome: integrating biological pathways with evidence from clinical trials}},
author = {John Nzobokela and Simweene C. Choolwe and Sepiso K. Masenga},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1987811},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1987811/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanism-based therapeutic strategies in cardiovascular-kidney-metabolic syndrome: integrating biological pathways with evidence from clinical trials
AU - John Nzobokela
AU - Simweene C. Choolwe
AU - Sepiso K. Masenga
PY - 2026
DA - 2026/10/22
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1987811
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1987811/full
AB - Cardiovascular-kidney-metabolic (CKM) syndrome describes the close relationship between metabolic dysfunction, chronic kidney disease, and cardiovascular disease, which share several biological pathways and frequently progress together. This review examines the mechanisms and clinical trial evidence supporting established and emerging therapies relevant to CKM syndrome. Sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and lipid-lowering therapies have shown cardiovascular, kidney, and metabolic benefits across several high-risk populations. However, most evidence comes from trials enrolling patients with individual conditions, such as type 2 diabetes, chronic kidney disease, heart failure, obesity, or atherosclerotic cardiovascular disease, rather than populations defined by CKM stage or phenotype. Evidence for the added clinical benefit of specific treatment combinations also remains limited. Newer therapies targeting aldosterone synthesis, endothelin signaling, inflammation, incretin pathways, and lipid-related pathways may broaden treatment options. In clinical practice, CKM stage and the predominant clinical phenotype may help identify treatment priorities while accounting for coexisting conditions, safety, treatment burden, cost, and access. This approach may provide a practical basis for selecting therapies across the CKM spectrum, although prospective studies are needed to determine whether phenotype-directed treatment improves clinical outcomes.
SN - 1664-2392
ER -