Exercise as a Cornerstone Therapy for Cardiovascular-Kidney-Metabolic Syndrome: A Stage-Informed, Mechanistic, and...

Cardiovascular-kidney-metabolic (CKM) syndrome reflects convergent vascular, renal, hepatic, and skeletal muscle pathways that are modifiable with exercise. Clinical application remains fragmented without a stage-informed framework.

This review provides a stage-informed, mechanistic, and pragmatic framework for CKM exercise prescription. Metabolic dysfunction-associated steatotic liver disease is positioned as a central driver, integrating exercise with contemporary pharmacotherapy and equitable real-world delivery.

Synthesizing evidence from 2022 onward, we standardize organ-system specific outcomes and safety targets for endothelial function, autonomic balance, skeletal muscle oxidative capacity, systemic inflammation, hepatic steatosis, and cardiorenal function. Frequency-intensity-time-type-based prescriptions are detailed for CKM stages 0-4. Modalities are compared by physiologic targets and pragmatic attributes. Implementation strategies pair structured training with sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and nutritional support for metabolic dysfunction-associated steatotic liver disease. We outline practical monitoring pathways, translating heart-rate reserve or oxygen-uptake reserve to perceived exertion, when formal testing is unavailable.

Across CKM stages, multimodal exercise that combines moderate-intensity continuous training, high-intensity interval training, and resistance training produces reproducible improvements in VO₂ peak, endothelial function, hepatic steatosis, blood pressure, and functional status when dosed to minimal effective thresholds and tracked with harmonized outcomes. Embedding exercise within guideline-directed therapy, nutritional support, equity-aware delivery, and scalable monitoring is recommended for maximal clinical impact. Future trials should prioritize phenotype-guided dosing and unified endpoint sets.