Inhibition of Sympathetic Nervous System activity with SGLT2 Inhibitors: a neglected mechanism of cardiorenal protection in CKM syndrome

Cardiovascular-Kidney-Metabolic (CKM) syndrome encompasses the interconnected progression of cardiovascular disease, chronic kidney disease, obesity, diabetes and metabolic dysfunction. Sympathetic nervous system (SNS) hyperactivity is increasingly recognised as a key driver of CKM progression through its effects on vascular haemodynamics, inflammation, insulin resistance and end-organ damage. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed as glucose-lowering agents, substantial cardiovascular and renal benefits were observed in clinical trials, suggesting additional mechanisms of action. Emerging clinical and preclinical evidence indicates that SGLT2 inhibitors improve autonomic balance and reduce sympathetic activity. Reported effects include reductions in circulating norepinephrine, muscle sympathetic nerve activity, renal and cardiac sympathetic signalling, and improvements in heart rate variability. Mechanistic studies suggest these actions may involve modulation of catecholamine signalling, inflammation, ketone metabolism and parasympathetic activation. Furthermore, SGLT2 inhibitors may provide beneficial hepatic effects, potentially through attenuation of sympathetic overactivity directed towards the liver. This review summarises current evidence supporting SNS modulation as a novel mechanism underlying the cardiorenal and metabolic benefits of SGLT2 inhibitors. Understanding the contribution of sympathoinhibition to organ protection may help refine therapeutic strategies and expand the role of SGLT2 inhibitors across the CKM spectrum.