Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review)

Cardiovascular‑kidney‑metabolic (CKM) syndrome is an emerging clinical construct that emphasizes the intertwined pathophysiology of cardiovascular disease, chronic kidney disease, and metabolic disorders. Accumulating evidence reveals profound sex‑based differences in the incidence, progression, and outcomes across the spectrum of CKM syndrome. These disparities are rooted in complex interactions between sex hormones and pathophysiological processes such as inflammation, endothelial dysfunction, oxidative stress, and metabolic regulation. Premenopausal women generally exhibit protective cardiovascular and renal profiles due to estrogenic effects, whereas men, influenced by androgens, often experience more severe organ damage and faster disease progression. However, this female advantage is attenuated after menopause, and available clinical data suggest that women may experience poorer outcomes at comparable CKM stages in some cohorts. Furthermore, sex differences extend to clinical manifestations, epidemiologic patterns, and therapeutic responses, influencing the efficacy and tolerance of medications including statins, renin‑angiotensin‑aldosterone system inhibitors, sodium‑glucose cotransporter 2 inhibitors, and insulin. Sex‑related factors, including healthcare access, referral patterns, adherence, and trial representation, may further modify clinical outcomes. The present review synthesizes current knowledge on sex‑specific mechanisms of CKM pathogenesis, clinical trajectories, and pharmacologic responses, and highlights gaps between basic and clinical research. Future directions include designing sex‑stratified clinical trials, developing sex‑sensitive guidelines, and leveraging translational research to inform precision medicine. Addressing sex‑related differences in CKM syndrome represents a crucial step toward equitable and personalized care in cardio‑renal‑metabolic medicine.