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

  • Authors:
    • Yanqin Fan
    • Hongtu Hu
    • Jing Cheng
  • View Affiliations / Copyright

    Affiliations: Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
    Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 202
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    Published online on: May 27, 2026
       https://doi.org/10.3892/ijmm.2026.5873
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Abstract

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.
View Figures

Figure 1

Sex differences in endocrine
regulation, immune response, inflammation, and endothelial
function. The sex-specific differences in endocrine regulation,
immune response, inflammation, and endothelial function are
illustrated. Female individuals exhibit protective effects
predominantly mediated by estrogens, which contrast with the
pro-inflammatory effects associated with testosterone in males.
Dyslipidemia is more prevalent in males, contributing to
cardiovascular risk. In terms of immune response and inflammation,
females demonstrate greater T-cell activity along with higher
levels of interferons and immunoglobulins, indicative of a more
robust adaptive immune response. Conversely, males exhibit a
heightened inflammatory profile. Regarding endothelial function,
females maintain more preserved endothelial function, whereas males
experience greater endothelial injury accompanied by elevated
levels of inflammatory markers. These differences highlight the
influence of sex hormones on the pathophysiology of inflammatory
and vascular conditions. ET-1, endothelin-1; RAAS,
renin-angiotensin-aldosterone system; GPER1, G protein-coupled
estrogen receptor 1; PCSK9, proprotein convertase subtilisin/kexin
type 9; ROS, reactive oxygen species.

Figure 2

Sex differences in cardiovascular and
metabolic disease prevalence and outcomes. The sex-specific
differences in the prevalence and clinical manifestations of
cardiovascular and metabolic diseases are highlighted, focusing on
cardiac, renal and metabolic outcomes. Men tend to develop earlier
coronary artery disease, more visceral adiposity, and greater
microvascular diabetic complications, whereas women more commonly
develop heart failure with preserved ejection fraction,
postmenopausal metabolic deterioration, and disproportionate
cardiovascular risk once diabetes is established. These patterns
should be interpreted together with sex-related factors such as
access to prevention, referral timing, and treatment intensity.
Overall, these findings illustrate how biological sex and
healthcare-related factors jointly shape CKM outcomes across the
life course. CKM, cardiovascular-kidney-metabolic; CVD,
cardiovascular disease; CKD, chronic kidney disease.

Figure 3

Sex differences in pharmacological
treatment response and drug sensitivity. Sex-related differences in
pharmacological treatment response and drug sensitivity in CKM
syndrome are summarized. Current evidence supports the
effectiveness of statins, RAAS inhibitors, SGLT2 inhibitors, GLP-1
receptor agonists, and insulin-based therapies in eligible patients
of both sexes. However, sex-related differences in prescribing
patterns, tolerability, pharmacokinetics, and adverse-event
profiles have been reported, including ACEI-related cough, SGLT2
inhibitor-associated genital mycotic infection, and
treatment-initiation barriers for insulin. Because robust sex
interactions have not been consistently demonstrated for several
drug classes, these observations should be viewed as signals for
individualized monitoring rather than as grounds for withholding
guideline-directed therapy. CKM, cardiovascular-kidney-metabolic;
RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium-glucose
cotransporter 2; GLP-1, glucagon-like peptide-1; ACEI,
angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor
blocker; MRA, mineralocorticoid receptor agonist; ARNI, angiotensin
receptor-neprilysin inhibitor; HFpEF, heart failure with preserved
ejection fraction; SGLT2i, SGLT2 inhibitor; GLP-1RA, GLP-1 receptor
agonist; HOMA-IR, homeostatic model assessment of insulin
resistance; CYP, cytochrome 450 enzymes; GPER1, G protein-coupled
estrogen receptor 1; ET-1, endothelin-1; PD, pharmacodynamic; ACE
I/D, ACE insertion/deletion; PCSK9, proprotein convertase
subtilisin/kexin type 9; LDL, low-density lipoprotein.
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Copy and paste a formatted citation
Spandidos Publications style
Fan Y, Hu H and Cheng J: Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review). Int J Mol Med 58: 202, 2026.
APA
Fan, Y., Hu, H., & Cheng, J. (2026). Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review). International Journal of Molecular Medicine, 58, 202. https://doi.org/10.3892/ijmm.2026.5873
MLA
Fan, Y., Hu, H., Cheng, J."Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review)". International Journal of Molecular Medicine 58.1 (2026): 202.
Chicago
Fan, Y., Hu, H., Cheng, J."Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review)". International Journal of Molecular Medicine 58, no. 1 (2026): 202. https://doi.org/10.3892/ijmm.2026.5873
Copy and paste a formatted citation
x
Spandidos Publications style
Fan Y, Hu H and Cheng J: Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review). Int J Mol Med 58: 202, 2026.
APA
Fan, Y., Hu, H., & Cheng, J. (2026). Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review). International Journal of Molecular Medicine, 58, 202. https://doi.org/10.3892/ijmm.2026.5873
MLA
Fan, Y., Hu, H., Cheng, J."Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review)". International Journal of Molecular Medicine 58.1 (2026): 202.
Chicago
Fan, Y., Hu, H., Cheng, J."Sex differences in cardiovascular‑kidney‑metabolic syndrome: From pathogenesis to treatment response (Review)". International Journal of Molecular Medicine 58, no. 1 (2026): 202. https://doi.org/10.3892/ijmm.2026.5873
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