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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Association of Frailty Status with Staging and Mortality Risk of Cardiovascular-Kidney-Metabolic Syndrome in Middle-Aged and Older Populations: Insights from the 1999–2018 National Health and Nutrition Examination Survey

by
Zhenkun Yang
1,†,
Shuang Wu
2,3,†,
Yuanjie Li
4,
Hongyu Liu
5,6,
Manlin Zhao
5,7,
Yang Xu
8,
Yunyu Chen
9,10,11,12,
Yang Chen
5,13,* and
Gregory Y. H. Lip
5,14,15,*
1
Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China
2
National Center for Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
3
Department of Emergency Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
4
Tianjin Research Institute of Anesthesiology, Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
5
Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, Liverpool Heart and Chest Hospital, Liverpool L14 3PE, UK
6
Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
7
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Engineering Research Center of Medical Devices for Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing 100029, China
8
Department of Cardiology, Tianjin Medical University General Hospital, Tianjin 300052, China
9
Department of Medical Research, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 407219, Taiwan
10
Cardiovascular Center, Taichung Veterans General Hospital, Taichung 407219, Taiwan
11
Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan
12
Cardiovascular Research Center, College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan
13
Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 7ZX, UK
14
Danish Centre for Health Services Research, Department of Clinical Medicine, Aalborg University, DK-9220 Aalborg, Denmark
15
Department of Cardiology, Lipidology and Internal Medicine, Medical University of Bialystok, ul. Żurawia 14, 15-540, Bialystok, Poland
 
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*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2025, 14(17), 6008; https://doi.org/10.3390/jcm14176008 (registering DOI)
Submission received: 18 July 2025 / Revised: 20 August 2025 / Accepted: 22 August 2025 / Published: 25 August 2025
(This article belongs to the Section Cardiovascular Medicine)
Versions Notes

Abstract

Background: Cardiovascular-kidney-metabolic syndrome (CKM) represents a multisystem condition involving obesity, diabetes, chronic kidney disease, and cardiovascular diseases. Frailty, as measured by the Frailty Index (FI), is linked to adverse outcomes, but its association with CKM severity and mortality remains unclear. This study aimed to evaluate the relationship between frailty status, CKM staging, and mortality risk. Methods: We analysed data from 19,407 adults aged ≥ 45 years from NHANES 1999–2018. Frailty status was assessed using a 49-item Frailty Index (FI) and categorised as robust (FI ≤ 0.08), pre-frail (0.08 < FI < 0.25), or frail (FI ≥ 0.25). CKM was staged from 1 to 4 based on established clinical criteria. Multinomial logistic regression assessed the association between frailty status and CKM staging. Cox proportional hazards models evaluated the associations between frailty status and all-cause, cardiovascular, and non-cardiovascular mortality among CKM patients. Results: A total of 19,407 participants (median [IQR] age: 63.00 [54.00–72.00] years, 50.77% male), with 19,089 CKM patients. Frail individuals exhibited significantly higher odds of being assigned to advanced CKM stages. Over a median follow-up of 8.4 years, 4794 participants died. Kaplan–Meier curves and restricted cubic spline analyses demonstrated a clear gradient in mortality risk across frailty categories. Compared with the robust group, pre-frail and frail individuals had significantly higher risks of all-cause (HR = 1.47 and 2.83, respectively), cardiovascular (HR = 1.71 and 3.78), and non-cardiovascular mortality (HR = 1.40 and 2.57). Conclusions: Frailty status demonstrated a significant association with CKM staging and mortality outcomes. Early identification of frailty may help guide risk stratification and inform tailored interventions for individuals with CKM.
Keywords: frailty; cardiovascular-kidney-metabolic syndrome; staging; mortality; NHANES frailty; cardiovascular-kidney-metabolic syndrome; staging; mortality; NHANES

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MDPI and ACS Style

Yang, Z.; Wu, S.; Li, Y.; Liu, H.; Zhao, M.; Xu, Y.; Chen, Y.; Chen, Y.; Lip, G.Y.H. Association of Frailty Status with Staging and Mortality Risk of Cardiovascular-Kidney-Metabolic Syndrome in Middle-Aged and Older Populations: Insights from the 1999–2018 National Health and Nutrition Examination Survey. J. Clin. Med. 2025, 14, 6008. https://doi.org/10.3390/jcm14176008

AMA Style

Yang Z, Wu S, Li Y, Liu H, Zhao M, Xu Y, Chen Y, Chen Y, Lip GYH. Association of Frailty Status with Staging and Mortality Risk of Cardiovascular-Kidney-Metabolic Syndrome in Middle-Aged and Older Populations: Insights from the 1999–2018 National Health and Nutrition Examination Survey. Journal of Clinical Medicine. 2025; 14(17):6008. https://doi.org/10.3390/jcm14176008

Chicago/Turabian Style

Yang, Zhenkun, Shuang Wu, Yuanjie Li, Hongyu Liu, Manlin Zhao, Yang Xu, Yunyu Chen, Yang Chen, and Gregory Y. H. Lip. 2025. "Association of Frailty Status with Staging and Mortality Risk of Cardiovascular-Kidney-Metabolic Syndrome in Middle-Aged and Older Populations: Insights from the 1999–2018 National Health and Nutrition Examination Survey" Journal of Clinical Medicine 14, no. 17: 6008. https://doi.org/10.3390/jcm14176008

APA Style

Yang, Z., Wu, S., Li, Y., Liu, H., Zhao, M., Xu, Y., Chen, Y., Chen, Y., & Lip, G. Y. H. (2025). Association of Frailty Status with Staging and Mortality Risk of Cardiovascular-Kidney-Metabolic Syndrome in Middle-Aged and Older Populations: Insights from the 1999–2018 National Health and Nutrition Examination Survey. Journal of Clinical Medicine, 14(17), 6008. https://doi.org/10.3390/jcm14176008

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