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

<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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). <b>Conclusions:</b> 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.