Supplementary Material for: Association between the frailty and cardiovascular disease risk in populations with cardiovascular-kidney-metabolic syndrome stages 0-3: a prospective cohort study

Introduction: Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, the relationship between frailty and CVD risk across different cardiovascular-kidney-metabolic (CKM) syndrome stages remains poorly understood. This study investigated the association between frailty and incident CVD in populations with CKM syndrome stages 0-3. Methods: We analyzed 6,049 middle-aged and older adults without pre-existing CVD data from the China Health and Retirement Longitudinal Study (2011-2020). Participants were categorized into CKM syndrome stages 0-3 based on the American Heart Association's criteria. Frailty was assessed using the Frailty Index (FI) and classified as robust, pre-frail, or frail. Cox proportional hazard models examined the association between frailty and incident CVD. Results: During a median follow-up of 7.5 years, 1,441 participants developed CVD. Compared to robust individuals, pre-frail and frail participants had multivariable-adjusted hazard ratios of 1.58 and 2.13 for incident CVD, respectively. Each standard deviation increase in FI was associated with a 28% higher risk of incident CVD. A dose-response relationship was observed between FI and CVD risk, with no significant nonlinearity was detected. These associations remained consistent across all CKM syndrome stages, although significant effect modifications were observed by age, gender, and hypertension status. Sensitivity analyses yielded consistent results. Conclusions: Frailty is independently associated with increased CVD risk across the spectrum of CKM syndrome stages, with a clear dose-response relationship.