Associations of cumulative exposure and change patterns of the normalised creatinine-to-cystatin C ratio with incident cardiovascular disease in CKM stage 0–3 adults: a CHARLS analysis

Background Creatinine-to-cystatin C ratio–derived indices have been linked to cardiovascular disease (CVD), yet most evidence relies on single time-point assessments. Whether cumulative exposure and pre-baseline change patterns of the normalised creatinine-to-cystatin C ratio (NCCR) inform CVD risk within cardiovascular–kidney–metabolic (CKM) stages 0–3 remains unclear. Purpose To examine associations of cumulative NCCR burden (cumNCCR) and NCCR change patterns with incident CVD among adults with CKM stage 0–3. Methods We analysed the China Health and Retirement Longitudinal Study (CHARLS; 2011–2020). Participants aged ≥45 years at the 2015 baseline, free of baseline CVD, with eGFR >30 mL/min/1.73 m², and classified as CKM stage 0–3 were included. NCCR was calculated as serum creatinine-to-cystatin C ratio normalised by body weight. CumNCCR from 2011 to 2015 was computed using a time-weighted trapezoidal area-under-the-curve approach and analysed per SD and tertiles. NCCR change patterns (2011–2015) were derived using k-medoids clustering. Incident CVD (heart disease and/or stroke) was ascertained at 2018/2020 follow-up interviews. Cox models adjusted for demographics, lifestyle factors, BMI, hypertension, diabetes, dyslipidaemia, and eGFR. Results Among 3,222 participants, 635 incident CVD events occurred over 14,922 person-years (42.6 per 1,000 person-years). Higher cumNCCR was associated with lower CVD risk (per SD: HR 0.83, 95% CI 0.74–0.93; P=0.002); the highest versus lowest tertile showed reduced risk (HR 0.68, 0.53–0.87; P=0.002; P-trend=0.002). Baseline NCCR showed similar inverse associations. Compared with the low-stable pattern, the high level with increase pattern was associated with lower CVD risk (HR 0.72, 0.55–0.94; P=0.016). Restricted cubic splines supported a largely linear inverse dose–response (P for non-linearity=0.471). Conclusion In adults with CKM stage 0–3, greater pre-baseline cumulative NCCR burden and favourable NCCR change patterns were associated with lower subsequent CVD risk, supporting time-integrated muscle-related biomarkers for upstream prevention risk stratification.