Associations of cumulative exposure and dynamic trajectories of the normalized creatinine-to-cystatin C ratio with incident cardiovascular disease in middle-aged and older Chinese adults with metabolic dysfunction-associated steatotic liver disease:

The normalized creatinine-to-cystatin C ratio (NCCR) serves as an indirect indicator of skeletal muscle mass and has been linked to metabolic health. However, its cumulative exposure and dynamic trajectories as they relate to incident cardiovascular disease (CVD) remain unknown in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). This nationwide prospective cohort study included 1,428 middle-aged and older Chinese adults with MASLD from the China Health and Retirement Longitudinal Study (2011–2020). Cumulative NCCR was calculated from 2012 and 2015 measurements. K-means clustering identified NCCR trajectory patterns. The primary outcome was incident CVD, assessed using Cox regression, restricted cubic splines, and Kaplan–Meier curves. Subgroup and sensitivity analyses evaluated the robustness of the findings. Over a median 7.77-year follow-up, 470 (32.91%) CVD events occurred. In fully adjusted models, higher cumulative NCCR exposure was independently associated with a 16% lower risk of incident CVD per 10-units increase (HR = 0.84 per 10-units increase, 95%CI: 0.76–0.94, P = 0.002). Compared with the lowest tertile, the highest tertile had a 34% risk reduction (HR = 0.66, 95%CI: 0.52–0.84, P = 0.001; P for trend = 0.001). K-means clustering identified two distinct NCCR trajectory patterns, with Cluster 2 showing a persistently higher NCCR trajectory and a significantly lower CVD risk (23% reduction) compared to Cluster 1 (HR = 0.77; 95% CI: 0.63–0.95; P = 0.015). Restricted cubic spline analysis revealed a linear inverse association between cumulative NCCR and incident CVD risk (P for non-linearity = 0.224). Kaplan–Meier analysis confirmed that participants with the highest cumulative NCCR or a persistently higher NCCR trajectory had the lowest cumulative incidence of CVD (log-rank P = 0.0028 and 0.0045, respectively). Subgroup and interaction analyses demonstrated generally consistent effect across most subgroups, with no significant interactions detected (all P for interaction > 0.05). Sensitivity analyses further confirmed the robustness of these findings. Higher cumulative NCCR exposure is independently associated with lower incident CVD risk in middle-aged and older Chinese adults with MASLD. NCCR distinct trajectory patterns were differentially associated with CVD risk, positioning this ratio as a independent association in this population. Associations of cumulative exposure and dynamic trajectories of the NCCR with incident CVD in middle-aged and older Chinese adults with MASLD: a nationwide cohort study