Associations of C-reactive protein-triglyceride glucose index and its long-term cumulative exposure with stroke risk in adults with cardiovascular-kidney-metabolic syndrome stages 0–3: a prospective cohort study

Metaflammation is pivotal in contributing to residual stroke risk in Cardiovascular-Kidney-Metabolic (CKM) syndrome. The C-reactive protein-triglyceride-glucose index (CTI) represents a novel biomarker that encapsulates systemic inflammatory activity and insulin resistance. Nevertheless, evidence remains limited regarding the relationship between CTI, along with its cumulative burden, and the risk of stroke in CKM syndrome stages 0–3. Data from the China Health and Retirement Longitudinal Study was used in this prospective cohort study. The main cohort comprised 6,618 participants with no prior stroke history, all in CKM syndrome stages 0–3, to calculate CTI. A sub-cohort comprising 3,667 participants with repeated measurements was employed to calculate the cumulative CTI (cuCTI = (CTI 2012 + CTI 2015 )/2 × time). To analyze the primary outcome of incident stroke, multivariable Cox proportional hazards models, restricted cubic splines, two-piecewise linear regression, and time-dependent receiver operating characteristic (ROC) curves were utilized. A total of 495 stroke cases were observed over a median follow-up of 9.0 years. According to RCS analysis, CTI exhibits a significant nonlinear saturation effect on stroke risk, with an estimated inflection point at 8.98. A unit rise in CTI below this threshold was associated with a 79.8% higher risk of stroke (hazard ratio (HR) = 1.798, 95% CI: 1.347–2.402, P < 0.001). The risk reached a steady state after passing this threshold. Conversely, cuCTI revealed a linear connection between dose and response, with subjects in the highest quartile having a 78% higher stroke risk than those in the lowest quartile (HR = 1.78, 95% CI: 1.17–2.73, P = 0.01). Time-dependent ROC analysis showed that CTI yielded a slightly higher AUC than the triglyceride-glucose (TyG) index and C-reactive protein (CRP), although overall discrimination remained moderate. For those with CKM syndrome stages 0–3, CTI exhibits a nonlinear saturation threshold effect on stroke risk, while cuCTI exposure was associated with a graded, linear increase in stroke risk, underscoring the need for early intervention before the saturation point and warranting a shift from single assessments to longitudinal monitoring for accurate stroke prediction. Not applicable.