Abstract
BACKGROUND: Elevated urinary albumin-to-creatinine ratio (UACR) within the normal range (< 30 mg/g) and the triglyceride-glucose (TyG) index are associated with cardiovascular disease (CVD) incidence, yet their joint effect remains underexplored. METHODS: This prospective cohort study used data from the 2016 Shandong-MOH Salt and Hypertension (SMASH) project, linked to CVD records until September 30, 2023, including 14,481 adults with normal UACR. Participants were stratified by TyG index and UACR quantiles. Multivariable Cox proportional hazards models and restricted cubic splines (RCS) were employed to evaluate individual and joint effects on overall CVD, coronary heart disease (CHD), and stroke. The incremental predictive value was assessed using the C-index, Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI). Additionally, an exploratory mediation analysis was performed to examine the potential bidirectional effects between the TyG index and UACR. RESULTS: Mean age was 41.75 ± 13.06 years, with median follow-up of 7.2 years. Among 420 incident overall CVD cases (309 stroke, 111 CHD), Compared to the Low TyG & Low UACR group, the High TyG & High UACR group demonstrated the highest risks for overall CVD (HR = 2.632, 95% CI: 1.695-4.085, P < 0.001), CHD (HR = 2.680, 95% CI: 1.144-6.282, P = 0.023), and stroke (HR = 2.628, 95% CI: 1.573-4.392, P < 0.001). The TyG index showed nonlinear associations with overall CVD and stroke risk but a linear association with CHD, while UACR exhibited linear positive correlations with all outcomes. The model combining the TyG index and UACR significantly enhanced the predictive ability for CVD events. Mediation analysis revealed that elevated UACR significantly mediated 4.9% of the association between TyG index and CVD, while elevated TyG index mediated 11.2% of the association between UACR and CVD. CONCLUSION: The study demonstrates that both elevated UACR (within normal range) and higher TyG index are jointly associated with increased CVD risk, with evidence suggesting potential bidirectional mediation. Their combined assessment provides significant incremental predictive value, supporting its integration into high-risk population screening for precise CVD prevention and management.