Joint association of the cholesterol–HDL–glucose index and frailty with new-onset cardiovascular disease in middle-aged and older adults: evidence from the prospective cohort

Cardiovascular disease (CVD) is the leading cause of death and disability among middle-aged and older adults. Metabolic burden and frailty frequently co-occur in this population. However, few quantitative indicators capture their combined contribution to cardiovascular risk. We examined the association between a composite indicator integrating the cholesterol–HDL–glucose (CHG) index and the frailty index (FI) and the risk of incident CVD. Using baseline data from 2011 and follow-up data from the China Health and Retirement Longitudinal Study (CHARLS), we included participants aged ≥ 45 years without baseline CVD. CHG-FI was constructed by integrating CHG and FI in a multiplicative form; FI was derived using a cumulative deficit model. Cox proportional hazards models were used to estimate HRs and 95% CIs. Restricted cubic splines (RCS) were used to assess dose–response relationships. Subgroup and sensitivity analyses were performed to examine the robustness of the findings. A total of 7,123 participants were included. During a median follow-up of 9 years, 1,655 participants developed incident CVD (23.2%), including 554 cases of stroke (7.8%) and 1,287 cases of heart disease (18.1%). In the fully adjusted model, each one-unit increase in CHG-FI was associated with a 61% higher risk of CVD (HR 1.61, 95% CI 1.48–1.75), a 56% higher risk of stroke (HR 1.56, 95% CI 1.35–1.80), and a 64% higher risk of heart disease (HR 1.64, 95% CI 1.49–1.80) (all P < 0.001). Compared with Q1, the risks of incident CVD, stroke, and heart disease generally increased across higher quartiles of CHG-FI. RCS analyses revealed a positive dose–response association of CHG-FI with incident CVD and heart disease, with significant nonlinearity for both outcomes (all P for non-linearity < 0.001). In contrast, stroke risk showed a more nearly linear pattern after full adjustment (P for non-linearity = 0.074). Subgroup and sensitivity analyses yielded findings broadly consistent with the primary analysis. Higher CHG-FI was independently associated with increased risks of incident CVD, stroke, and heart disease. CHG-FI may provide complementary information for early cardiovascular risk identification in middle-aged and older adults, although its incremental predictive value beyond FI alone appears modest. Further validation is needed before its clinical utility can be more firmly established.