Association between the HbA1c/HDL-C ratio and cardiovascular disease risk: a cross-cohort analysis in NHANES and CHARLS

Abstract

Cardiovascular disease (CVD) remains a leading cause of mortality worldwide, with glucose and lipid metabolic disturbances closely involved. We therefore assessed how the glycated hemoglobin (HbA1c)/ high-density lipoprotein cholesterol (HDL-C) ratio (HHC) relates to composite CVD and individual subtypes across two population-based cohorts, while also testing whether the associations varied by population and cardiovascular outcome. Two nationally representative data sources were analyzed: the U.S. National Health and Nutrition Examination Survey (NHANES, 2001–2018) and the China Health and Retirement Longitudinal Study (CHARLS, 2011–2020). Within NHANES, receiver operating characteristic (ROC) curves compared how well HHC, HbA1c, and HDL-C discriminated prevalent composite CVD. Survey-weighted logistic regression was used for the cross-sectional NHANES analysis, whereas Cox proportional hazards regression was used for the longitudinal CHARLS analysis. We further assessed how HHC relates to CVD and its subtypes through restricted cubic splines (RCS), separate subgroup analyses, and an exploratory mediation analysis. In NHANES, higher HHC was associated with prevalent composite CVD and several cardiovascular subtypes after multivariable adjustment. After full adjustment, the odds of composite CVD were greater in the highest than in the lowest HHC quartile (OR = 1.77, 95% CI: 1.40–2.22). In the ROC analysis, HHC showed an AUC of 0.680, compared with 0.620 for HbA1c and 0.564 for HDL-C. Within CHARLS, higher HHC predicted incident composite CVD (HR = 1.23, 95% CI: 1.04–1.45) and stroke (HR = 1.70, 95% CI: 1.29–2.24), whereas heart disease was not associated (HR = 0.86, 95% CI: 0.70–1.05). The NHANES restricted cubic spline models indicated nonlinear patterns across several examined cardiovascular outcomes; CHARLS showed no statistically significant evidence of nonlinearity. In the exploratory mediation model, serum albumin explained 3.79% of what was observed as the HHC-CVD association. Higher HHC was associated with cardiovascular outcomes, although the magnitude and pattern of the associations differed across populations and CVD subtypes. HHC showed potential as a complementary metabolic marker, particularly for stroke risk assessment in CHARLS; however, its incremental predictive value requires further validation.