AbstractBackgroundThe progression of carotid atherosclerotic plaques is a significant predictor of cardiovascular events; however, there is a paucity of comparative analyses regarding metabolic biomarkers that can forecast short-term carotid plaque progression in middle-aged adults.MethodsThis prospective cohort study included adults without initial carotid abnormalities who underwent serial carotid ultrasounds and metabolic profiling. A total of 11 blood lipid and glucose profiles were examined. Carotid artery plaque progression was defined as the emergence of new plaques within a 2-year period. The association between each metabolic indicator and the outcome was analyzed using Pearson correlation, restricted cubic splines, multivariable logistic regression, and receiver operating characteristic curves. The five indicators with the strongest associations were identified, and a logistic regression model, adjusted for covariates, was utilized to assess the impact of the coexistence of risk factors on the progression of carotid atherosclerosis.ResultsA total of 7703 individuals were included in the study, among which 9.52% (n = 733) developed new carotid plaques over the 2-year period. The elevated total cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio [odds ratio (OR) = 1.38, 95% confidence interval (CI) 1.28–1.49], low-density lipoprotein cholesterol to HDL-C ratio (OR = 1.66, 95% CI 1.49–1.85), and triglyceride-glucose index (OR = 1.34, 95% CI 1.17–1.53) demonstrated the strongest correlations with plaque progression. Cumulative risk factor analysis indicated that individuals with five or more risk factors faced a 3-fold increased risk (OR = 3.02, 95% CI 2.28–4.01) relative to those with no risk factors. Subgroup analyses confirmed the robustness of the total cholesterol/HDL-C ratio across various metabolic subgroups, while the triglyceride-glucose index diminished in hypertensive and obese populations.ConclusionsBoth traditional lipid ratios, particularly the total cholesterol/HDL-C ratio, and indices of insulin resistance, such as triglyceride-glucose index, are significant risk factors of carotid plaque progression. A dose–response relationship was observed between the accumulation of identified risk factors and the progression of carotid atherosclerotic plaques. Therefore, risk stratification in health screenings should prioritize these biomarkers to improve early detection and prevention strategies for atherosclerosis.Key messagesWhat is already known on this topic: Existing evidence has established associations between various individual lipid parameters [e.g. low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG)] and glucose metabolism markers with the presence of carotid atherosclerosis. Furthermore, composite ratios like TC/high-density lipoprotein cholesterol (HDL-C) and the triglyceride-glucose index (TyG) index have shown superior predictive capability for cardiovascular risk compared to individual parameters in cross-sectional studies. However, comparative longitudinal analyses of these biomarkers for predicting short-term carotid plaque progression specifically in middle-aged, screening populations are scarce.What this study adds: This prospective cohort study demonstrates that among 11 lipid and glucose profiles, traditional lipid ratios—especially the TC/HDL-C ratio—and the insulin resistance index (TyG) are the strongest independent risk factors for short-term carotid plaque progression in a middle-aged health-screening cohort. We further established a clear dose–response relationship, where the accumulation of identified risk factors (specifically elevated LDL-C, TC/HDL-C, LDL-C/HDL-C, TC, and TG) significantly increased the risk of plaque development.How this study might affect research, practice or policy: Our findings suggest that the TC/HDL-C ratio, a cost-effective and readily available metric, should be prioritized in routine health screenings for better early risk stratification of subclinical atherosclerosis. For clinical practice, this supports integrated risk assessment that considers the cumulative effect of multiple lipid abnormalities. Future research should validate the established cut-off values prospectively and explore whether interventions targeting these key biomarkers can effectively retard plaque progression.