Relationship between homocysteine levels and carotid plaque burden in patients with diabetes: the mediating role of inflammation

Abstract Diabetic patients are more likely to develop carotid plaque (CP). However, whether homocysteine (Hcy) levels are associated with plaque occurrence in this population remains unconfirmed. This study aimed to investigate the association between Hcy levels and CP (including single and multiple plaques) in diabetic patients and to explore the mediating role of inflammation. This multicenter cross-sectional study enrolled 5414 diabetic patients from four medical centers. Hcy levels were measured, and CP was assessed by professional ultrasonographers. Multivariate logistic regression, restricted cubic splines, random forest variable importance analysis, and mediation analysis were employed to evaluate the associations and the mediating effect of C-reactive protein (CRP). Hcy levels showed a significant non-linear increasing association with CP and its subtypes, with threshold effects at 15.5 µmol/L for overall plaque, 15.0 µmol/L for single plaque, and 15.9 µmol/L for multiple plaques. Hcy ranked as a core variable in plaque formation, second only to HbA1c. Mediation analysis revealed that CRP mediated 19.11%, 25.67%, and 13.95% of the effects on overall plaque, single plaque, and multiple plaques, respectively. Elevated Hcy levels were significantly associated with CP and its subtypes in diabetic patients, with inflammation appearing to play a potential mediating role in these associations. Although the observational design precludes definitive causal inference, these findings suggest that lowering Hcy and modulating inflammation may represent promising strategies for preventing CP in this population, warranting verification in future prospective studies.