This study uncovers a strong association between TyG-i, RFM, and their combined effect on the occurrence of new-onset CVD events. While no synergistic interaction was detected, the joint assessment of TyG-i and RFM improved the predictive ability for new-onset CVD events beyond the individual markers. These findings highlight the potential of these accessible tools for early CVD risk identification, contributing to preventive strategies aimed at reducing the burden of non-communicable diseases in aging populations.