Associations of the Triglyceride-Glucose Index and Its Obesity-Related Derivative with All-Cause Mortality, Cardiovascular Events, and Long-Term Survival and Functioning in Older Adults

• We investigated the longitudinal associations of the TyG index and its obesity-related derivative (TyG-WHtR) with all-cause mortality, cardiovascular events, and disability-free survival (DFS) in older adults using both confirmatory and exploratory analytical approaches. • Higher TyG and TyG-WHtR values were associated with increased risk of adverse clinical outcomes, with non-linear patterns and sex-specific thresholds observed; among higher-risk individuals, lower mortality risk were observed in aspirin users. • These findings highlight the potential utility of TyG-based indices as cost-effective, scalable biomarkers for early risk stratification and targeted intervention to promote healthy aging. Although the triglyceride–glucose (TyG) index has been associated with cardiovascular disease (CVD), its association with longer-term outcomes, including disability-free survival (DFS), has not been well characterised. We utilised data from the ASPREE trial, community-dwelling older adults aged ≥70 years (≥65 for U.S. minorities), and post-trial observational follow-up (2010-2021). We examined the associations between baseline and time-updated TyG index and TyG-WHtR with CVD, DFS, and mortality. Previously proposed cut-offs were applied in a confirmatory manner. In sensitivity analyses, cohort-derived tertiles were used, and restricted cubic spline models were fitted to examine continuous and potentially non-linear associations between TyG indices and clinical outcomes. Subgroup analyses assessed associations in populations with cardiometabolic conditions. Effect modification by aspirin, statins, and antidiabetic medications was evaluated. 18,684 participants were included, with a median follow-up of 8.4 years. Non-linear associations were observed between TyG and TyG-WHtR indices and clinical outcomes, with stronger associations between the TyG index and adverse outcomes among individuals with diabetes. Aspirin use was associated with a 14% lower mortality risk in participants within the highest TyG tertile. These findings support the utility of TyG and TyG-WHtR as risk markers for adverse outcomes in older adults and suggest that sex-specific TyG-WHtR thresholds may improve risk stratification.