Associations of cumulative insulin resistance–frailty integrated indices with incident cardiovascular disease in middle-aged and older adults with cardiovascular–kidney–metabolic syndrome stages 0–3: a prospective cohort study

Insulin resistance-related metabolic abnormalities and frailty are both associated with cardiovascular disease (CVD). Whether combining these dimensions as cumulative product-based scores provides information beyond their individual components remains uncertain, particularly among adults with cardiovascular-kidney-metabolic (CKM) syndrome stages 0–3. We conducted a prospective landmark cohort analysis using data from the China Health and Retirement Longitudinal Study. Participants with CKM stages 0–3 who were free of CVD by Wave 3 were included. Fourteen cumulative insulin resistance–frailty index (IR-FI) products were constructed from insulin resistance-related surrogate markers and frailty index values assessed at Waves 1 and 3. Incident CVD was defined as newly self-reported physician-diagnosed heart disease or stroke after Wave 3. We examined associations with incident CVD and compared models containing IR alone, FI alone, IR and FI as separate terms, and the IR-FI product. Wave 3 and cumulative specifications were also compared. Among 3,110 participants, 631 developed incident CVD during a median follow-up of 5.00 years. All 14 cumulative IR-FI products were associated with incident CVD per 1-standard-deviation increase. Representative HRs were 1.387 (95% CI, 1.290–1.490) for TyG-FI, 1.383 (95% CI, 1.287–1.486) for CHG-FI, 1.371 (95% CI, 1.281–1.467) for METS-IR-FI, and 1.388 (95% CI, 1.293–1.489) for TyG-WC-FI. Nonlinear associations were observed for all products, and the main findings remained stable across sensitivity analyses. The FI-only model had a Harrell’s C of 0.6615. Across all 14 indicators, models entering cumulative IR and cumulative FI as separate terms had higher Harrell’s C statistics than the corresponding product models. Among five representative indicators, Harrell’s C ranged from 0.6646 to 0.6683 for the parallel models and from 0.6250 to 0.6645 for the product models. Differences between Wave 3 and cumulative product specifications were small. Among adults with CKM stages 0–3, insulin resistance-related metabolic burden and frailty were each associated with incident CVD. Product-based IR-FI scores summarized their coexisting burden but did not outperform models in which IR and FI were entered separately. The cumulative product measures also showed little improvement over the corresponding Wave 3 measures. External validation is required before clinical application.