Joint Association of Longitudinal Single-Point Insulin Sensitivity Estimator Patterns and Hypertension Status with Incident Stroke Among Adults with Cardiovascular-Kidney-Metabolic Syndrome Stages 0-3: A Nationwide Prospective Cohort Study

Background: The prognostic value of longitudinal single-point insulin sensitivity estimator (SPISE) patterns for stroke, particularly when considered in combination with hypertension (HTN), remains unclear among adults with cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3. Aims: This study aimed to examine the association of combined longitudinal SPISE patterns and HTN status with incident stroke among adults with CKM syndrome stages 0-3. Study Design: A nationwide prospective cohort study. Methods: We included adults aged ≥ 45 years with CKM stages 0-3 from the China Health and Retirement Longitudinal Study. SPISE was calculated at Waves 1 and 3, and incident stroke was ascertained through Wave 5. K-means clustering was used to identify longitudinal SPISE patterns, which were dichotomized as persistently low or non-persistently low. Participants were then cross-classified according to longitudinal SPISE pattern and baseline HTN status. Cumulative SPISE exposure was calculated from repeated SPISE measurements. Cox models were used to examine associations with incident stroke. Dose-response, subgroup, sensitivity, and model-performance analyses were also performed. Results: Among 4,443 participants, 348 incident strokes occurred. A persistently low longitudinal SPISE pattern was associated with a higher risk of incident stroke than a persistently high pattern [hazard ratio (HR), 2.29; 95% confidence interval (CI), 1.59-3.29]. Compared with the group with no HTN and a non-persistently low SPISE pattern, stroke risk was higher in the group with no HTN and a persistently low SPISE pattern (HR, 1.48; 95% CI, 1.12-1.95), the group with HTN and a non-persistently low SPISE pattern (HR, 1.57; 95% CI, 1.10-2.23), and the group with HTN and a persistently low SPISE pattern (HR, 2.45; 95% CI, 1.84-3.26). Higher cumulative SPISE exposure was inversely associated with incident stroke (HR per 1-unit increment, 0.95; 95% CI, 0.93-0.97), with an approximately linear dose-response relationship. Incorporating the combined longitudinal SPISE pattern and HTN status increased the apparent C-index from 0.612 to 0.646. However, optimism-corrected discrimination was comparable between the combined model and the HTN-only model. Conclusion: The combination of longitudinal SPISE patterns and HTN status identified a subgroup at the highest risk of incident stroke in this CKM population.