Abstract Body (Do not enter title and authors here): Background: Insulin resistance is central to metabolic dysfunction and a recognized risk factor for cardiovascular disease. Surrogate markers of insulin sensitivity, such as estimated glucose disposal rate (eGDR), derived from routine clinical variables, have gained attention for vascular risk stratification. Although multiple studies across diverse populations suggest an association between lower eGDR and stroke risk, the magnitude and consistency of this relationship remain uncertain.

Hypothesis: We hypothesized that lower eGDR reflecting higher insulin resistance is associated with an increased risk of stroke, and that this inverse relationship would remain consistent across populations stratified by age and diabetes status.

Methods: We systematically searched PubMed, Scopus, and Cochrane through May 2025 for studies evaluating the association between eGDR and stroke. Hazard ratios (HRs) were pooled using a random-effects model. Heterogeneity was assessed using the I² statistic, and leave-one-out sensitivity analysis was performed. Subgroup analyses were conducted by diabetes status and age group (<60/65 vs ≥60/65 years). Publication bias was assessed using the Luis Furuya-Kanamori (LFK) index.

Results: Of 158 studies found on initial screening, 4 observational studies with a total population of 485,382 were included in the meta-analysis. Pooled analysis showed that individuals with higher eGDR had significantly lower risk of stroke (HR 0.52, 95% CI 0.36-0.74; P < 0.01). Heterogeneity was high (I² = 89.9%), but leave-one-out analysis confirmed the stability of our results. Subgroup analysis by diabetes status revealed consistent inverse associations in both diabetic (HR 0.82, 95% CI 0.79-0.86) and non-diabetic populations (HR 0.78, 95% CI 0.67-0.92), with no significant interaction (P = 0.54). Similarly, inverse associations were observed in both younger (<60/65 years: HR 0.81, 95% CI 0.78-0.84) and older (≥60/65 years: HR 0.83, 95% CI 0.75-0.92) subgroups, with no significant subgroup difference (P = 0.66). The LFK index (-1.32) suggested minor asymmetry, indicating no major publication bias.

Conclusion: Lower eGDR is significantly associated with increased stroke risk across age groups and diabetic status. These findings support the role of insulin sensitivity, as captured by eGDR, in stroke risk assessment. Incorporating eGDR into routine clinical evaluation may improve identification of high-risk individuals and inform targeted prevention strategies.