Objective:

To examine the association of hemoglobin glycation index (HGI) with large-artery atherosclerosis (LAA) and in-hospital mortality in ischemic stroke (IS) patients.

Approach:

• Study Design: Retrospective analysis of 4,500 IS patients from MIMIC-IV and 330 patients from an external clinical cohort.
• HGI Calculation: HGI was calculated using cohort-specific fasting plasma glucose (FPG)-HbA1c regression equations.
• Statistical Analysis: Multivariable logistic regression and restricted cubic spline analyses were used to assess associations with LAA and mortality.
• Feature Selection: Boruta feature selection and exploratory Mendelian randomization (MR) were performed, along with post hoc stress hyperglycemia ratio (SHR) sensitivity analyses.

Key Findings:

• Lower HGI was independently associated with higher LAA risk in both cohorts (MIMIC-IV: OR = 0.579, p < 0.001; clinical cohort: OR = 0.599, p < 0.001).
• Lower HGI was associated with higher in-hospital mortality in MIMIC-IV (OR = 0.488, p < 0.001).
• HGI showed the highest feature importance among measured baseline variables.
• HGI and SHR were strongly inversely correlated in both cohorts (Spearman’s ρ = −0.711 and −0.723; both p < 0.001).
• MR did not provide significant genetic evidence linking HGI to LAA.

Interpretation:

Low HGI is associated with higher LAA risk and in-hospital mortality in IS.

Limitations:

• The study is retrospective and may be subject to biases inherent in such designs.
• Mendelian randomization did not yield significant genetic evidence, limiting causal inference.

Conclusion:

Low HGI correlates with increased risks of LAA and in-hospital mortality in IS patients.