Sodium-glucose cotransporter protein 2 inhibition, plasma proteins, and ischemic stroke: A mediation Mendelian randomization and colocalization study

Purpose
To determine the effect of the sodium-glucose cotransporter protein 2 (SGLT2) inhibition on ischemic stroke (IS) and investigate the circulating proteins that mediate the effects of SGLT2 inhibition on IS.
Methods
The effects of SGLT2 inhibition on IS were evaluated using two-sample Mendelian randomization (MR) analyses. The 4,907 circulating proteins from the plasma proteome were assessed to identify potential mediators. Sensitivity, colocalization, and external validation analyses were conducted to validate critical findings. MR analyses were also used to evaluate the associations of SGLT2 inhibition with magnetic resonance imaging (MRI)-based biomarkers and functional prognoses post-IS.
Results
SGLT2 inhibition was significantly associated with decreased risks of IS (odds ratio (OR): 0.39, 95 % confidence interval (CI): 0.25–0.61, p = 3.53 × 10-5) and cardioembolic stroke (OR: 0.16, 95 % CI: 0.07–0.37, p = 1.82 × 10-5); the effect of SGLT2 inhibition on IS was indirectly mediated through pathways involving tryptophanyl-transfer RNA synthetase (WARS) (β:0.08, 95 % CI:0.15 – -0.01, p = 0.034) and matrix metalloproteinase 12 (MMP12) (β:0.06, 95 % CI:0.12 – -0.01, p = 0.016), with mediation proportions of 8.2 % and 6.8 %, respectively. The external validation confirmed the WARS mediating effect. In addition, the sensitivity and colocalization analyses and MR analyses of MRI biomarker-based and functional prognostic outcomes supported these results.
Conclusion
In this study, we demonstrated from a genetic perspective that SGLT2 inhibitors prevent the development of IS and improve functional prognostic outcomes and brain microstructural integrity. WARS and MMP12 may act as potential mediators, presenting a novel approach for IS intervention.