Although essential for cardiovascular therapy, the pleiotropic effects of statins on ischemic stroke lack clinical evidence. This study examined the effects of statins beyond low-density lipoprotein cholesterol (LDL-C) levels on mortality and stroke severity. A total of 825,874 patients with ischemic stroke were included in this study, of whom 125,650 statin users were 1:1 matched with non-users based on their LDL-C levels (±0.05 mmol/L), forming the LDL-C-matched cohort. Associations between preceding statin treatment, in-hospital mortality, and stroke severity (National Institutes of Health Stroke Scale score ≥16) were estimated by multivariate and conditional logistic regression models in overall cohort and LDL-C-matched cohort, respectively. The overall statin effects reduced in-hospital mortality (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.65-0.79, p < 0.001) and moderate-to-severe stroke (OR: 0.93, 95% CI: 0.90-0.96, p < 0.001). After matching for LDL-C levels, the reduction in mortality persisted (OR: 0.63, 95% CI: 0.52-0.77, p < 0.001) but not for moderate-to-severe stroke (OR: 0.96, 95% CI: 0.90-1.02, p = 0.215). Stratified by LDL-C levels, the effects of statin beyond LDL-C in reducing mortality remained consistent across all LDL-C ranges but increased with LDL-C reduction for stroke severity and achieved statistical significance at LDL-C <2.60 mmol/L. Mediation analyses showed that LDL-C reduction explained 0.35% (95% CI: 0.23-0.93, p = 0.235) of the statin treatment-mortality relationship and 12.47% (95% CI: 6.78-18.16, p < 0.001) for moderate-to-severe stroke. When examining the overall statin efficacy, LDL-C <2.60 mmol/L was not necessary for mortality reduction but for reducing stroke severity. The efficacy of statins in ischemic stroke outcomes is primarily derived from their effects beyond the LDL-C levels, suggesting that their neuroprotective effects should be considered in addition to their lipid-lowering effects.
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