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Repurposing antihypertensive, lipid-lowering and antidiabetic drugs for lacunar stroke

Background To estimate the causal associations of modifiable risk factors with lacunar stroke (LS) and repurposing of common antihypertensive, lipid-lowering and antidiabetic drugs to prevent LS. Methods The effects of common antihypertensive, lipid-lowering and antidiabetic drugs on LS were estimated using a drug-target Mendelian randomization (MR) approach. LS data for the transethnic analysis were derived from meta-analyses comprising 7,338 cases and 254,798 controls. Findings Genetically predicted hypertension and type 2 diabetes significantly increased LS risk. Elevated triglyceride and apolipoprotein B levels caused a 14% increased LS risk, while elevated apolipoprotein A-I and high-density lipoprotein levels caused a 12% decreased risk. Elevated triglyceride levels remained significantly associated with a higher LS risk in multivariable MR analysis (OR, 1.21; 95% CI, 1.06-1.40, P =0.005). Drug-target MR demonstrated that genetic variants mimicking calcium channel blockers most stably prevented LS (OR, 0.75; 95% CI, 0.61-0.92, P =0.006). The genetic variants at or near HMGCR (i.e., mimicking the effect of statins), NPC1L1 (mimicking the effects of ezetimibe) and APOC3 (mimicking antisense anti-apoC3 agents) were predicted to decrease LS incidence. Genetically proxied GLP1R agonism showed a marginal effect on LS, while a genetically proxied improvement in overall glycemic control was associated with a reduced LS risk (OR, 0.94; 95% CI, 0.92–0.96; P=4.58×10−7). Interpretation Repurposing several drugs with well-established safety and low costs for LS prevention in clinical practice may contribute to healthier brain aging. Funding This study was supported by National Natural Science Foundation of China (grant numbers 8210051863).