Dose–Response Association Between High-Density Lipoprotein Cholesterol and Stroke: A Systematic Review and Meta-Analysis of Prospective Cohort Studies

INTRODUCTION: Studies investigating the effect of high-density lipoprotein cholesterol (HDL-C) on stroke and stroke subtypes have reached inconsistent conclusions. The purpose of our study was to clarify the dose–response association between HDL-C level and risk of total stroke and stroke subtypes by a systematic review and meta-analysis. METHODS: We performed a systematic search of PubMed, Embase, and Web of Science databases through July 30, 2020, for prospective cohort studies that reported the HDL-C–stroke association and extracted the estimate that was adjusted for the greatest number of confounding factors. Restricted cubic splines were used to evaluate the linear and nonlinear dose–response associations. RESULTS: We included 29 articles, which reported on 62 prospective cohort studies including 900,501 study participants and 25,678 with stroke. The summary relative risk per 1-mmol/L increase in HDL-C level for total stroke was 0.82 (95% CI, 0.76–0.89; I (2) = 42.9%; n = 18); ischemic stroke (IS), 0.75 (95% CI, 0.69–0.82; I (2) = 50.1%; n = 22); intracerebral hemorrhage (ICH), 1.21 (95% CI, 1.04–1.42; I (2) = 33.4%; n = 10); and subarachnoid hemorrhage (SAH), 0.98 (95% CI, 0.96–1.00; I (2) = 0%; n = 7). We found a linear inverse association between HDL-C level and risk of total stroke and SAH, a nonlinear inverse association for IS risk, but a linear positive association for ICH risk. The strength and the direction of the effect size estimate for total stroke, IS, ICH, and SAH remained stable for most subgroups. We found no publication bias with Begg’s test and Egger’s test for the association of HDL-C level with risk of total stroke, IS, and ICH. CONCLUSION: A high HDL-C level is associated with reduced risk of total stroke and IS and an increased risk of ICH.