Primary prevention refers to actions aimed at avoiding the manifestation of a disease. In atherosclerotic cardiovascular diseases (ASCVD), ranging from acute coronary syndrome, those with history of myocardial infarction, stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack, to peripheral artery disease including aortic aneurysm, low density lipoprotein cholesterol (LDL-C) is known to play a key role in the pathogenesis. Large-scale clinical trials, such as WOSCOPS (mean LDL-C before treatment, 192; 142 mg/dL finally), AFCAPS/TexCAPS (before, 150 mg/dL; 25% reduction finally), JUPITOR (before, below 130; finally 55 mg/dL), and HOPE-3 (before, 128 mg/dL; 39.6 mg/dL reduction at one year), have unequivocally shown that lipid–lowering therapy with statins reduced the risk of ASCVD in people with certain risk factors, such as hypertension, hypercholesterolemia, type 2 diabetes, chronic kidney disease, and C-reactive protein ≥2 mg/L. Meta-analysis conducted for both primary and secondary prevention trials showed a similar relative risk reduction and that the post-treatment LDL-C was positively correlated with CVD events, indicating that lower post-treatment LDLs were correlated with lower event rates. However, compared to secondary prevention trials, primary prevention trials have a lower absolute risk reduction. Regarding ezetimibe and PCSK9 monoclonal antibody, there is limited evidence of their role in primary prevention and the effects of monotherapy in the prevention of CVD.
　　Now, is there any room to reduce LDL-C to a lower level (less than 55 mg/dL) to gain clinical benefit? Although currently available lipid-lowering drugs other than statins are capable of achieving a lower level, we should consider side effects and cost before effectiveness. For side effects, intracerebral hemorrhage (ICH) has been a concern in lipid-lowering therapy. Two recent studies of Chinese showing that a significant association between lower LDL-C and higher risk of ICH. In addition, another study revealed that the lower ratio of LDL-C to HDL-C is associated with increased risks of hemorrhagic transformation in patients with acute ischemic stroke. Apart from ICH, cost is a barrier to use, especially for PCSK9 monoclonal antibody. Further studies to identify high-risk patients without established ASCVD with subsequent lipid-lowering trials are required to clarify the issue.