Editorial
Non–high-density Lipoprotein Cholesterol for Secondary Prevention after Minor Stroke
2025 Volume 32 Issue 2 Pages 122-124
Details
2025 Volume 32 Issue 2 Pages 122-124
See article vol. 32: 141-162
The global burden of stroke is increasing, with minor strokes accounting for approximately 50% of all acute ischemic strokes1). Minor stroke carries a high risk of stroke recurrence, with approximately 9% of patients experiencing recurrent stroke2) and 30% experiencing unfavorable functional outcomes by 90 days1). Comprehensive strategies to prevent recurrent stroke include control of vascular risk factors, lifestyle modification, and medications3). In addition, lipid-lowering treatment is widely adopted in practice for secondary prevention, with the level of low-density lipoprotein cholesterol (LDL-C) as a key treatment target4). However, patients with minor stroke may still experience recurrent stroke despite treatment with dual antiplatelet therapy (DAPT) and high-intensity statins5). The lack of biomarkers for the assessment of therapeutic effect of antiplatelet treatment may partly explain the suboptimal effect of secondary prevention. In addition, the LDL-C level does not fully reflect the lipid profile and pathophysiology of atherosclerosis in patients with stroke. In this issue of the Journal of Atherosclerosis and Thrombosis, Fan and colleagues6) conducted a cohort study with 2544 patients with mild (National Institutes of Health Stroke Scale score ≤ 5), non-cardioembolic stroke within 72 hours after the onset of symptoms, which assessed the level of non-high-density lipoprotein cholesterol (non-HDL-C) at baseline. The study found that a higher level of non-HDL-C was associated with a higher risk of symptomatic intracranial artery stenosis (sICAS) and a reduced risk of intracranial hemorrhage (ICH), but no association with recurrent ischemic stroke at 3 months or 12 months. This study implies the potential underlying mechanisms of sICAS associated with non-HDL-C. However, the absence of an association with recurrent ischemic stroke requires further investigation, especially in the group of patients with a background of statin treatment. Furthermore, the association between a higher level of non-HDL-C and a lower risk of intracerebral hemorrhage may reflect the intensity of statin treatment, which is worthy of further investigation by a subgroup analysis of different statins and different dosages. It should be noted that, as stated by the authors, hemorrhagic transformation rather than primary intracerebral hemorrhage accounted for the majority of ICH events following the incident ischemic stroke. Future studies are needed to explore the underlying mechanisms and potential interventions to prevent ICH.
Atherosclerosis is the major pathophysiology of ischemic stroke. Statin therapy is part of the guideline-recommended therapy for secondary prevention of atherosclerotic stroke. Statins can reduce the serum level of LDL-C, stabilize atherosclerotic plaques, and alleviate inflammation7). Together with LDL-C, very-low-density lipoprotein, intermediate-density lipoprotein, chylomicron remnants, and lipoprotein(a) are collectively termed non-HDL-C. These triglyceride-rich lipoproteins contribute to the development of atherosclerosis. High levels of triglycerides can disrupt the balance between LDL-C and high-density lipoprotein cholesterol (HDL-C) and increase levels of chylomicrons and very-low-density lipoprotein8). Therefore, non-HDL-C better represents the atherogenic burden and risk of stroke.
Conventional lipid-lowering therapy after stroke is mainly based on statins, which target LDL-C levels. Alternative options are available for lipid lowering for stroke prevention by different mechanisms9). Ezetimibe blocks the absorption of cholesterol in the intestines and thus reduces serum levels of cholesterol. Fibrates activate peroxisome proliferator-activated receptor alpha, which boosts lipoprotein lipase activity, reduces triglyceride levels, and increases HDL-C levels. Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors prevent the degradation of LDL receptors in the liver, which enhances the clearance of LDL-C from the bloodstream. Inclisiran is a small interfering RNA (siRNA) that reduces the production of PCSK9 in the liver, thereby increasing availability of LDL receptors and promoting LDL-C clearance. These therapies, along with novel agents under investigation (e.g., angiopoietin-like 3 inhibitors), offer promising avenues for optimizing lipid management in patients with stroke.
DAPT is the standard treatment for secondary prevention in patients with minor stroke or high-risk transient ischemic attack (TIA). A recent two-by-two factorial trial investigated the effect of DAPT combined with high-intensity statins for secondary prevention after minor stroke, and found that the benefits were primarily driven by antiplatelet therapies5). However, the effect of DAPT may be influenced by lipid levels. An observational study indicated that patients with a lower level of non-HDL-C received more clinical benefit from DAPT than those with a higher level of non-HDL-C10). These findings suggest that levels of non-HDL-C may inform more precise management for secondary prevention by antiplatelet therapy and statins.
The non-HDL-C level has emerged as a potential novel biomarker for assessing the risk of recurrent stroke and the effect of therapeutic treatment for secondary prevention. However, whether a panel of lipid biomarkers of non-HDL-C works better than a single biomarker of LDL-C in predicting recurrent stroke is unknown and warrants further exploration. In addition, randomized controlled trials are required to validate the influence of non-HDL-C on sICAS, ischemic stroke, and ICH and to determine the optimal level of non-HDL-C to guide lipid-lowering therapy for secondary prevention. Furthermore, methods of controlling the level of HDL-C, for example, through lifestyle modification and a certain medication regimen, require further investigation. In general, more effective treatments and more sensitive biomarkers for therapeutic effects are needed for secondary prevention after minor stroke.
Yanan Wang received grants from the Postdoctoral Research Fund of the West China Hospital, Sichuan University (2024HXBH139). Simiao Wu received grants from the National Natural Science Foundation of China (82171285), the Science and Technology Department of Sichuan Province (2024YFHZ0330), and the 1·3·5 project for disciplines of excellence–Clinical Research Fund, West China Hospital, Sichuan University (2024HXFH022).
