Optimal Low-Density Lipoprotein Cholesterol Level: Time to Reconsider Stroke Subtypes

Article information

J Stroke. 2025;27(2):159-160

Publication date (electronic) : 2025 May 31

doi : https://doi.org/10.5853/jos.2025.02159

Jong S. Kim

Department of Neurology, Gangneung Asan Hospital, University of Ulsan, Gangneung, Korea

Correspondence: Jong S. Kim Department of Neurology, Gangneung Asan Hospital, University of Ulsan, 38 Bangdong-gil, Gangneung 25440, Korea Tel: +82-2-8702-3440 E-mail: jongskim@amc.seoul.kr

Received 2025 May 12; Accepted 2025 May 12.

About 20 years ago, when Michael Welch presented the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial at the International Stroke Conference, he received a standing ovation. Although previous studies have shown the benefit of statin therapy in reducing stroke occurrence, the result was a secondary endpoint in patients with coronary heart disease. Doctor Welch was the first to demonstrate a significant risk reduction in cerebrocardiovascular events when intense-dose atorvastatin (80 mg/day) was used in patients with a history of stroke but not coronary disease [1]. At that time, there were small concerns regarding the stroke subtype because statins appeared to increase the incidence of intracerebral hemorrhage, especially in patients who initially presented with intracerebral hemorrhage.

The Treat Stroke to Target (TST) trial was the next important study that compared the risk of cerebrocardiovascular events in patients who had experienced a stroke or transient ischemic attack based on the low-density lipoprotein cholesterol (LDL-C) target [2]. A total of 2,860 patients from France and South Korea were recruited. The results showed a 22% risk reduction in the low LDL-C target group (LT; <70 mg/dL) compared to the high LDL-C target group (HT; 100±10 mg/dL). A separate analysis using the French cohort only showed a similar result [3]. These results have set the background for the belief that “the lower the LDL-C level, the better the clinical outcome” in patients with stroke.

However, the stroke subtype issue remains. The TST trial only enrolled stroke patients with “evidence of atherosclerosis.” Therefore, whether or not lipid-lowering therapy is indeed beneficial for stroke not directly related to atherosclerosis, such as small vessel disease (SVD) or cardiac embolism, remains unclear. Indeed, J-STARS data reported that pravastatin was effective for secondary stroke prevention in patients with atherosclerotic stroke but not in those with SVD [4]. Moreover, reviewing the SPARCL result, the efficacy of statins appears to vary according to the location of atherosclerosis. Although the benefit of preventing the primary outcome (overall odds ratio) was 16% in this study, greater (33%) reduction in the primary outcome was observed in patients with carotid artery disease, an important type of extracranial atherosclerosis (ECAS) [5], suggesting that the benefit of high-dose statins may be lower in stroke patients without ECAS. These data heightened the degree of concern among Asian physicians because Asian stroke patients more often have distal cerebral artery pathologies, such as intracranial atherosclerosis (ICAS) and SVD, than their Caucasian counterparts [6].

In this issue of the Journal of Stroke, a paper from Korean TST investigators was published [7]. The study aimed to determine whether the benefit of LT over HT is reproducible in Asian stroke patients. Among 712 Korean patients, the mean LDL-C level was 71.0 mg/dL in 357 LT patients and 86.1 mg/dL in 355 HT patients. Ischemic stroke was further analyzed according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification and the location of atherosclerosis (ECAS vs. ICAS vs. ECAS+ICAS). Notably, the main result was neutral; the primary endpoint occurred in 24 patients (6.7%) in the LT group and 31 (8.7%) in the HT group (adjusted hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.45–1.33, P=0.353). Among secondary endpoints, cardiovascular events alone occurred significantly less frequently in the LT than in the HT group (HR 0.26, 95% CI 0.09–0.80, P=0.019), a finding similar to that observed in French TST patients. Meanwhile, no significant difference in ischemic stroke events (HR 1.12, 95% CI 0.60–2.10, P=0.712) was observed. Further analysis suggested that LT may be less effective in patients with ICAS or SVD than in patients with ECAS.

Given the smaller number and shorter follow-up period of the Korean patients compared to the French patients, the data need to be interpreted cautiously. Nevertheless, the principle of “the lower the LDL-C level, the better the clinical outcome” may not be true, especially for certain subtypes of stroke [8]; future research is needed to determine whether statins are effective and, if so, what would be an appropriate LDL-C target in patients with ICAS or SVD.