Impact of Low-Density Lipoprotein Cholesterol Target on Atherosclerotic Ischemic Stroke in Asian Patients:

Article information

J Stroke. 2025;27(3):434-435

Publication date (electronic) : 2025 September 29

doi : https://doi.org/10.5853/jos.2025.04028

Luis Castilla-Guerra^,1,2, Carmen Fernandez-Moreno^2,3, Eduardo Carmona-Nimo^1,2

¹Vascular Risk Unit, Department of Internal Medicine, Hospital Virgen Macarena, Seville, Spain

²Department of Medicine, University of Seville, Seville, Spain

³Department of Neurology, Hospital de Valme, Seville, Spain

Correspondence: Luis Castilla-Guerra Vascular Risk Unit, Department of Internal Medicine, Hospital Virgen Macarena, University of Seville, Avenida Dr Fedriani sn. 41900 Sevilla, Spain Tel: +34-955008000 E-mail: lcastilla@us.es

Received 2025 August 19; Accepted 2025 September 2.

Dear Sir:

We congratulate the authors for reporting the Korean Treat Stroke to Target (TST) cohort [1], the first trial to compare two low-density lipoprotein cholesterol (LDL-C) target levels in patients with atherothrombotic strokes. This is particularly valuable because it provides direct and applicable data for clinicians across Asia, where intracranial and small vessel diseases are more prevalent and often underrepresented in stroke trials in Western countries. Such localized insights significantly enhance global generalizability and help fill important knowledge gaps.

We believe that intensive LDL-C lowering does not prevent recurrent stroke in Asian patients who have experienced ischemic stroke or transient ischemic attack, with evidence of atherosclerosis overstated relative to available evidence. This study does not directly assess whether the benefit of reduced LDL-C levels is reproducible in Asian populations affected by stroke: the Korean subgroup had a relatively small number of events (primary endpoints: 24 vs. 31 [low vs. high LDL-C target group], hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.45–1.33, P=0.353; any stroke: 20 vs. 26, HR 1.35, 95% CI 0.75–2.42, P=0.321) and achieved only a modest LDL-C separation (approximately 15 mg/dL between arms), and the follow-up duration was shorter than that in the broader trial. Moreover, inclusion of cases with small vessel occlusion (SVO; 189 patients, 26.5%), which are less responsive to LDL-C reduction, likely diluted the observable LDL-specific benefits.

In contrast, robust evidence from larger randomized trials, such as Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) [2], and the full TST [3], with lipid-lowering interventions including ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [4], along with current stroke guidelines [5], consistently support LDL-C lowering in patients with atherosclerosis who are affected by stroke.

In a recent meta-analysis that included 11 randomized clinical trials comprising 20,163 patients with stroke, the risk of recurrent stroke was 8% with intensive LDL-C reduction and 9% with less intensive LDL-C reduction. This difference was statistically significant. However, the benefits associated with more intensive LDL-C reduction were only detected in patients with ischemic stroke with evidence of atherosclerosis [6].

In particular, in intracranial atherosclerosis (ICAS), “treat-to-target <70 mg/dL” is currently part of best medical therapy. The aggressive medical arm of the Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial (which targets LDL-C <70 mg/dL alongside tight blood pressure control and lifestyle changes) performed better than stenting for managing symptomatic ICAS [7]. Observational analyses within SAMMPRIS linked achieving LDL-C <70 mg/dL to fewer vascular events, arguing against disregarding LDL-C lowering in populations with ICAS common in Asia.

A single-center randomized controlled trial including 120 Chinese patients with 50%–99% symptomatic ICAS found that high-intensity atorvastatin led to significantly reduced recurrent cerebrovascular events compared to those after treatment with low-intensity atorvastatin after 52 weeks of follow-up (cumulative probability, 0.05 vs. 0.25; log-rank, P=0.012), with no significant difference in adverse events reported [8].

Current evidence from PCSK9 inhibitor trials indicates that aggressive LDL-C targeting may benefit high-risk patients. For instance, aiming for an LDL-C level <55 mg/dL in individuals with a history of ischemic stroke has resulted in updated European Stroke Guidelines. These guidelines now recommend intensive LDL-C lowering in patients with intracranial atherosclerotic disease, reflecting a shift towards more stringent lipid targets for secondary stroke prevention [9].

The observations from the Korean subgroup in the present study should be portrayed as hypothesis-generating and not as practice-changing results. Although differences are apparent in the efficacy of lipid-lowering therapy across stroke subtypes, particularly in patients who have experienced cardioembolic strokes or SVO, the message to clinicians managing stroke survivors must be clear and straightforward, even in Asian patients: for secondary prevention in patients with ischemic stroke or transient ischemic attack with evidence of atherosclerosis, lowering LDL-C levels to <70 mg/dL is strongly supported by evidence and should be standard practice. In patients at exceptionally high risk, including those with recurrent vascular events, pursuing even lower targets (<55 mg/dL and potentially <40 mg/dL), may offer additional benefits, especially with highly effective agents such as PCSK9 inhibitors being available. Clinicians should weigh these LDL-C goals against individual bleeding risk, comorbidities, and the overall clinical status of each patient.