Optimal LDL-C Levels for Ischemic Stroke Prevention: A Neurologist’s Perspective

Abstract

Low-density lipoprotein cholesterol (LDL-C) lowering is a central therapeutic strategy in atherosclerotic cardiovascular disease (ASCVD) and is also important for ischemic stroke. As outcome-driven evidence has accumulated, lipid management guidelines have progressively adopted more stringent LDL-C targets. Landmark trials of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors have shown consistent cardiovascular benefit across progressively lower achieved LDL-C levels in ASCVD. In the stroke field, randomized controlled trials, including Stroke Prevention by Aggressive Reduction in Cholesterol Levels and Treat Stroke to Target, have provided stroke-specific evidence supporting intensive LDL-C lowering for secondary prevention, particularly in patients with atherosclerotic stroke. Beyond its established role in long-term secondary prevention, emerging evidence suggests that intensive LDL-C lowering may also affect the early clinical course after ischemic stroke. Nevertheless, important knowledge gaps remain. Ischemic stroke is a heterogeneous disease with diverse etiologic mechanisms, including nonatherosclerotic subtypes such as small vessel occlusion and cardioembolism. Because evidence-based LDL-C targets for these populations remain poorly defined, current guidelines focus mainly on atherosclerotic stroke, leaving uncertainty regarding optimal lipid management in nonatherosclerotic stroke subtypes. Ongoing large-scale clinical trials specifically targeting these populations are expected to address this gap and to inform more tailored lipid-lowering strategies in stroke care. This review summarizes current evidence on LDL-C targets and lipid-lowering therapy in ischemic stroke and considers the implications for clinical practice and future research.

INTRODUCTION

Stroke is one of the leading causes of death and disability worldwide and imposes a major global health burden. According to the Global Burden of Disease 2021 data, stroke was the third leading cause of death worldwide and a major contributor to disability-adjusted life years, underscoring its profound public health impact.¹ Despite substantial advances in acute stroke care, many stroke survivors are left with long-term disability, creating considerable burdens for both individuals and society. Accordingly, both primary stroke prevention and secondary prevention after stroke are critically important.

Effective prevention strategies target modifiable vascular risk factors, including hypertension, diabetes, smoking, and dyslipidemia. Among these, elevated low-density lipoprotein cholesterol (LDL-C) is a well-established and clinically important risk factor for stroke, and epidemiological data indicate that it contributes substantially to the global stroke burden.² Accordingly, lipid-lowering therapy (LLT) has become a cornerstone of both primary and secondary stroke prevention.

Early guideline recommendations for lipid management in patients with stroke were largely extrapolated from randomized controlled trials (RCTs) conducted in populations with coronary heart disease. Consequently, the initial stroke guidelines reflected evidence derived predominantly from coronary-dominant atherosclerotic cardiovascular disease (ASCVD) rather than from stroke-specific populations. Over time, however, accumulating evidence from stroke-specific trials has provided more directly relevant data and has driven important refinements in lipid-lowering recommendations for cerebrovascular disease.

In this review, we examine the evolution of clinical practice guidelines for LLT in stroke care, with a primary focus on ischemic stroke, and trace how evidence from landmark ASCVD trials, stroke-specific RCTs, major post hoc analyses, and representative observational studies has shaped contemporary recommendations. We also highlight key unresolved clinical issues, including the debated risk of hemorrhagic stroke associated with intensive LDL-C lowering and the limited evidence base for nonatherosclerotic stroke subtypes. Finally, we discuss LLT in the acute phase of ischemic stroke, emphasizing emerging evidence that early lipid modulation may influence short-term neurological stability and recurrence risk.

LANDMARK TRIALS OF LLT FOR SECONDARY PREVENTION OF ASCVD

As evidence supporting LLT for secondary prevention in patients with ASCVD accumulated, therapeutic strategies progressively shifted toward lower LDL-C targets. This shift reflected a gradual convergence between achieved LDL-C levels and demonstrable cardiovascular benefit in pivotal secondary prevention trials, giving rise to the widely accepted principle that “the lower, the better.”³,⁴,⁵,⁶,⁷ Accordingly, contemporary LDL-C targets have been derived primarily from outcome data rather than from predefined theoretical thresholds.

Early support for intensive LDL-C lowering emerged from large-scale statin trials. The Heart Protection Study showed that simvastatin 40 mg significantly reduced major vascular events even among patients with baseline LDL-C levels below 100 mg/dL, establishing that the benefit extended beyond traditionally defined high-LDL-C populations.³ This concept was reinforced by the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, which directly compared 2 statin intensities and demonstrated superior cardiovascular outcomes with high-intensity atorvastatin 80 mg versus moderate-intensity pravastatin 40 mg after acute coronary syndrome (ACS). In PROVE IT-TIMI 22, the atorvastatin group achieved a significantly lower mean LDL-C level of approximately 62 mg/dL, compared with 95 mg/dL in the pravastatin group, providing clear evidence that lowering LDL-C well below 100 mg/dL translated into greater clinical benefit.⁴ These findings contributed to the 2004 update of the Adult Treatment Panel III guidelines, which introduced an LDL-C target of <70 mg/dL for patients at very high ASCVD risk. However, given the limited lipid-lowering options available at the time, the guidelines also acknowledged practical challenges, noting that LDL-C reductions of more than 50% were often difficult to achieve and that an LDL-C target of <70 mg/dL might not be attainable in patients with markedly elevated baseline levels.⁸

Further refinement of LDL-C targets was driven by the emergence of combination therapy with ezetimibe. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial provided definitive evidence that adding a nonstatin agent could further reduce cardiovascular risk. In patients with recent ACS, simvastatin plus ezetimibe significantly reduced major adverse cardiovascular events (MACE) compared with simvastatin alone, achieving a mean LDL-C level of 53.2 mg/dL versus 69.9 mg/dL in the statin monotherapy group.⁵ This trial established LDL-C lowering beyond statin monotherapy as a clinically meaningful strategy and accelerated the incorporation of combination therapy into routine practice, prompting the 2017 American Association of Clinical Endocrinologists guidelines to recommend a lower LDL-C target of <55 mg/dL for high-risk patients.⁹

The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors further expanded the achievable range of LDL-C lowering in secondary prevention and enabled rigorous assessment of the lower limits of cardiovascular risk reduction. In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk and ODYSSEY Outcomes trials, adding PCSK9 inhibitors to background statin therapy produced profound LDL-C reductions to levels below 40 mg/dL and conferred additional cardiovascular benefit in high-risk ASCVD populations.⁶,⁷ These data confirmed that even extremely low LDL-C levels were both attainable and beneficial, prompting the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines to recommend an LDL-C target of <40 mg/dL for patients with recurrent ASCVD events despite maximally tolerated statin therapy.¹⁰

Overall, LDL-C targets for secondary prevention of ASCVD have progressively declined in parallel with advances in LLT and have been anchored to the LDL-C levels achieved in pivotal outcome-driven clinical trials that demonstrated cardiovascular benefit.

LLT IN STROKE: EVIDENCE, LIMITATIONS, AND UNRESOLVED QUESTIONS

Although the landmark trials described above predominantly enrolled patients with coronary artery disease, early stroke guidelines were largely extrapolated from evidence derived from those studies. However, patients with a prior history of stroke or cerebrovascular disease accounted for only approximately 3% to 20% of participants in these trials.³,⁶,⁷,¹¹,¹² This limited representation reduced the direct applicability of these findings to stroke-specific lipid management. In this context, RCTs conducted exclusively in patients with stroke, most notably the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) and Treat Stroke to Target (TST) trials, played pivotal roles in informing subsequent updates to stroke-specific lipid management guidelines.

Published in 2006, the SPARCL trial compared high-intensity atorvastatin 80 mg with placebo in patients with ischemic stroke or transient ischemic attack (TIA) who had no known coronary artery disease or major cardioembolic (CE) source. Treatment with atorvastatin reduced the mean LDL-C level from a baseline of 132.7 to 61.3 mg/dL and significantly lowered the risk of recurrent stroke.¹³ This study provided robust evidence supporting high-intensity statin therapy in patients with ischemic stroke and remains one of the most influential trials in stroke prevention. On the basis of the SPARCL findings, current stroke guidelines recommend high-intensity statin therapy, particularly atorvastatin 80 mg, for patients with ischemic stroke who do not have coronary artery disease or a major CE source and whose LDL-C levels exceed 100 mg/dL.¹⁴ However, SPARCL also reported a significantly higher incidence of hemorrhagic stroke in the atorvastatin group, raising important safety concerns. A decade later, the TST trial provided definitive evidence supporting a lower LDL-C target in patients with ischemic stroke and atherosclerotic disease. In this study, patients with ischemic stroke or TIA and documented atherosclerotic disease were randomized to 1 of 2 predefined LDL-C targets (<70 vs. 90–110 mg/dL), whereas the choice of LLT was left to the discretion of the treating investigators. Achieving the lower LDL-C target resulted in a 22% relative reduction in MACE compared with the higher-target group.¹⁵ These findings directly informed current guidelines, which now explicitly endorse an LDL-C target of <70 mg/dL for patients with ischemic stroke or TIA related to atherosclerotic disease.¹⁴ As supportive evidence, the Japan Statin Treatment Against Recurrent Stroke (J-STARS) trial demonstrated a significant reduction in atherothrombotic infarction with low-intensity pravastatin, despite no significant effect on overall stroke/TIA recurrence.¹⁶ More recently, in the ROSuvastatin plus Ezetimibe Treatment for Target LDL-C goal Achievement in patients with recent ischemic Stroke trial, moderate-intensity rosuvastatin plus ezetimibe achieved lower LDL-C levels and was associated with fewer major vascular events than high-intensity rosuvastatin alone in patients with atherosclerotic stroke.¹⁷ Although the lower rate of major vascular events, a secondary outcome, should be interpreted cautiously because the trial was not powered for clinical event comparisons, the finding was broadly consistent with prior evidence supporting the benefit from intensive LDL-C lowering.

In contrast to lipid management guidelines issued by cardiology and atherosclerosis societies, in which recommended LDL-C targets closely parallel the levels achieved in landmark secondary prevention trials, LDL-C targets in stroke guidelines appear relatively conservative, particularly when viewed against the LDL-C levels attained in SPARCL. The hemorrhagic stroke signal observed in SPARCL may have tempered enthusiasm for uniformly aggressive LDL-C lowering in patients with stroke. This discrepancy may reflect fundamental differences between ischemic stroke and coronary artery disease. Whereas coronary artery disease is predominantly atherosclerotic, ischemic stroke encompasses heterogeneous etiologic mechanisms, not all of which are primarily driven by atherosclerosis.¹⁸ Accordingly, aggressive LDL-C lowering cannot be assumed to provide equivalent benefit across the full spectrum of ischemic stroke.

Despite the important contributions of SPARCL and TST, the evidence base guiding lipid-lowering strategies in stroke remains considerably narrower than that for coronary-dominant ASCVD populations. In particular, it remains uncertain whether the increased risk of hemorrhagic stroke observed in SPARCL reflects a causal effect of intensive LDL-C lowering or was instead driven by underlying patient and stroke characteristics. Furthermore, large-scale RCT data are lacking for nonatherosclerotic stroke subtypes, including small vessel occlusion (SVO) and CE stroke, raising concerns about the generalizability of uniform LDL-C targets across heterogeneous stroke populations. These unresolved issues frame the following discussion on hemorrhagic stroke risk with LLT and on the suitability of a uniform LDL-C target across heterogeneous stroke subtypes, including nonatherosclerotic entities.

REVISITING HEMORRHAGIC STROKE RISK IN SPARCL AND CONTEMPORARY LIPID-LOWERING TRIALS

In the SPARCL trial, the reduction in recurrent ischemic stroke with high-intensity statin therapy was accompanied by a reported 66% relative increase in hemorrhagic stroke risk compared with placebo.¹³ This finding was consistent with earlier epidemiological observations describing an inverse relationship between LDL-C levels and hemorrhagic stroke risk¹⁹,²⁰,²¹ and prompted substantial concern regarding aggressive lipid lowering in routine stroke practice.

Subsequent post hoc analyses of the SPARCL data, however, suggested that the observed increase in hemorrhagic stroke was not directly attributable to intensive LDL-C lowering. This interpretation was supported by several lines of evidence. First, when patients were stratified by percentage LDL-C reduction from baseline (no change or increase, <50% decrease, and ≥50% decrease) or by achieved LDL-C level (≥100, 70–99, and <70 mg/dL), hemorrhagic stroke risk did not increase in parallel with the magnitude of LDL-C lowering, whereas greater LDL-C reductions were consistently associated with larger reductions in ischemic stroke risk.²² Second, hemorrhagic stroke events were more common among patients with higher blood pressure during follow-up, highlighting the potential contribution of inadequate blood pressure control, a well-established and potent risk factor for intracerebral hemorrhage, to the observed outcomes.²³ Third, SPARCL uniquely allowed enrollment of patients whose qualifying event was either ischemic or hemorrhagic stroke, and those with hemorrhagic stroke as the entry event had a markedly higher risk of recurrent hemorrhagic stroke during follow-up.²³ Evidence from contemporary large-scale trials has not supported a consistent association between intensive LDL-C lowering and increased hemorrhagic stroke risk. In the TST trial, targeting an LDL-C level of <70 mg/dL did not significantly increase hemorrhagic stroke compared with the higher-target group.¹⁵ Similarly, the J-STARS trial showed that the incidence of intracerebral hemorrhage was comparable between the statin and nonstatin groups.¹⁶ Trials evaluating PCSK9 inhibitors, which achieve substantially lower LDL-C levels than statins alone, have likewise not demonstrated an excess risk of hemorrhagic stroke.⁶,⁷ In a recent extension study of evolocumab, patients with a prior history of ischemic stroke had lower risks of MACE and recurrent ischemic stroke at achieved LDL-C levels down to <20 mg/dL, without a clear increase in hemorrhagic stroke.²⁴ Taken together, these findings suggest that the increased hemorrhagic stroke risk observed in SPARCL was more likely influenced by factors such as blood pressure control and prior hemorrhagic stroke than by intensive LDL-C lowering itself. Consistent with this interpretation, a recently published American Heart Association Scientific Statement concluded that current evidence does not indicate a clinically meaningful increase in vulnerability to hemorrhagic stroke with intensive LDL-C lowering, while supporting a consistent association between lower LDL-C levels and reduced ischemic stroke risk.²⁵

Nevertheless, post hoc analyses of SPARCL also reported an increased risk of hemorrhagic stroke among patients with SVO stroke, despite the low absolute event rate.²³ This finding raises the possibility that underlying small-vessel pathology in patients with SVO stroke, such as cerebral microbleeds or other markers of hemorrhage-prone arteriopathy,²⁶ may modify the relationship between lipid lowering and hemorrhagic risk. In addition, because hypertension is the most prominent risk factor for SVO stroke,²⁷ variation in blood pressure control may also have contributed to the hemorrhagic stroke risk observed in SPARCL, consistent with prior analyses demonstrating a strong association between higher on-treatment blood pressure and hemorrhagic stroke.²³ Because SPARCL was not designed to exclusively enroll patients with SVO stroke, dedicated subtype-specific studies are required to clarify the safety profile of intensive LDL-C lowering in this population.

IS ONE LDL-C TARGET ENOUGH FOR ALL STROKE SUBTYPES?

Another important issue in LLT after ischemic stroke is that optimal LDL-C targets have not been clearly defined for all stroke subtypes. Although intensive LDL-C lowering is well established in ASCVD, ischemic stroke comprises multiple etiologic subtypes in which the expected benefit of LDL-C reduction may differ. Although large artery atherosclerosis is an important mechanism, ischemic stroke more commonly results from nonatherosclerotic etiologies such as SVO, CE sources, arterial dissection, systemic hypercoagulable states, or cryptogenic mechanisms despite comprehensive evaluation.¹⁴,²⁸ For these nonatherosclerotic subtypes, the applicability of LDL-C targets derived primarily from coronary-dominant ASCVD trials remains uncertain. This section focuses on the available evidence and key knowledge gaps regarding LLT in the 2 major nonatherosclerotic stroke subtypes, SVO and CE stroke.

SVO stroke predominantly results from occlusive disease of the perforating arteries. The cerebral circulation contains numerous small perforating arteries that supply functionally critical deep brain structures. Because these vessels arise directly from larger parent arteries with an abrupt reduction in diameter, they are exposed to disproportionately high arterial pressure relative to their small caliber and are therefore particularly susceptible to hypertensive injury. Chronic hypertension promotes lipohyalinosis, characterized by concentric wall thickening and luminal occlusion of penetrating arteries, ultimately leading to cerebral infarction in the absence of overt atherosclerosis.²⁷ CE stroke is caused by emboligenic material of cardiac origin that occludes cerebral arteries. Principal sources include atrial fibrillation or flutter, prosthetic valves, heart failure, recent myocardial infarction, intracardiac thrombus, and paradoxical embolism through a patent foramen ovale.²⁹ This subtype results from thrombus formation at a remote source followed by embolization to cerebral arteries, rather than from primary pathology of the cerebral arterial wall. Accordingly, the direct applicability of atherosclerosis-based therapeutic paradigms to CE stroke is limited. Stroke of undetermined etiology and other determined etiologies represent even more heterogeneous categories and may include occult CE sources, nonstenotic atherosclerosis, arterial dissection, cancer-associated stroke, moyamoya disease, and other mechanisms.³⁰ Given this heterogeneity, stroke-specific LDL-C targets for these groups are difficult to standardize, and lipid management is generally individualized according to the suspected mechanism and overall vascular risk.

The TST trial strengthened the evidence base for intensive LDL-C lowering in atherosclerotic stroke, leading to adoption of a target LDL-C level of <70 mg/dL in current guidelines. In contrast, for nonatherosclerotic stroke subtypes, which account for more than half of ischemic strokes, evidence guiding optimal LDL-C targets remains limited. Consequently, lipid-lowering strategies in nonatherosclerotic stroke are largely left to the discretion of individual physicians, and this uncertainty represents a major knowledge gap in stroke care. Because no RCT has exclusively enrolled patients with SVO stroke or CE stroke, evidence guiding LLT in these populations has relied primarily on post hoc analyses of large trials and retrospective observational studies. In a post hoc analysis of the SPARCL trial comparing clinical outcomes by index stroke subtype, patients with SVO stroke showed a trend toward reduced risks of recurrent stroke and MACE with high-intensity statin therapy, although the magnitude of benefit was smaller than that observed in atherosclerotic stroke.³¹ In contrast, an analysis of Korean patients enrolled in the TST trial showed numerically higher rates of stroke-related outcomes in the lower-target LDL-C group among those with index SVO stroke.³² In a post hoc analysis of the J-STARS study, no clear benefit was observed for prevention of SVO stroke, whereas statin-associated LDL-C reduction was clearly linked to a lower risk of atherothrombotic stroke.³³ Importantly, safety concerns further complicate the interpretation of these findings. As discussed in the previous section, another post hoc analysis of SPARCL suggested that SVO stroke may be associated with an increased risk of hemorrhagic stroke,²³ raising uncertainty regarding the optimal intensity of LLT in this population. These findings underscore the uncertainty surrounding application of the “the lower, the better” concept to patients with SVO stroke. For CE stroke, RCT data are limited because this subtype has been excluded or underrepresented in most stroke-specific lipid-lowering trials. Retrospective studies have reported more favorable clinical outcomes among patients receiving LLT, particularly high-intensity statins.³⁴,³⁵,³⁶ However, these findings remain hypothesis-generating and require validation in appropriately designed prospective studies. Table 1 provides an overview of available evidence, hemorrhagic risk considerations, and guideline implications across major stroke etiologies.

Table 1. Evidence for intensive low-density lipoprotein cholesterol-lowering therapy after ischemic stroke, stratified by major stroke etiology.

Etiologic subtype	Evidence from RCTs		Considerations for hemorrhagic stroke risk	Guideline implications
Large artery atherosclerosis stroke	Stroke	SPARCL*: 13.1% vs. 18.6% (HR, 0.70; 95% CI, 0.49–1.02); TST†‡: 7.2% vs. 8.8% (HR, 0.82; 95% CI, 0.63–1.07); TST (Korean population only)§: 6.2% vs. 6.1% (HR, 0.98; 95% CI, 0.44–2.18)	Intensive LDL-C lowering is prioritized.	Strongly recommended
	Stroke or TIA	SPARCL*: 16.1% vs. 24.9% (HR, 0.63; 95% CI, 0.46–0.87)
	Ischemic stroke or TIA	TST†‡: 8.4% vs. 9.7% (HR, 0.87; 95% CI, 0.68–1.11); TST (Korean population only)§: 5.2% vs. 6.1% (HR, 0.81; 95% CI, 0.35–1.89)
	MACE	SPARCL*: 15.8% vs. 22.5% (HR, 0.70; 95% CI, 0.50–0.97); TST†‡: 8.5% vs. 10.9% (HR, 0.78; 95% CI, 0.61–0.98)
Small vessel occlusion stroke	Stroke	SPARCL*: 13.1% vs. 15.5% (HR, 0.85; 95% CI, 0.64–1.12); TST (Korean population only)§: 7.4% vs. 3.2% (HR, 3.24; 95% CI, 0.72–14.55)	The overall benefit of LDL-C-lowering therapy may still be substantial; however, intensification may warrant caution in selected patients with marked hemorrhagic vulnerability (e.g., uncontrolled hypertension, prior intracerebral hemorrhage, or extensive cerebral microbleeds).	Guideline-supported, but may need to be individualized
	Stroke or TIA	SPARCL*: 17.5% vs. 19.7% (HR, 0.89; 95% CI, 0.70–1.13)
	Ischemic stroke or TIA	TST (Korean population only)§: 7.4% vs. 2.1% (HR, 3.64; 95% CI, 0.74–17.82)
	MACE	SPARCL*: 16.9% vs. 20.1% (HR, 0.84; 95% CI, 0.66–1.08)
Cardioembolic stroke	Evidence from RCTs specific to this etiology is limited.		Robust randomized evidence is lacking to inform hemorrhagic considerations specific to intensive LDL-C lowering.	Insufficient stroke-specific evidence

RCT, randomized controlled trial; SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; HR, hazard ratio; CI, confidence interval; TST, Treat Stroke to Target; LDL-C, low-density lipoprotein cholesterol; TIA, transient ischemic attack; MACE, major adverse cardiovascular events; SVO, small vessel occlusion.

^*Subgroup n=749 for large artery atherosclerosis stroke, subgroup n=1,409 for SVO stroke; median follow-up duration, 4.9 years.

^†n=2,860; median follow-up duration, 3.5 years.

^‡The TST trial included patients with ischemic stroke or transient ischemic attack with evidence of atherosclerotic disease; thus, eligibility was not based on the index stroke etiology (e.g., large artery atherosclerosis), and the results should be interpreted as evidence from an atherosclerosis-enriched stroke/TIA population rather than an etiology-specific trial of large artery atherosclerosis stroke.

^§Subgroup n=389 for large artery atherosclerosis stroke, subgroup n=189 for SVO stroke; median follow-up duration, 2.9 years.

Addressing this gap requires prospective clinical trials that exclusively enroll patients with specific nonatherosclerotic stroke subtypes. Two such prospective studies are currently underway in Korea. The SVO70 trial (ClinicalTrials.gov identifier: NCT06649240) is enrolling patients with neuroimaging-confirmed SVO stroke to compare intensive LDL-C lowering (<70 mg/dL) with standard treatment (90–110 mg/dL).³⁷ In parallel, the STACE study is a registry-based RCT comparing statin therapy with no statin therapy in patients with acute ischemic stroke or TIA caused by high-risk CE sources.³⁸ If successfully completed, these trials are expected to help refine lipid management strategies and inform future clinical guidelines for patients with nonatherosclerotic stroke.

BEYOND LDL-C LESS THAN 70 MG/DL: LLT IN ACUTE ISCHEMIC STROKE

In addition to defining optimal LDL-C targets for secondary prevention, LLT may also influence the clinical course of ischemic stroke during the acute phase. This section focuses on the role of LLT initiated promptly after stroke onset, with particular attention to early neurological deterioration (END) and stroke recurrence.

The prognosis of patients with ischemic stroke is largely determined by 2 major factors: the severity of acute neurological injury and the occurrence of recurrent cerebrovascular or cardiovascular events after the index stroke. END is a major determinant of the extent of acute neurological injury. Approximately 10%–20% of patients with acute ischemic stroke experience END within the first few days after onset, with a higher incidence in atherosclerotic stroke.³⁹ Recurrent stroke causes additional neurological injury and directly worsens functional outcomes in patients with ischemic stroke. These recurrences occur predominantly in the early post-stroke period and are particularly common in atherosclerotic stroke,⁴⁰ mirroring the pattern observed for END. Together, these considerations identify the early post-stroke period as a key therapeutic window during which prevention of END and recurrent stroke may substantially influence outcomes.

Given the higher incidence of END and early stroke recurrence in atherosclerotic stroke, intensive LDL-C lowering represents a potentially relevant acute-phase intervention for improving post-stroke outcomes. Emerging clinical evidence supports the benefit of early and intensive LDL-C lowering in acute ischemic stroke. In an RCT conducted in China, the addition of a PCSK9 inhibitor to background statin plus ezetimibe therapy significantly reduced the incidence of END and was associated with more favorable neurological outcomes at 3 months. This clinical benefit was accompanied by a significantly higher rate of early LDL-C target achievement within 7 days in the PCSK9 inhibitor group.⁴¹ Additional evidence comes from a Korean RCT in statin-naive patients with acute ischemic stroke, in which early high-intensity rosuvastatin was associated with lower rates of END and hemorrhagic transformation.⁴² Evidence also suggests that early LDL-C reduction after stroke may reduce the risk of early recurrence. In a post hoc analysis of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial, prior LLT was associated with lower risks of recurrent stroke and MACE.⁴³ In another prospective study of patients with atherosclerotic stroke, early recurrent stroke within 1 month was significantly less frequent among those treated with PCSK9 inhibitors in addition to statin plus ezetimibe therapy.⁴⁴ These findings suggest that rapid and intensive LDL-C lowering early after stroke onset may improve short-term clinical outcomes. At the same time, the currently available studies were not designed to evaluate hard clinical endpoints such as long-term stroke recurrence or MACE, and further studies are needed to determine whether these early benefits translate into sustained clinical benefit.

Extending these observations to real-world settings, registry-based studies from Korea have shown that earlier initiation of statin therapy in patients with acute ischemic stroke treated with thrombolysis is associated with better neurological outcomes at 3 months.⁴⁵,⁴⁶ Notably, the potential benefit of LLT in the acute stroke setting appears to extend even to patients who have already achieved guideline-recommended LDL-C targets. In other retrospective, registry-based studies from Korea, patients with baseline LDL-C levels <70 mg/dL who were not receiving statin therapy before stroke had a significantly lower risk of recurrent vascular events when statin therapy was initiated after stroke.⁴⁷,⁴⁸ These findings suggest that, beyond LDL-C reduction per se, the pleiotropic effects of statins, such as plaque stabilization, improved endothelial function, and anti-inflammatory properties,⁴⁹ may play a meaningful role in improving acute stroke outcomes.

Overall, the available evidence suggests that LLT in acute ischemic stroke may extend beyond its role as a long-term secondary prevention strategy. Early and more intensive LDL-C lowering during the acute phase may contribute to prevention of END, reduction of early stroke recurrence, and improvement of functional outcomes, even among patients who already meet conventional LDL-C targets at baseline. In particular, the acute phase may warrant a more aggressive LDL-C-lowering approach in patients with atherosclerotic stroke.

CONCLUSION

As evidence has accumulated, intensive LDL-C lowering has become firmly established as a core strategy in ASCVD, and its relevance to ischemic stroke has likewise become clearer, most notably in atherosclerotic stroke. However, uniformly extending the single paradigm of “the lower, the better” across all ischemic stroke subtypes remains challenging because ischemic stroke is etiologically heterogeneous and the risk-benefit balance of intensive LDL-C lowering may differ across subtypes. Key knowledge gaps include the limited prospective evidence for nonatherosclerotic stroke subtypes and the need to better define hemorrhagic vulnerability in SVO stroke when considering intensive LDL-C lowering. Addressing these questions is essential to advancing more tailored lipid-lowering strategies that reflect both stroke mechanism and individual risk profiles. Ongoing trials focusing on nonatherosclerotic stroke populations in Korea are expected to provide important insights. Continued research is needed to optimize LDL-C goals and clarify the magnitude of benefit of intensive LDL-C lowering across the full spectrum of ischemic stroke.