Lower LDL-C Correlated With Lower Risk of MACE in Ischemic Stroke Survivors

In patients with prior ischemic stroke, low-density lipoprotein cholesterol (LDL-C) below 40 mg/dL was correlated with a lower risk of major adverse cardiovascular events (MACE), including recurrent stroke, without a clear increase in hemorrhagic stroke risk, according to findings from an analysis of the FOURIER clinical trial (NCT01764633) published by investigators in Circulation.^1,2

Are Very Low LDL-C Levels Safe?

The merits of very low LDL-C levels have been thoroughly discussed in literature. With novel cholesterol-lowering agents entering the market at rapid speed, there are increasingly more patients achieving lower levels of LDL-C. These are often lower than the recommended 40 mg/dL target and sometimes reach extremely low levels less than 20 mg/dL. Despite being associated with cardiovascular benefits, concerns have been raised about possible risks and long-term safety implications of very low LDL-C levels.³

Randomized clinical trials featuring new lipid-lowering agents in the form of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or ezetimibe (Zetia; Merck & Co) have affirmed the benefits of intensive LDL-C reduction in patients with atherosclerotic cardiovascular disease (ASCVD). However, limited data are available in patients with prior ischemic stroke. There is a clear association between lipid levels and the risk of ischemic stroke, but the impacts of low LDL-C levels after the stroke itself—and what it means for their risk of MACE—have yet to be elucidated.^1,4

The current authors conducted a secondary analysis of the FOURIER trial and its open-label extension, a multinational, double-blind, placebo-controlled study of patients with ASCVD and elevated LDL-C who were treated with evolocumab (Repatha; Amgen). Through this analysis, they sought to examine whether very low levels of achieved LDL-C in stable patients with prior ischemic stroke were associated with lower rates of MACE, including recurrent stroke.¹

Can Low LDL-C Levels Reduce Incidence of MACE?

The incidence of a 5-way composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization was primarily evaluated by the investigators. In total, 5291 patients were included in the analysis, with a total exposure of 14,418 patient-years. As per the inclusion guidelines, all patients had a history of ischemic stroke, occurring at a median of 3.3 years before trial entry.¹

A monotonic relationship between lower achieved LDL-C and a lower adjusted annualized incidence rate of the composite primary end point was observed. Compared with patients who achieved LDL-C values of 70 mg/dL or higher, LDL-C levels less than 40 mg/dL were associated with an adjusted incidence rate ratio of 0.69 (95% CI, 0.57—0.84).¹

Stroke end points were also examined. There were 284 recurrent strokes that occurred during follow-up, of which 248 were ischemic. As achieved LDL-C decreased, the incidence of recurrent stroke decreased in a monotonic fashion, both for all stroke and ischemic stroke. Importantly, there was no apparent relationship between achieved LDL-C and the incidence of hemorrhagic stroke.¹

A sensitivity analysis in stroke patients without a history of myocardial infarction revealed similar results. Lower event rates were observed at lower values of LDL-C in this population, especially for MACE composite end points and key secondary end points of all stroke and ischemic stroke. Achieving LDL-C of 40 mg/dL was associated with lower adjusted incidence rate ratios of MACE compared with those achieving higher LDL-C values.¹

What Are the Implications for Pharmacists?

This data demonstrates the benefits of very low LDL-C levels in ischemic stroke survivors. There was no apparent relationship between achieved LDL-C and hemorrhagic stroke, which contrasts with prior reports of some statin trials. Lipid-lowering intensity should be determined by a patient’s past and current cardiovascular risk while considering the long-term health implications of very low LDL-C levels.¹

Pharmacists should ensure that patients at risk of MACE are prescribed appropriate LDL-C–lowering therapies. PCSK9 inhibitors present as effective options for lipid lowering, especially newer agents like evolocumab. For patients who have recovered from a past ischemic stroke, they may be concerned that their history puts them at risk of recurrent events. They should be counseled that, with sound lipid-lowering strategies in place, their MACE risk can be drastically reduced.

“These data support that an LDL-C below 40 mg/dL may represent a reasonable target to improve cardiovascular outcomes in patients with prior ischemic stroke,” the study investigators concluded.¹

REFERENCES

1. Monguilon V, Kelly P, O’Donoghue ML, et al. Efficacy and safety of very low achieved LDL-cholesterol in patients with prior ischemic stroke. Circulation. 2025. doi:10.1161/CIRCULATIONAHA.125.077549

2. Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER). ClinicalTrials.gov Identifier: NCT01764633. Last Updated May 28, 2024. Accessed November 4, 2025. https://clinicaltrials.gov/study/NCT01764633

3. DelPizzo M, Cepo O. Reassessing the safety and efficacy of very low LDL cholesterol. Pharmacy Times. Published July 9, 2025. Accessed November 4, 2025. https://www.pharmacytimes.com/view/reassessing-the-safety-and-efficacy-of-very-low-ldl-cholesterol

4. Glasser SP, Mosher A, Banach M, Howard G. What is the association of lipid levels and incident stroke? Int J Cardiol. 2016;220:890-894. doi:10.1016/j.ijcard.2016.06.091