Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association

Abstract

The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein cholesterol lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke. The writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize existing evidence and to identify gaps in current knowledge. Although some retrospective, case control, and prospective longitudinal studies suggest that statins and low-density lipoprotein cholesterol lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion. The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is nonsignificant, and achieving very low levels of low-density lipoprotein cholesterol does not increase that risk. Data reflecting the risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke are not robust and require additional focused study.

Outcomes of Patients with Normal LDL-Cholesterol at Admission for Acute Coronary Syndromes: Lower Is Not Always Better

“…A recent study [24] found that higher LDL-C levels were associated with a lower risk of major depressive disorder (MDD), whereas one relatively recent case-control study found that higher LDL-C and total cholesterol levels and lower HDL-C levels were connected to anxiety disorder risk [25]. There are numerous gaps in our understanding of the role of cholesterol and its biosynthesis, so at this moment we could only suggest reasons for the described connection between "spontaneous" low LDL and psychological disorders in ACS patients [26]. Whatever the reason for that finding, it is clear from our data and from previous research [27], that psychological disorders are linked with worse outcomes after ACS.…”

Current and Future Treatments of Vascular Cognitive Impairment

“…On the other hand, aggressive lowering of LDL cholesterol by statins was inconsistently associated with ICH and dementia in observational studies, 120,121 which could be relevant in patients with cSVD. Conversely, more recent evidence failed to find such associations.…”

“…Overall available evidence suggests that the protection against atherosclerotic cardiovascular disease with lowering LDL cholesterol outweighs the potential risk of ICH among patients with high atherosclerotic cardiovascular disease risks. 121…”

Evolution of More Aggressive LDL-Cholesterol Targets and Therapies for Cardiovascular Disease Prevention

“…Although the IMPROVE-IT trial found a non-significant trend towards increased hemorrhagic stroke in those treated to a lower LDL-C goal with ezetimibe and simvastatin, a subsequent 2017 analysis showed significant reductions in major adverse cardiovascular events (MACE) with LDL-C < 30 mg/dL compared to ≥70 mg/dL, without a concomitant increase in rates of neurocognitive events, hemorrhagic stroke, or non-CVD deaths [58,99]. The American Heart Association recently published a scientific statement on LDL-C lowering and the risk for dementia and hemorrhagic stroke, stating that achieving very low LDL-C does not increase the risk for hemorrhagic stroke and that the risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is small and consistently nonsignificant [100].…”