Do PCSK9 Inhibitors Cause Cognitive Impairment? Michael J. Lipinski, MD, PhD MedStar Washington Hospital Center

Michael J. Lipinski, MD, PhD   I have no relevant financial relationships

Cholesterol Plays a Critical Role in Brain Development Cholesterol is critical for neural development 20% of your cholesterol is in your brain In vitro experiments demonstrate that increased cholesterol increases synaptic connections Lipoproteins are too large to cross the blood brain barrier Astrocytes generate lipoproteins Mutations in ApoE are associated with Alzheimers dementia However, fetal LDL levels range from 40 mg/dL and decrease below 20 mg/dL

J Clin Lipidol 2014

Effects not related to statin use Analysis of 4,428 individuals age 70-82 randomized to pravastatin or placebo from the PROSPER Study Whether on statin or placebo, greater variability in LDL-c from visit-to-visit was associated with lower cognitive performance Higher LDL-c variability associated with decreased cerebral blood flow and increased white matter disease Effects not related to statin use Smit, Circulation 2016

Mechanism of how PCSK9 inhibitors decrease LDL Lambert, J Lipid Res 2012

Mechanism of how PCSK9 inhibitors decrease LDL Lambert, J Lipid Res 2012

Neurocognitive Impairment with PCSK9 Inhibitors? Events Cardiovascular Events

Things I personally hope to avoid

Utilizing high-dose regimens Network Meta-Analysis of 17 RCTs with 13,083 patients: PCSK9 inhibitors (n=8,250), Placebo (n=3,957), Ezetimibe (n=846) Utilizing high-dose regimens Evolocumab 140 mg every 2 weeks or 420 mg monthly Alirocumab 150 mg every 2 weeks or 300 mg monthly

LDL Cholesterol Reduction * p<0.05 ** p<0.001 >80% of patients on statin therapy ** ** 36% further reduction beyond Ezetimibe ** Lipinski, Eur Heart J 2016

Total Cholesterol Reduction * p<0.05 ** p<0.001 * ** 20% further reduction beyond Ezetimibe ** Lipinski, Eur Heart J 2016

Lp(a) Reduction ** * * p<0.05 ** p<0.001 22% further reduction beyond Ezetimibe * Lipinski, Eur Heart J 2016

All-Cause Mortality Lipinski, Eur Heart J 2016

Neurocognitive Events Lipinski, Eur Heart J 2016

With the Addition of GLAGOV

Neurocognitive Events Circ Cardiovasc Qual Outcomes 2017

EBBINGHAUS met the outcome of non-inferiority 1204 pts underwent neurocognitive assessment prior to receiving therapy EBBINGHAUS met the outcome of non-inferiority FOURIER met primary outcome without safety concerns Clin Cardiol 2017

Conclusion Cholesterol is critical in brain development and function Statins do not worsen neurocognitive function Early Outcomes Studies appear to suggest PCSK9 inhibitors increase neurocognitive events This debate will likely be clarified at the ACC