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

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

3. 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

4. J Clin Lipidol 2014

5. Effects not related to statin use
Analysis of 4,428 individuals age 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

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

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

8. Neurocognitive Impairment with PCSK9 Inhibitors?
Events
Cardiovascular
Events

9. Things I personally hope to avoid

10. 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

11. 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

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

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

14. All-Cause Mortality
Lipinski, Eur Heart J 2016

15. Neurocognitive Events
Lipinski, Eur Heart J 2016

16. With the Addition of GLAGOV

17. Neurocognitive Events
Circ Cardiovasc Qual Outcomes 2017

18. 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

19. 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