Do PCSK9 Inhibitors Cause Cognitive Impairment?

Zara M. Risoldi Cochrane, PharmD


April 21, 2016


Concerns have emerged about an association of neurocognitive impairment with PCSK9 inhibitor therapy. Are they warranted?

Response from Zara M. Risoldi Cochrane, PharmD
Associate Professor of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions; Associate Director, Center for Drug Information and Evidence-Based Practice, Omaha, Nebraska

A new class of antihyperlipidemic agents entered the market in 2015: proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. These agents lower low-density lipoprotein (LDL) cholesterol by approximately 50% as monotherapy and by 70% when combined with background lipid-lowering treatment.[1,2] However, concerns have emerged about the association of PCSK9 inhibitors with cognitive impairment.

Alirocumab (Praluent®) and evolocumab (Repatha™) are included in this class of antihyperlipidemic agents, having been approved by the US Food and Drug Administration (FDA) in July 2015 and August 2015, respectively. They are fully human monoclonal antibodies that bind and inhibit the PCSK9 enzyme. PCSK9 promotes the degradation of LDL receptors, interfering with the major pathway of LDL cholesterol removal from the circulation. By inhibiting PCSK9, alirocumab and evolocumab upregulate LDL receptors on the surface of liver cells that bind and clear LDL cholesterol from the serum.[3,4,5]

Because cholesterol plays a role in cellular signaling and the blood/brain barrier, in theory all lipid-lowering therapies may impair neurocognitive function.[6] Although rare, neurocognitive events have been reported in two phase 3 clinical trials of the PCSK9 inhibitors. These reactions are not well characterized but have included memory loss or impairment, delirium, cognitive and attention disorders, dementia, or mental impairment. For alirocumab, neurocognitive events were reported in 1.2% of patients vs 0.5% in the placebo group. For evolocumab, neurocognitive events were reported in 0.9% of patients vs 0.3% in the standard of care group.[2,6] Rates cannot be directly compared owing to differences in study design and assessment of adverse reactions, but they appear to be similar between the two available agents.

Several factors confound assessment of the relationship between PCSK9 inhibitor administration and neurocognitive function. Coronary heart disease has been associated with cognitive impairment.[7] Elderly patients with genetic polymorphisms that inhibit PCSK9 function do not have impaired cognitive performance or activities of daily living; however, the genetic mutation does not lower LDL cholesterol to the same degree as pharmacologic inhibition.[8]

The phase 3 studies that first raised the issue of cognitive adverse events relied on patients' spontaneous reports, rather than using an objective or standardized assessment tool.[7] The correlation between LDL cholesterol level and the appearance of cognitive adverse effects in patients receiving PCSK9 inhibitors is unclear, suggesting either that no causal relationship exists or that the adverse cognitive events are caused by pharmacologic effects unrelated to LDL cholesterol lowering.[9]

In an attempt to clarify the risk for neurocognitive adverse reactions, in 2014 the FDA asked the developers of PCSK9 inhibitors to monitor for these effects in ongoing late-stage trials and to consider neurocognitive testing in at least a subset of trial participants.[6,7] There are currently at least four ongoing phase 3 trials of PCSK9 inhibitors, and no safety signals related to cognitive performance have been reported to date. Amgen is performing a dedicated neurocognitive substudy of evolocumab therapy. This trial will evaluate approximately 4000 patients and is expected to finish in 2017.[6]

At this point, the data remain inconclusive, but neurocognitive impairment is associated with PCSK9 inhibitor therapy as a rare adverse reaction. Only a randomized controlled trial can detect a cause-and-effect relationship between PCSK9 inhibitor administration and cognitive impairment, and the results of such studies will not be available for 1 year or more.


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