PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of medications that greatly lower low-density lipoprotein cholesterol (LDL-C) by upregulating LDL receptor availability. In early 2014, the US Food and Drug Administration (FDA) directed developers of PCSK9 inhibitors to monitor neurocognitive adverse effects and consider neurocognitive testing in at least a subset of participants in ongoing late-stage trials. Available trial evidence indicates that neurocognitive adverse events may occur more commonly in individuals receiving an antibody to PCSK9, but these events are uncommon and have not been associated with on-treatment LDL-C levels. Moreover, it is unclear to what extent closer monitoring of trial participants allocated to PCSK9 inhibitors has led to an ascertainment bias. Regardless, further trial data are needed, and long-term outcomes trials are ongoing, with at least one including a neurocognitive substudy. Considering lessons learned from the statin experience, high-quality prospective cohort studies and randomized trials may not be enough to allay concerns or settle debate since the focus of effect in these studies is the group average. Therefore, we suggest that n-of-1 trials could be considered to bring the focus to the individual while retaining the benefits of blinding and randomization in evidence generation. Ultimately, any neurocognitive adverse effects that might exist with PCSK9 inhibition and lipid lowering must be weighed against potential benefits of therapy, including avoidance of myocardial infarction and stroke, and a reduced risk of dementia due to neurovascular benefits from long-term lipid lowering.