Neurological effects of proprotein convertase subtilisin/kexin type 9 inhibitors: direct comparisons

Abstract

Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably alter the lipid profile. We sought to examine the rates of ischaemic stroke and neurocognitive deficits in patients treated with and without PCSK9 inhibitors. Methods and results Randomized controlled trials (RCTs) reporting rates of ischaemic stroke and neurocognitive deficits in patients using PCSK9 inhibitors were identified. Standard meta-analysis techniques were used to compare these outcomes among patients treated with and without PCSK9 inhibitors and the two US Food and Drug Administration-approved PCSK9 inhibitors, evolocumab and alirocumab. The results were presented in terms of risk ratio (RR) with 95% confidence intervals (CIs). Sixteen RCTs with 39 104 patients were included. Evolocumab was used in six RCTs with 33 450 patients, whereas alirocumab was used in 10 RCTs with 5654 patients. We observed a significantly lower risk of ischaemic stroke among those treated with PCSK9 inhibitors (RR 0.77, 95% CI 0.64–0.93) when compared with those without. We did not observe any difference in the risk of neurocognitive deficits between the aforementioned groups (RR 1.11, 95% CI 0.93–1.32). The lower stroke risk in the PCSK9 inhibitors group was driven by evolocumab studies. We observed no difference in the risk of neurocognitive deficits among evolocumab and alirocumab when compared with no PCSK9 inhibitors group. Conclusion Treatment with PCSK9 inhibitors significantly lowers the risk of ischaemic stroke, without any increased risk of neurocognitive deficits. PCSK9 inhibitors are neuroprotective due to the decrease in ischaemic-mediated neurovascular events and should be considered cognitively innocuous medications.

Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

“…Our review did not yield an increased risk for diabetes mellitus or neurocognitive events in PCSK9 inhibitor use compared to placebo in line with most published reviews [3,11,66]. One previous review showed that alirocumab had a higher risk of neurocognitive disorders.…”

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer’s Disease

“…In this study, a total of 1,204 subjects with mean age of 65 years, that did not present neurological disorders on treatment with evolocumab or placebo, were followed for 1.6 years without evidencing any association with adverse cognitive effects (Giugliano et al, 2017b). This result was further confirmed by a recent meta-analysis (Bajaj et al, 2018; Harvey et al, 2018). However, considering the short follow-up period of the EBBINGHAUS, a 5-year extension of the FOURIER trial will provide further findings on neurocognitive functions 1 .…”

<p>Safety and Tolerability of PCSK9 Inhibitors: Current Insights</p>

“…This may have led to a reporting bias contributing to the increase in neurocognitive deficits noted in the earlier studies and especially in the OSLER studies which were an open-label trial. 50 Notwithstanding, in order to better clarify this issue, a randomized, double-blind, placebo-controlled, multicenter study (EBBINGHAUS study) was conducted, which involved a subgroup of patients from the FOURIER trial. The EBBINGHAUS study prospectively assessed the cognitive function in 1204 patients using the Cambridge Neuropsychological Test Automated Battery.…”

“…51 The findings of the EBBINGHAUS study were corroborated by the results of two more recent meta-analyses, which demonstrated that there was no difference in the risk of neurocognitive deficits between PCSK9 inhibitors and control groups. 50,52 In addition, no association was found between neurocognitive treatment-emergent adverse events and LDL-C<25 mg/dL. 50 Furthermore, in a very recent study, which evaluated patient-reported cognition in the entire FOURIER trial using a self-survey, it was shown that the addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C levels <20 mg/dl.…”

“…50,52 In addition, no association was found between neurocognitive treatment-emergent adverse events and LDL-C<25 mg/dL. 50 Furthermore, in a very recent study, which evaluated patient-reported cognition in the entire FOURIER trial using a self-survey, it was shown that the addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C levels <20 mg/dl. 53 Based on the above, it appears reasonable to conclude that PCSK9 inhibitor therapy does not cause any major harmful cognitive effects.…”