RESUMEN
BACKGROUND AND AIMS: Trials of the fully human monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9) alirocumab in hypercholesterolemia demonstrated substantial low-density lipoprotein cholesterol (LDL-C) lowering, reduction in cardiovascular (CV) events and outcomes, and a generally acceptable safety and tolerability profile. The impact of maintaining low LDL-C levels on higher order brain function is unclear, with reports of neurocognitive disorders with other lipid-lowering therapies. METHODS: Patients (n = 2176) with heterozygous familial hypercholesterolemia (HeFH) or non-FH, at high or very-high CV risk despite maximally tolerated statin therapy, randomly received subcutaneous alirocumab 75/150 mg or placebo every 2 weeks in this double-blind, placebo-controlled trial. The primary outcome was prospectively evaluated every 24 weeks over 96 weeks by Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Among 2086 patients with CANTAB cognitive domain Spatial Working Memory Strategy (SWMS) assessments, change from baseline to Week 96 in SWMS z-score (primary outcome) achieved noninferiority between alirocumab and placebo (least squares [LS] mean change at Week 96, -0.180 vs -0.200; LS mean difference vs placebo [95% confidence interval]: -0.020 [-0.094 to 0.055], p = 0.6055). Exploratory outcome measures, which further assessed neurocognitive function in the CANTAB domains, did not differ significantly over 96 weeks and achieved nominal noninferiority between treatment groups. Alirocumab resulted in nominally significant reductions in LDL-C and other lipid parameters, and was generally well tolerated. CONCLUSIONS: Confirming previous PCSK9 inhibitor data, alirocumab showed no effect on neurocognitive function over 96 weeks' treatment, substantially reduced LDL-C and was generally well tolerated in patients with HeFH or non-FH at high or very-high CV risk.
