Zimerman André, O'Donoghue Michelle L, Ran Xinhui, Im KyungAh, Ott Brian R, Mach François, Zavitz Kenton, Kurtz Christopher E, Monsalvo Maria Laura, Wang Bei, Atar Dan, Keech Anthony, Sabatine Marc S, Giugliano Robert P
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston.
Clinical Trials Unit, Hospital Moinhos de Vento, Moinhos de Vento College of Health Sciences, Porto Alegre, Brazil.
NEJM Evid. 2025 Jan;4(1):EVIDoa2400112. doi: 10.1056/EVIDoa2400112. Epub 2024 Dec 24.
Concerns persist regarding the cognitive safety of achieving very low levels of low-density lipoprotein (LDL) cholesterol. Although short-term studies are reassuring, the long-term cognitive effects of sustained exposure to very low LDL cholesterol levels through combined proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition and statin therapy remain unknown.
This prospective study enrolled a subset of adults with atherosclerotic cardiovascular disease who had completed a neurocognitive substudy (EBBINGHAUS) of a placebo-controlled randomized trial of evolocumab (FOURIER) and were eligible for a long-term open-label extension. The objective of this current study was to assess the long-term effect of evolocumab on cognitive function. Cognitive function was assessed annually, and the primary end point was change from baseline in executive function within each group, measured using the spatial working memory strategy index score (range, 4-28), with lower scores indicating better performance.
A total of 473 patients out of the 1974 patients in the parent EBBINGHAUS study were enrolled and additionally followed for a median of 5.1 years (maximum follow-up since original random assignment 7.2 years). The median age was 62 years; 70% were male, and 91% were White. At 12 weeks into the open-label extension period, median LDL cholesterol across the overall population was 35 mg/dl (interquartile range, 21-55 mg/dl). Treatment with evolocumab was not associated with a change in executive function during the open-label extension in either patients who were originally randomly assigned to and continued evolocumab (mean±standard deviation of 0.1±2.8, P=0.49) or patients originally randomly assigned to placebo who then started on evolocumab (-0.1±2.5, P=0.64). At the final study visit, executive function scores were similar between randomly assigned groups (17.5±3.7 and 17.3±3.7, respectively).
Exposure to very low levels of LDL cholesterol, achieved via PCSK9 inhibition and statin therapy, was not associated with cognitive impairment through long-term follow-up. Further studies are needed to assess the generalizability to adults at higher risk of dementia.
对于将低密度脂蛋白（LDL）胆固醇水平降至极低水平的认知安全性，人们一直存在担忧。尽管短期研究令人放心，但通过联合使用前蛋白转化酶枯草溶菌素9型（PCSK9）抑制剂和他汀类药物治疗持续暴露于极低LDL胆固醇水平的长期认知影响仍不清楚。
这项前瞻性研究纳入了一部分患有动脉粥样硬化性心血管疾病的成年人，他们完成了一项关于依洛尤单抗（FOURIER）的安慰剂对照随机试验的神经认知子研究（EBBINGHAUS），并且符合长期开放标签扩展试验的条件。本研究的目的是评估依洛尤单抗对认知功能的长期影响。每年评估认知功能，主要终点是每组执行功能相对于基线的变化，使用空间工作记忆策略指数评分（范围为4 - 28）进行测量，分数越低表明表现越好。
在母研究EBBINGHAUS的1974名患者中，共有473名患者被纳入并额外随访了中位数为5.1年（自最初随机分组以来的最大随访时间为7.2年）。中位年龄为62岁；70%为男性，91%为白人。在开放标签延长期的第12周，总体人群的中位LDL胆固醇水平为35mg/dl（四分位间距为21 - 55mg/dl）。在开放标签延长期，接受依洛尤单抗治疗与执行功能的变化无关，无论是最初随机分配并继续使用依洛尤单抗的患者（均值±标准差为0.1±2.8，P = 0.49）还是最初随机分配接受安慰剂治疗随后开始使用依洛尤单抗的患者（-0.1±2.5，P = 0.64）。在最终研究访视时，随机分组的两组之间执行功能评分相似（分别为17.5±3.7和17.3±3.7）。
通过PCSK9抑制和他汀类药物治疗实现极低水平的LDL胆固醇暴露，经长期随访与认知障碍无关。需要进一步研究以评估其对痴呆症高风险成年人的普遍性。
