依洛尤单抗在自身免疫性或炎性疾病中强化降低低密度脂蛋白胆固醇水平：FOURIER试验分析
Intensive Lowering of LDL Cholesterol Levels With Evolocumab in Autoimmune or Inflammatory Diseases: An Analysis of the FOURIER Trial.
作者信息
Zimerman Andre, Kunzler Ana Laura F, Weber Brittany N, Ran Xinhui, Murphy Sabina A, Wang Huei, Honarpour Narimon, Keech Anthony C, Sever Peter S, Sabatine Marc S, Giugliano Robert P
机构信息
Hospital Moinhos de Vento, Moinhos de Vento College of Health Sciences, Porto Alegre, Brazil (A.Z., A.L.F.K.).
Division of Cardiovascular Medicine (B.N.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
出版信息
Circulation. 2025 May 20;151(20):1467-1476. doi: 10.1161/CIRCULATIONAHA.124.072756. Epub 2025 Apr 21.
BACKGROUND
Patients with an autoimmune or inflammatory disease (AIID) are at increased cardiovascular risk and may benefit more from statin therapy. In the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab lowered low-density lipoprotein cholesterol levels, but not hsCRP (high-sensitivity C-reactive protein) levels, and reduced the risk of cardiovascular events.
METHODS
FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with stable atherosclerosis who were taking statins. This analysis focused on the effect of evolocumab in patients with or without an AIID, defined as any autoimmune or chronic inflammatory condition. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization.
RESULTS
At baseline, 889 patients (3.2%) had an AIID, most commonly rheumatoid arthritis (33.7%) or psoriasis (15.6%). Median (interquartile range) low-density lipoprotein cholesterol levels were 90.0 mg/dL (79.5-105.5) and 91.5 mg/dL (79.5-108.5) in patients with or without an AIID, respectively (=0.025), and the placebo-adjusted percent reduction with evolocumab was consistent (60.2% versus 59.0%; =0.57). Baseline hsCRP was higher in patients with an AIID (median 2.1 versus 1.7 mg/L; <0.001) and did not significantly change with evolocumab in either group. Compared with placebo, evolocumab reduced the rate of the primary end point by 14% in patients without an AIID (hazard ratio, 0.86 [95% CI, 0.80-0.93]) and by 42% in patients with an AIID (hazard ratio, 0.58 [95% CI, 0.38-0.89]; =0.066). Likewise, evolocumab reduced the key secondary end point of cardiovascular death, myocardial infarction, or stroke by 19% in patients without an AIID (hazard ratio, 0.81 [95% CI, 0.74-0.89]) and 58% in those with an AIID (hazard ratio, 0.42 [95% CI, 0.24-0.74]; =0.022).
CONCLUSIONS
Intensive lowering of low-density lipoprotein cholesterol levels with evolocumab may lead to greater relative reduction in cardiovascular events in patients with an AIID.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633.
背景
自身免疫性或炎性疾病（AIID）患者心血管风险增加，他汀类药物治疗可能使其获益更多。在FOURIER试验（高危受试者PCSK9抑制进一步心血管结局研究）中，前蛋白转化酶枯草溶菌素9型（PCSK9）抑制剂依洛尤单抗降低了低密度脂蛋白胆固醇水平，但未降低高敏C反应蛋白（hsCRP）水平，并降低了心血管事件风险。
方法
FOURIER是一项在27564例服用他汀类药物的稳定动脉粥样硬化患者中比较依洛尤单抗与安慰剂的随机试验。该分析聚焦于依洛尤单抗在有无AIID患者中的作用，AIID定义为任何自身免疫性或慢性炎性疾病。主要终点为心血管死亡、心肌梗死、卒中、不稳定型心绞痛或冠状动脉血运重建的复合终点。
结果
基线时，889例患者（3.2%）患有AIID，最常见的是类风湿关节炎（33.7%）或银屑病（15.6%）。有无AIID患者的低密度脂蛋白胆固醇水平中位数（四分位间距）分别为90.0mg/dL（79.5 - 105.5）和91.5mg/dL（79.5 - 108.5）（P = 0.025），依洛尤单抗相对于安慰剂的降低百分比一致（60.2%对59.0%；P = 0.57）。AIID患者的基线hsCRP更高（中位数2.1对1.7mg/L；P < 0.001），两组中依洛尤单抗治疗后hsCRP均无显著变化。与安慰剂相比，依洛尤单抗使无AIID患者的主要终点发生率降低14%（风险比，0.86[95%CI，0.80 - 0.93]），使有AIID患者降低42%（风险比，0.58[95%CI，0.38 - 0.89]；P = 0.066）。同样，依洛尤单抗使无AIID患者心血管死亡、心肌梗死或卒中的关键次要终点降低19%（风险比，0.81[95%CI，0.74 - 0.89]），使有AIID患者降低58%（风险比，0.42[95%CI，0.24 - 0.74]；P = 0.022）。
结论
依洛尤单抗强化降低低密度脂蛋白胆固醇水平可能使AIID患者心血管事件相对降低幅度更大。
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