TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.L.O., R.P.G., E.K., K.A.I., M.S.S.).
Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (S.F.).
Circulation. 2019 Mar 19;139(12):1483-1492. doi: 10.1161/CIRCULATIONAHA.118.037184.
BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS: The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
背景：脂蛋白(a)[Lp(a)]可能在动脉粥样硬化中起因果作用。前蛋白转化酶枯草溶菌素 9（proprotein convertase subtilisin/kexin 9）抑制剂已被证明可显著降低血浆 Lp(a)浓度。然而，Lp(a)水平、PCSK9 抑制与心血管风险降低之间的关系仍未确定。
方法：在 FOURIER 试验（载脂蛋白升高的患者中用 PCSK9 抑制剂进一步心血管结局研究）中，25096 例患者检测了 Lp(a)水平，这是一项依洛尤单抗与安慰剂治疗有明确动脉粥样硬化性心血管疾病患者的随机试验（中位随访 2.2 年）。Cox 模型用于评估 Lp(a)的独立预后价值，以及基于基线 Lp(a)浓度的依洛尤单抗对冠状动脉风险降低的疗效。
结果：中位（四分位距）基线 Lp(a)浓度为 37（13-165）nmol/L。在安慰剂组中，基线 Lp(a)处于最高四分位的患者发生冠心病死亡、心肌梗死或紧急血运重建的风险更高（调整后的危险比四分位 4 比四分位 1，1.22；95%CI，1.01-1.48），独立于低密度脂蛋白胆固醇之外。在 48 周时，依洛尤单抗可使 Lp(a)中位数（四分位距）降低 26.9%（6.2%-46.7%）。服用依洛尤单抗的患者在第 48 周时 Lp(a)和低密度脂蛋白胆固醇的百分比变化呈中度正相关（r=0.37；95%CI，0.36-0.39；P<0.001）。在基线 Lp(a)>中位数的患者中，依洛尤单抗降低了 23%（危险比，0.77；95%CI，0.67-0.88）的冠心病死亡、心肌梗死或紧急血运重建风险，在基线 Lp(a)≤中位数的患者中降低了 7%（危险比，0.93；95%CI，0.80-1.08；P 交互=0.07）。由于基线风险较高，3 年内的绝对风险降低和需要治疗的人数分别为 2.49%和 40 与 0.95%和 105。
结论：在患有明确心血管疾病的患者中，较高水平的 Lp(a)与心血管事件风险增加相关，无论低密度脂蛋白胆固醇水平如何。依洛尤单抗可显著降低 Lp(a)水平，基线 Lp(a)水平较高的患者 Lp(a)水平的绝对降低幅度更大，并且从 PCSK9 抑制中获益的趋势更大。
Circulation. 2019-3-19
Circulation. 2018-3-12
Am Heart J Plus. 2025-8-6
Proc (Bayl Univ Med Cent). 2025-7-9
Am Heart J Plus. 2025-7-21
Curr Cardiovasc Risk Rep. 2025-12
BMC Cardiovasc Disord. 2025-7-23
Zotero 插件