载脂蛋白(a)降低后 LDL-C、估计真实 LDL-C、载脂蛋白 B-100 和 PCSK9 水平的关系。 采用反义寡核苷酸。
Relationship between "LDL-C", estimated true LDL-C, apolipoprotein B-100, and PCSK9 levels following lipoprotein(a) lowering with an antisense oligonucleotide.
机构信息
Ionis Pharmaceuticals, Carlsbad, CA, USA.
Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA, USA.
出版信息
J Clin Lipidol. 2018 May-Jun;12(3):702-710. doi: 10.1016/j.jacl.2018.02.014. Epub 2018 Mar 1.
BACKGROUND
The laboratory measurement of "low-density lipoprotein cholesterol (LDL-C)" includes the cholesterol content of lipoprotein(a) (Lp(a)-C).
OBJECTIVE
To estimate the "true" LDL-C in relation to changes in apolipoprotein B-100 (apoB-100) and assess changes in proprotein convertase subtilisin/kexin 9 (PCSK9) levels in patients with elevated Lp(a) treated with IONIS-APO(a) METHODS: A pooled placebo group (n = 29), and cohort A (n = 24, baseline Lp(a) 50-175 mg/dL) and cohort B (n = 8, baseline Lp(a) > 175 mg/dL) treated with IONIS-APO(a) were studied. Lp(a) particle number, ultracentrifugation-measured "LDL-C", apoB-100, total PCSK9, and lipoprotein-associated PCSK9 (PCSK9-Lp(a), PCSK9-apoB, PCSK9-apoAI) were measured. Lp(a)-cholesterol (Lp(a)-C) and LDL-C corrected for Lp(a)-C (LDL-C) were calculated.
RESULTS
Baseline mean (standard deviation) "LDL-C" was 120 (42), 128 (45), and 112 (39) mg/dL in placebo, cohorts A and B, respectively, whereas LDL-C was 86 (48), 96 (43), and 57 (37) mg/dL (P < .001 compared with placebo), representing 28%, 25%, and 50% lower levels than "LDL-C". Following IONIS-APO(a) treatment at day 85/99, Lp(a) particle number and Lp(a)-C decreased -66.8% and -71.6%, apoB-100 -10.3% and -17.5%, "LDL-C" -11.8% and -22.7%, (P < .001 for all vs placebo), whereas LDL-C increased +10.4% (P = .66) and +49.9% (P < .001) in cohorts A and B, respectively. Total PCSK9 did not change but PCSK9-Lp(a) decreased with IONIS-APO(a) vs placebo (-39.0% vs +8.4%, P < .001).
CONCLUSION
LDL-C is lower than laboratory "LDL-C" in patients with elevated Lp(a). Following apolipoprotein(a) inhibition and decline in Lp(a) and Lp(a)-C, the decline in apoB-100 is consistent with the notion that LDL devoid of apo(a) is cleared faster than Lp(a). These types of analyses may provide insights into the mechanisms of drugs affecting Lp(a) levels in clinical trials.
背景
实验室测量“低密度脂蛋白胆固醇（LDL-C）”包括脂蛋白（a）（Lp(a)-C）的胆固醇含量。
目的
估计与载脂蛋白 B-100（apoB-100）变化相关的“真实”LDL-C，并评估在接受 IONIS-APO(a)治疗的高脂蛋白（a）患者中，前蛋白转化酶枯草溶菌素/激肽释放酶 9（PCSK9）水平的变化。
方法
对安慰剂组（n=29）、队列 A（n=24，基线脂蛋白（a）为 50-175mg/dL）和队列 B（n=8，基线脂蛋白（a）>175mg/dL）进行了研究。测量了脂蛋白（a）颗粒数、超速离心法测量的“LDL-C”、载脂蛋白 B-100、总 PCSK9、脂蛋白相关 PCSK9（PCSK9-Lp(a)、PCSK9-apoB、PCSK9-apoAI）。计算了脂蛋白（a）胆固醇（Lp(a)-C）和校正脂蛋白（a）-C 的 LDL-C（LDL-C）。
结果
安慰剂、队列 A 和 B 的基线平均（标准差）“LDL-C”分别为 120（42）、128（45）和 112（39）mg/dL，而 LDL-C 分别为 86（48）、96（43）和 57（37）mg/dL（与安慰剂相比，均 P<.001），分别比“LDL-C”低 28%、25%和 50%。在第 85/99 天接受 IONIS-APO(a)治疗后，脂蛋白（a）颗粒数和 Lp(a)-C 分别下降了-66.8%和-71.6%，载脂蛋白 B-100 下降了-10.3%和-17.5%，“LDL-C”下降了-11.8%和-22.7%（与安慰剂相比，均 P<.001），而在队列 A 和 B 中，LDL-C 分别增加了+10.4%（P=.66）和+49.9%（P<.001）。总 PCSK9 没有变化，但与安慰剂相比，PCSK9-Lp(a)在接受 IONIS-APO(a)治疗后下降了-39.0%（P<.001）。
结论
在高脂蛋白（a）患者中，LDL-C 低于实验室“LDL-C”。在载脂蛋白（a）抑制和脂蛋白（a）和 Lp(a)-C 下降后，apoB-100 的下降与 LDL 中没有载脂蛋白（a）的 LDL 比 Lp(a)清除得更快的概念一致。这些类型的分析可能为临床试验中影响 Lp(a)水平的药物机制提供见解。
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