Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy.
Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy.
复制标题
循环成熟PCSK9水平预测他汀类药物治疗反应降低。
DOI：
10.1161/jaha.120.019525
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发表时间：
2021-06
影响因子：
5.4
通讯作者：
Yasuda S
中科院分区：
文献类型：
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作者：
Kuyama N;Kataoka Y;Takegami M;Nishimura K;Harada-Shiba M;Hori M;Ogura M;Otsuka F;Asaumi Y;Noguchi T;Tsujita K;Yasuda S
他汀类药物介导的降低低密度脂蛋白（LDL）胆固醇的功效因人而异，其反应减弱与更差的结果相关。然而，目前还没有确定的方法来预测他汀类药物的低反应。PCSK 9（前蛋白转化酶subxilisin/kexin 9型）是一种与LDL代谢相关的丝氨酸蛋白酶，以成熟和弗林蛋白酶裂解的PCSK 9形式循环。由于成熟的PCSK 9更有效地降解LDL受体，其评价可能有助于识别他汀类药物低应答者。我们分析了101例开始使用他汀类药物的未接受过他汀类药物治疗的冠心病患者。通过ELISA测量基线和使用他汀类药物后1个月的PCSK 9亚型。对他汀类药物的低反应定义为LDL胆固醇降低百分比<15%。研究了每种PCSK 9亚型水平与他汀类药物低应答之间的关系。他汀类药物显著降低LDL胆固醇水平（降低百分比，40%±21%），而11%的研究参与者对他汀类药物表现出低反应。多变量logistic回归分析表明，即使在调整临床特征后，基线成熟PCSK 9水平仍是他汀类药物低反应的独立预测因子（成熟PCSK 9每增加10 ng/mL：比值比[OR]，1.12; 95% CI，1.01-1.24 [P=0.03]），而弗林蛋白酶裂解水平不（每增加10 ng/mL：OR，1.37; 95% CI，0.73-2.58 [P=0.33]）。受试者工作特征曲线分析确定成熟PCSK 9水平228 ng/mL为预测他汀类药物低反应的最佳截止值（曲线下面积，0.73 [灵敏度，0.91;特异性，0.56]）。基线成熟PCSK 9水平>228 ng/mL与他汀类药物低反应相关。这一发现表明，成熟的PCSK 9可能是对他汀类药物低反应的潜在决定因素。
Statin‐mediated efficacy of lowering low‐density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine‐protease associated with LDL metabolism, which circulates as mature and furin‐cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. We analyzed 101 statin‐naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10‐ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01–1.24 [P=0.03]), whereas furin‐cleaved level was not (per 10‐ng/mL increase: OR, 1.37; 95% CI, 0.73–2.58 [P=0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.