Bhatia Harpreet S, Wandel Simon, Willeit Peter, Lesogor Anastasia, Bailey Keith, Ridker Paul M, Nestel Paul, Simes John, Tonkin Andrew, Schwartz Gregory G, Colhoun Helen, Wanner Christoph, Tsimikas Sotirios
Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (H.S.B., S.T.).
Novartis Pharma AG, Basel, Switzerland (S.W., A.L., K.B.).
Circulation. 2025 Jan 28;151(4):312-321. doi: 10.1161/CIRCULATIONAHA.124.069556. Epub 2024 Nov 4.
Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined.
A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models.
Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1-77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06-1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46-2.48]).
These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.
低密度脂蛋白胆固醇（LDL-C）和脂蛋白(a) [Lp(a)]水平与动脉粥样硬化性心血管疾病（ASCVD）独立相关。然而，Lp(a)水平、LDL-C水平与不同阈值下ASCVD风险之间的关系尚不清楚。
对纳入6项安慰剂对照他汀类药物试验的27658名参与者进行个体水平的荟萃分析，以评估LDL-C和Lp(a)水平与致命或非致命冠心病事件、中风或任何冠状动脉或颈动脉血运重建（ASCVD）风险的关联。使用广义相加模型对基线Lp(a)水平与ASCVD风险之间的多变量调整关联进行连续建模，并通过具有随机效应的Cox比例风险模型按基线Lp(a)水平分析基线LDL-C水平与ASCVD风险之间的关联。使用Cox比例风险模型评估Lp(a)水平与他汀类药物治疗后达到的LDL-C水平与ASCVD风险之间的联合关联。
与Lp(a)水平为5mg/dL相比，他汀类药物治疗组和安慰剂治疗组中，Lp(a)水平升高与ASCVD风险呈对数线性相关。在接受他汀类药物治疗的个体中，Lp(a)水平>50mg/dL（≈125nmol/L）的患者在所有LDL-C水平四分位数和LDL-C水平的绝对变化中风险均增加。即使在LDL-C水平最低的四分位数（3.1-77.0mg/dL）的患者中，Lp(a)水平>50mg/dL的患者的ASCVD风险（风险比，1.38[95%CI，1.06-1.79]）也高于Lp(a)水平≤50mg/dL的患者。Lp(a)水平>50mg/dL且LDL-C水平处于第四四分位数时观察到最大风险（风险比，1.90[95%CI，1.46-2.48]）。
这些发现证明了Lp(a)和LDL-C水平在ASCVD风险方面具有独立和相加的性质，并且降低LDL-C并不能完全抵消Lp(a)介导的风险。
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