In 1979, Avogaro et al¹ reported that apolipoprotein B (apoB) was a more accurate marker of the risk of a myocardial infarction than total cholesterol. In 1980, Sniderman et al² reported that low-density lipoprotein (LDL) apoB was a more accurate marker of the risk of angiographic coronary lesions than LDL cholesterol (LDL-C). They inferred that the mass of cholesterol per apoB particle could vary and they speculated that the number of apoB particles mattered more than the cholesterol they contained because it was the particle that entered and was deposited within the arterial wall.² Since then, there has been considerable debate whether apoB, LDL-C, or non–high-density lipoprotein cholesterol (non-HDL-C) should be the primary measure of apoB lipoprotein-related risk. The debate is over. In this issue, Marston and colleagues³ supply decisive evidence from a large, prospective observational study, UK Biobank, and 2 clinical trials, FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), that apoB should be the primary marker to assess the cardiovascular risk due to the apoB lipoproteins.

This line of thought has been driven as much by advances in basic science as by epidemiology and clinical trials. The discovery of cholesterol ester transfer protein by Pattnaik et al⁴ underpins the work by Krauss et al,⁵ which showed that the cholesterol content of LDL particles varied. By contrast, each apoB lipoprotein particle always has only a single apoB molecule; therefore, apoB equals atherogenic particle number. Because the mass of cholesterol per particle is variable, LDL-C and non-HDL-C can differ significantly from apoB. Because non-HDL-C and LDL-C are physiologically related and highly correlated with apoB, many have argued that LDL-C and non-HDL-C are “good enough” to measure lipoprotein-related risk. Meanwhile, evidence from prospective observational studies, including discordance analyses, mendelian randomization studies, and studies in statin-treated patients, has mounted steadily in favor of using apoB over LDL-C and non-HDL-C to measure atherogenic risk of apoB lipoproteins.^6,7

Not only does apoB better predict risk than LDL-C or non-HDL-C, it also better predicts benefit from lipid-lowering therapy. The landmark study by Ference et al,⁸ who applied mendelian randomization to simulate randomized clinical trials, demonstrated that reduction of equal numbers of very LDL and LDL particles produced equivalent clinical benefit. Johannesen et al⁹ recently demonstrated that apoB was a more accurate marker of cardiovascular risk in statin-treated patients than LDL-C or non-HDL-C. The present analysis by Marston et al³ should provide a final coup de grâce for LDL-C and non-HDL-C.

1979 年，Avogaro 等人¹报道载脂蛋白 B (apoB) 是比总胆固醇更准确的心肌梗死风险标志物。1980 年，Sniderman 等人²报道，低密度脂蛋白 (LDL) apoB 是比 LDL 胆固醇 (LDL-C) 更准确的血管造影冠状动脉病变风险标志物。他们推断每个apoB颗粒的胆固醇质量可能会有所不同，他们推测apoB颗粒的数量比它们所含的胆固醇更重要，因为它是进入并沉积在动脉壁内的颗粒。²从那时起，apoB、LDL-C 或非高密度脂蛋白胆固醇 (non-HDL-C) 是否应该是 apoB 脂蛋白相关风险的主要衡量指标，一直存在相当大的争论。辩论结束了。在本期中，Marston 及其同事³提供了来自英国生物库的一项大型前瞻性观察研究和 2 项临床试验 FOURIER（PCSK9 抑制对高风险受试者的进一步心血管结果研究）和 IMPROVE-IT（改善降低结果：Vytorin 功效国际试验），apoB 应该是评估 apoB 脂蛋白引起的心血管风险的主要标志物。

这一思路不仅受到流行病学和临床试验的推动，还受到基础科学进步的推动。^{Pattnaik 等人4}发现胆固醇酯转移蛋白为Krauss 等人^{5的工作奠定了基础}这表明低密度脂蛋白颗粒的胆固醇含量不同。相比之下，每个apoB 脂蛋白颗粒总是只有一个apoB 分子。因此，apoB 等于致动脉粥样硬化粒子数。因为每个颗粒的胆固醇质量是可变的，所以 LDL-C 和非 HDL-C 与 apoB 可能有显着差异。由于非 HDL-C 和 LDL-C 与 apoB 具有生理相关性和高度相关性，因此许多人认为 LDL-C 和非 HDL-C “足够好”以测量脂蛋白相关风险。同时，来自前瞻性观察研究的证据，包括不一致分析、孟德尔随机研究和对他汀类药物治疗患者的研究，已经稳定地支持使用 apoB 而不是 LDL-C 和非 HDL-C 来衡量 apoB 脂蛋白的致动脉粥样硬化风险。^{6 ,7}

与 LDL-C 或非 HDL-C 相比，apoB 不仅能更好地预测风险，而且还能更好地预测降脂治疗的益处。Ference 等人⁸的里程碑式研究应用孟德尔随机化来模拟随机临床试验，表明减少相同数量的 LDL 和 LDL 颗粒产生相同的临床益处。Johannesen 等人⁹最近证明，在接受他汀类药物治疗的患者中，apoB 是比 LDL-C 或非 HDL-C 更准确的心血管风险标志物。^{Marston 等人3}目前的分析应该为 LDL-C 和非 HDL-C 提供最后的妙招。