载脂蛋白(a)异构体大小对 HPS2-THRIVE 研究中脂蛋白(a)降低的影响。
Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study.
机构信息
From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13.
出版信息
Circ Genom Precis Med. 2018 Feb;11(2):e001696. doi: 10.1161/CIRCGEN.117.001696.
BACKGROUND
Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear.
METHODS
HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin-laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified.
RESULTS
Allocation to niacin-laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin-laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size (=4×10) and was only 18% in the quintile with the highest baseline Lp(a) level and low isoform size. Estimates from genetic studies suggest that these Lp(a) reductions during the short term of the trial might yield proportional reductions in coronary risk of ≈2% overall and 6% in the top quintile by Lp(a) levels.
CONCLUSIONS
Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin-laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a).
CLINICAL TRIAL REGISTRATION
URL: https://clinicaltrials.gov. Unique identifier: NCT00461630.
背景
遗传研究表明脂蛋白(a)（Lp[a]）是冠心病的一个重要因果风险因素。载脂蛋白(a)同工型大小是 Lp(a)水平的主要决定因素，但它对降低 Lp(a)的治疗益处的影响仍不清楚。
方法
HPS2-THRIVE（心脏保护研究 2-用烟酸-拉罗匹仑治疗高密度脂蛋白以降低血管事件的发生率）是一项在辛伐他汀治疗背景下，比较烟酸-拉罗匹仑与安慰剂的随机试验。在来自英国和中国的 3978 名参与者中，测量了基线和随机分组后 1 年的血浆 Lp(a)水平。通过琼脂糖凝胶电泳测量载脂蛋白(a)同工型大小，估计 Kringle IV 结构域的数量，并确定主要表达的同工型。
结果
烟酸-拉罗匹仑的分配使平均 Lp(a)降低 12（SE，1）nmol/L，基线 Lp(a)水平（Lp[a]≥128 nmol/L）最高五分位的 Lp(a)降低 34（6）nmol/L。烟酸-拉罗匹仑使 Lp(a)的平均比例降低 31%，但与主要载脂蛋白(a)同工型大小密切相关（=4×10），基线 Lp(a)水平最高且同工型较小的五分位中仅为 18%。遗传研究的估计表明，这些在试验短期 Lp(a)降低可能导致整体冠状动脉风险的比例降低约 2%，最高 Lp(a)五分位的比例降低 6%。
结论
Lp(a)的比例降低取决于载脂蛋白(a)同工型大小。考虑到这一点，烟酸-拉罗匹仑通过降低 Lp(a)降低冠状动脉风险的可能获益较小。需要新型治疗方法将高 Lp(a)水平降低至少 80 nmol/L（≈40%），才能为因 Lp(a）而处于最高风险的人群带来有价值的获益。
临床试验注册
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