致动脉粥样硬化性脂蛋白与剩留心血管风险课件

致动脉粥样硬化性脂蛋白与剩留心血管风险-从IAS血脂异常管理指南谈起,2013年国际动脉粥样硬化学会(IAS)立场报告：全球血脂异常管理建议,LDL：主要的致动脉粥样硬化性脂蛋白VLDL：同样具有致动脉粥样硬化性的脂蛋白LDL-C：传统的临床干预主要靶点非HDL-C：临床干预的恰当靶点,非HDL=LDL+VLDL,Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members. An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia-Full report. J Clin Lipidol, 2014, 8(1):29-60.,为什么非HDL-C较LDL-C具有更强的风险预测作用？,NCEP ATP III,National Cholesterol Education Panel. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation, 2002, 106:3143421.,非HDL,非HDL-C = TC - HDL-C同时包含LDL-C和其他致动脉粥样硬化性胆固醇,研究显示，预测冠心病风险Non-HDL-C优于LDL-C,CHD相对风险,在同一Non-HDL-C水平，LDL-C和冠心病风险无相关性相反，在每一LDL-C水平，Non-HDL-C水平与CHD风险强相关Non-HDL-C较LDL-C预测冠心病风险的能力更强,使用Framingham心脏研究的患者数据（2,693例男性，3,101例女性），这些患者基线时均无冠心病（CHD），评估不同LDL-C和non-HDL-C水平时的CHD风险。,Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol, 2006, 98(10):1363-8.,非HDL-C与主要心血管事件的关联较LDL-C更强,荟萃分析,Boekholdt SM, Arsenault BJ, Mora S et al, Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA, 2012, 28;307(12):1302-9.,共纳入8项大型RCT研究中的38153名他汀治疗患者数据,残粒胆固醇（Remnant Cholesterol, RC）的概念与临床意义,荟萃分析,Varbo A, Benn M, Nordestgaard BG, et al. Remnant cholesterol as a cause of ischemic heart disease: Evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther, 2014, 141(3):358-67,残粒胆固醇定义,残粒胆固醇：富含甘油三酯脂蛋白（TG rich lipoprotein, TRL，包括CM，VLDL和IDL）残粒（remnant）中的胆固醇成分。,遗传学方法证实残粒胆固醇是缺血性心脏病的致病性危险因素,荟萃分析,Varbo A, Benn M, Tybjærg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol, 2013, 61(4):427-36.,哥本哈根心脏研究&缺血性心肌病研究&总人群研究,遗传性的残粒胆固醇浓度升高1mmol/L,IHD风险 180%,（观察性的残粒胆固醇升高1mmol/L, IHD风险升高40%）,共纳入73513名患者，11984个IHD病例,残粒胆固醇与甘油三酯呈线性相关,荟萃分析,Varbo A, Benn M, Nordestgaard BG, et al. Remnant cholesterol as a cause of ischemic heart disease: Evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther, 2014, 141(3):358-67,Varbo等 研究,TG水平(mmol/L),患者数,14,906,28,041,10,722,3,826,1,418,982,残粒胆固醇与TG相关性： r2=0.96,APOC3 功能失活突变与血清TG水平及心血管疾病风险-2014年6月18号同时在线发表于NEJM的两篇论文,荟萃分析,NEJM 新英格兰医学杂志,研究结论,该研究发现3种APO C3的功能缺失突变与显著的非空腹TG降低相关,在一般人群中，这些突变也相应地与缺血性血管疾病和心脏病风险降低相关,1,2,研究结论,研究发现APO C3的罕见DNA序列变异与终生的血浆TG和APO C3水平下降相关，且这些突变可产生冠心病保护作用,和研究发现编码PCSK9基因的功能缺失突变会引起LDL-C降低和冠心病风险降低，进而促使PCSK9单抗的研发一样，本研究进一步提示自然发生的功能缺失突变在指导治疗靶点选择方面的作用,1,2,富含TG脂蛋白可直接致AS,Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 2011, 123(20):2292-333.,富含TG脂蛋白可间接致AS,Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 2011, 123(20):2292-333.,大量他汀单药治疗的2型糖尿病患者TG和HDL-C未达标,他汀单药治疗的糖尿病患者血脂未达标情况,在使用他汀治疗的2型糖尿病患者中，仍有超过40%患者血脂指标未达标,使用他汀治疗的2型糖尿病患者血脂未达标比例,Feher M, Greener M, Munro N. Persistent hypertriglyceridemia in statin-treated patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes, 2013, 6:11-5.,高TG与心血管死亡风险显著相关,61项前瞻性研究荟萃分析及系统综述,Liu J, Zeng FF, Liu ZM, et al. Effects of blood triglycerides on cardiovascular and all-cause mortality: a systematic review and meta-analysis of 61 prospective studies. Lipids Health Dis, 2013, 12(1):159.,高TG和低HDL-C的糖尿病患者的心血管风险显著高于其他患者,ACCORD研究,他汀+安慰剂组患者LDL-C=2.06mmol/L,ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010, 362(17):1563-74.,减少心血管剩留风险的现有治疗方案,高心血管风险患者,使用他汀保持理想的LDL-C水平,进一步降低LDL-C大剂量他汀治疗,改善TG和HDL-C他汀+烟酸他汀+贝特类,减少心血管剩留风险的治疗方案：强化他汀治疗,高心血管风险患者,使用他汀保持理想的LDL-C水平,进一步降低LDL-C大剂量他汀治疗,改善TG和HDL-C他汀+烟酸他汀+贝特类,他汀强化治疗进一步降低心血管风险程度有限，且不良事件发生率明显增加,TNT研究：强化他汀作用及不良反应,主要心血管事件 (%),*主要心血管事件定义为冠心病死亡，非致死性非操纵相关性心梗，心脏骤停后复苏或中风,低剂量和高剂量阿托伐他汀对主要心血管事件的作用* (总研究人群),治疗相关不良事件和由于治疗相关不良事件停止研究的发生率,LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med, 2005, 352(14):1425-35.,仅使用他汀无法解决高TG带来的心血管风险,CARE和LIPID研究,N = 13,173,尽管使用他汀可以降低心血管风险，但当TG水平升高时，其心血管事件风险仍会显著升高。,Sacks FM, Tonkin AM, Shepherd J, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation, 2000, 102(16):1893-900.,高心血管风险患者,使用他汀保持理想的LDL-C水平,进一步降低LDL-C大剂量他汀治疗,改善TG和HDL-C他汀+烟酸,减少心血管剩留风险的治疗方案：他汀联合烟酸,烟酸确实可以改善血脂水平，但是否能达到预期的心血管风险的减少？,AIM-HIGH 研究,AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med, 2011, 365(24):2255-67.,治疗2年后，自基线改变 (%),基线水平：LDL-C=1.91mmol/L, HDL-C=0.91mmol/L, TG=1.85mmol/L,对于LDL-C达标的低HDL-C患者，他汀联合烟酸治疗并未显示出获益,*第一次心血管风险事件发生,同时记录需要再住院的不稳定型心绞痛,血运重建与 PCI 或冠状动脉移植术,平均随访3年事件率 (%),AIM HIGH研究：主要终点*结果,p=0.80(NS),AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med, 2011, 365(24):2255-67.,对于经他汀治疗LDL-C已达标的患者，联合烟酸治疗并未显示出获益,*主要心血管事件定义为任一匹配项目： 非致命 MI 或冠心病死亡、 非致命或致命脑卒中、 冠心病或非冠状动脉手术或血管成形术 （包括截肢）,平均随访4年事件率 (%),HPS 2 THRIVE研究：主要终点* 结论,p=0.29(NS),Presented at the ACC 2013, Jane Armitage 代表HPS2-THRIVE 研究协作组,他汀联合烟酸治疗与他汀单药治疗相比，显著地增加严重不良事件的发生率,HPS 2 THRIVE研究：联用组对比单用组,HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J, 2013, 34(17):1279-91.,联用组：辛伐他汀40mg+缓释烟酸2g/拉罗皮兰40mg单用组：辛伐他汀40mg+安慰剂,高心血管风险患者,使用他汀保持理想的LDL-C水平,进一步降低LDL-C大剂量他汀治疗,改善TG和HDL-C他汀+贝特类,减少心血管剩留风险的治疗方案：他汀联合贝特类,贝特类能有效地降低TG，升高HDL-C,贝特类对TG与HDL-C的疗效,1.中华医学会心血管病学分会, 中国老年学学会心脑血管病专业委员会. 血脂相关性心血管剩留风险控制的中国专家共识. 中华心血管病杂志, 2012, 40(7):547-553 2.Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis, 2011, 217(1):3-46.,2011 ESC/ EAS血脂指南：贝特类药物是严重高TG血症的一线药物,Farnier等研究-非HDL-C达标率,患者非HDL-C达标率 %,291名患者进入随机化，药物治疗12周,非诺贝特联合他汀治疗比单用他汀能够更好地使患者的非HDL-C达标,*,*：与他汀单用组相比p=0.001：与他汀单用组相比p<0.05,Farnier M, Steinmetz A, Retterstøl K, et al. Fixed-dose combination fenofibrate/pravastatin 160/40 mg versus simvastatin 20 mg monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with simvastatin 20 mg: a double-blind, randomized comparative study. Clin Ther, 2011, 33(1):1-12,非诺贝特联用他汀可以更好地改善LDL颗粒亚型,*:联用组与单药组比较 p<0.001,*,*,SAFARI研究,Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005, 95(4):462-468.,非诺贝特联合他汀治疗高TG/低HDL-C的患者，可以显著地降低心血管风险,ACCORD研究：亚组分析,TG2.3mmol/LHDL-C0.88mmol/L,治疗5年预防1例事件的需治疗人数（NNT）= 20,*: p<0.05,*,ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010, 362(17):1563-74.,随访5年，主要心血管事件发生率(%l),力平之® -他汀联用IV期临床研究,力平之® -他汀联用IV期临床研究,力平之® -他汀联用IV期临床研究,力平之® -他汀联用IV期临床研究,力平之® -他汀联用IV期临床研究,*与基线相比 P0.01,治疗后血脂水平改变百分数,力平之® -他汀联用IV期临床研究,共报告7例（1.42%）严重不良事件，其中仅1例肝酶升高被判断为与研究药物相关。,研究过程中未发生横纹肌溶解不良事件,力平之® -他汀联用IV期临床研究,研究中发生有临床意义的实验室指标异常比例与既往研究中单药治疗相比没有显著增加,国内外指南共识推荐在混合性血脂异常患者中贝特类药物与他汀的联合应用,1. NICE clinical guideline 87. Type 2 diabetes: The management of type 2 diabetes. March 2010. Available at: http:/www.nice.org.uk/CG872. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis, 2011, 217(1):3-46.3. IDF Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. Brussel: International Diabetes Federation, 2012.4. Jellinger PS, Smith DA, Mehta AE, et al. American Association of Clinical Endocrinologists Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract, 2012,18Suppl1:1-78.5. Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members. An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia-Full report. J Clin Lipidol, 2014, 8(1):29-60.,总结,谢谢大家!,