Michel FARNIER, MD, PhD, Dijon, France 胆固醇管理的新思路 Michel FARNIER, MD, PhD, Dijon, France

背景 血浆低密度脂蛋白胆固醇（LDL-C）水平升高是动脉粥样硬化性心血管疾病（CVD）的主要危险因素

欧洲指南 高危患者 第四次联合委员会， 2007 Goals  TC < 4.5 mmol/l (175 mg/dL) < 4.0 mmol/l (155 mg/dL) 如果可能 Goals  LDL-C < 2.5 mmol/l (100 mg/dL) < 2.0 mmol/l (80 mg/dL) 如果可能 EHJ 2007; 28: 2375-2414

降低LDL-C的指南： 新的 “低一些更好” 的措施 Ref 8, p S7, C1, ¶1 Ref 9, p 3243, C1, Table IV.1-1 + calc Calc: 1000.02586=2.6 Ref 7, p 236, Table 2; p 237, Table 3; p 234, C2, ¶1, L17-19, ¶2, all + calc 700.02586=1.8 500.02586=1.29 Ref 1, p 2142, C1, ¶1, L8-12 欧洲及NCEP ATP III指南特别指出，对于高危患者，将LDL-C 水平控制于2.6 mmol/l (100 mg/dL) 以内是一个最低目标 对于极高危的患者，新的治疗意见认为需将LDL-C水平控制与 2 mmol/l (或 < 70-80 mg/dL) 以下 NCEP Coordinating Committee Circulation 2004;110:227–239 JTF4, Eur Heart J 2007; 28: 2374-2414 理想的 LDL-C 水平是1.3-1.8 mmol/l (50-70 mg/dL) : “越低越好且生理正常” O’Keefe JH J Am Coll Cardiol 2004;43(11): 2142–2146 Both European Guidelines on Cardiovascular Disease Prevention in Clinical Practice8 and the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines established an LDL-C goal of <100 mg/dl (2.6 mmol/L) for adults with CHD or CHD risk equivalents.9 Recent publications have summarized the evidence for even lower LDL-C goals. In one of these, the NCEP Coordinating Committee has proposed modifications to the ATP III guidelines based on results from five major new clinical trials of statin therapy: Heart Protection Study (HPS), Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Treat (ALLHAT-LLT), Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22). One of the proposed modifications to ATP III goals for very high-risk patients (risk factors include obesity, physical inactivity, elevated triglycerides, low high-density lipoprotein cholesterol [HDL-C], or metabolic syndrome) includes an optimal lower LDL-C goal of <70 mg/dl (1.8 mmol/L) for patients with CHD or CHD risk equivalents. This new recommendation is based on results from HPS and PROVE IT, which demonstrated that high-risk patients with low LDL-C levels at baseline benefit from additional lowering of LDL-C.7 The American Diabetes Association’s 2005 Clinical Practice Recommendations also include the optional goal of <70 mg/dl for high-risk patients with diabetes overt cardiovascular disease.10 Accumulating data consistently show that the optimal LDL-C level is approximately 50 to 70 mg/dl (1.3 to 1.8 mmol/L).1 Although this LDL-C range seems low by current standards, it is physiologically normal, that is, the range associated with the lifestyle and diet for which we are genetically programmed. In addition, this range represents a threshold for development of atherosclerosis.1 Ref 8, p S7, C1, ¶1 Ref 9, p 3243, C1, Table IV 1-1 Calc: 1000.02586=2.6 Ref 7, p 228, C1, ¶2, L1-3,11-14 Ref 7, p 237, Table 3, L4; p 232, C2, L19-20, C1, ¶3, L13-16; p 237, C1, ¶2, L1-5 Ref 10, p S3, C3, Bullet 1 Ref 1, p 2142, C1, ¶1, L8-12 Ref 1, p 2142, C2, ¶2, L22-23; p 2143, C1, L1-2 NCEP=National Cholesterol Education Program; ATP III=Adult Treatment Panel III; JTF = Joint Task Force Adapted from O’Keefe JH J Am Coll Cardiol 2004;43(11):2142–2146; Grundy SM et al Circulation 2004;110:227–239; Graham et al. Eur Heart J 2007;28: 2374-2414; NCEP Circulation 2002;106:3143–3421.

中国的指南 LDL-C = 主要目标 目标 : 高危的患者 < 2.59 mmol/L (冠心病和冠心病等危症) 极高危的患者 < 2.00 mmol/L (心血管疾病伴ACS或糖尿病)

他汀类单药治疗能使患者达到治疗目标吗?  现实中的情况如何 ?  达到LDL-C治疗目标的主要障碍是什么 ?  未达到他汀类治疗目标的患者的进一步治疗方案是什么?

他汀类单药治疗能使患者达到治疗目标吗?  现实中的情况如何 ?  达到LDL-C治疗目标的主要障碍是什么 ?  未达到他汀类治疗目标的患者的进一步治疗方案是什么?

EUROASPIRE I, II, 及 III 调查的比较： 8 个欧洲国家 血压升高 TC升高 DM p = 0.49 p < 0.0001 p = 0.004 % of Patients SBP  140 and/or DBP  90 mmHg (130/80 for DM) TC  4.5 mmol/L Kotseva et al. Lancet 2009; 373: 929-940

中国第二次血脂治疗现状调研结果 中国大部分高危/极高危患者未能达标 所有患者均采用他汀治疗 LDL <70mg/dl n=137 n=118 n=153 n=361 n=1325 n=2094 86%　 79% 66% 39% 36% 23% LDL <100mg/dl LDL <160mg/dl LDL <130mg/dl LDL <130mg/dl* # * 基线LDL: >100mg/dl, LDL<100mg/dl为达标目标值 # 基线LDL<=100mg/dl,　LDL下降>=30%为达标目标值 （采用2004年ATPⅢ的危险分层） 最需要治疗的患者却得不到有效的治疗！ 中国第二次血脂治疗现状调研结果显示中国大部分高危/极高危患者未能达标，且所有患者均已采用他汀治疗 Yangfeng Wu et al. The second multi-center survey of dyslipidemia management in China: goal attainment rate and related factors. Chin J Cardio 2007;35(5):420-427 9

他汀类单药治疗能使患者达到治疗目标吗?  现实中的情况如何 ?  达到LDL-C治疗目标的主要障碍是什么 ?  未达到他汀类治疗目标的患者的进一步治疗方案是什么?

他汀类对 HDL-C 及 LDL-C 的影响: 来自VOYAGER 数据库的结论 (32 258 名患者) LDL-C 和HDL-C 水平改变的百分数 Dose LDL-C HDL-C (mg) n LSM % change n LSM % change from baseline from baseline Rosuvastatin 5 668 -38.8 670 5.5 10 11650 -44.1 11690 6.1 20 3551 -49.5 3554 7.0 40 2981 -54.7 2993 7.9 Atorvastatin 10 7804 -35.5 7837 4.5 20 3896 -41.4 3908 3.5 40 1324 -46.2 1324 2.4 80 2070 -50.2 2072 2.3 Simvastatin 10 165 -27.4 165 4.2 20 2923 -33.0 2929 5.0 40 542 -38.9 548 5.0 80 478 -45.0 479 5.3 Barter et al, JACC 2009; 53: A209

对他汀类药物反应的个体差异

使用阿托伐他汀10mg/日后不同个体 LDL-C 的改变 In the majority of patients tested the mean percent change in LDL-C, TG and HDL-C was reasonably consistent. However, several patients showed a large inter-individual variability which produced and overall broad range of response. This was similar in men (mean±SD and range: −36.2±10.5, −2.7 to−57.8%; −15.8±33.7, −69.4 to +129.9%; +7.2 ±13.0, −26.4 to 54.3% and –39.9±10.9, −63.6–1.2%, for LDL-C, TG, HDL-C and LDL-C/HDL-C, respectively) and women (−38. ±19.1, −9.5 to−58.5%; −18.8±23.7, −64.6 to +71.7%; +8.1±12.2, −17.6–52.5% and −42.3±8.8, −62.8 to−20.8% and for LDL-C, TG, HDL-C and LDL-C/HDL-C, respectively) (see Fig. 1). Men Women Pedro-Botet J et al. Atherosclerosis 158 (2001) 183-193

使用最大剂量阿托伐他汀及罗苏伐他汀对胆固醇合成及吸收指标的影响的比较：对STELLAR研究的回顾分析 对干预LDL-C的治疗的个体反应差异很大 LDL cholesterol change (%) Rosuvastatin Atorvastatin 40 mg 80 mg Mean %  LDL-C - 55% - 53% van Himbergen et al J Lipid Res 2009; 50: 730-9

4S 后续分析 对胆固醇吸收位于高四分位数水平的个体， 辛伐他汀不能降低严重心血管不良事件 胆固醇吸收的四分位水平 38% 34% 25% 相对风险 % Major Coronary events 1 2 3 4 Placebo (n=434) Simvastatin 20-40 mg (n=434) 17% The efficacy of simvastatin treatment according to amount of cholesterol absorption was evaluated in a post hoc analysis of the 4S trial. As the quartile of cholesterol absorption increased, the percent of coronary events in patients treated with simvastatin also increased. This result indicates that simvastatin was most efficacious in patients with the lowest amount of cholesterol absorption. Thus, in patients who exhibit high cholesterol absorption, statin therapy alone may not be sufficient in reducing coronary events. In the 4S substudies, the statins were of no use in lowering LDL cholesterol or improving clinical outcomes in the absorber phenotype. If these pleiotropic effects were to translate into meaningful clinical end points, even patients with an absorber phenotype should show clinical benefit. There is currently no evidence for the clinical relevance of pleiotropic effects of statins. Indeed, we challenge those who believe that statins have clinically relevant pleiotropic effects to undertake a placebo-controlled trial that recruits patients with an absorber phenotype. If these pleiotropic effects are of any clinical relevance, there should be dissociation between the extent of LDL cholesterol-lowering and hard clinical end points. 对辛伐他汀 反应差 低胆固醇吸收水平 高胆固醇吸收水平 4S = Scandinavian Simvastatin Survival Study. Miettinen et al. BMJ. 1998;316:1127 15

对他汀类药物治疗的个体差异 内源性因素 外源性因素 (基因决定的) LDL-受体基因变异 apo-B-100基因变异 PCSK9基因变异 apoE 多态性 OATP 多态性 顺应性差 饮食习惯 药物的剂量和调整 合并的药物治疗 胆固醇生物合成的速度 胆固醇吸收的速度

胆固醇代谢通路中，吸收与合成 相互作用的影响

胆固醇吸收的机制 肠细胞 淋巴管 肠腔 Chylomicron ACAT Apo B 48 ABCG5/G8 NPC1L1 Protein Ezetimibe blocks the absorption of cholesterol and other sterols at the brush border of the intestine. The exact mechanism is unknown but it is thought the drug affects a protein facilitiating absorption called sterol “permease”. The enterocyte has reduced amounts of cholesterol to put in the chylomicrons. 肠细胞 淋巴管 肠腔

Less free cholesterol & sterol absorption 依折麦布：作用机制 CE Poor Chylomicron Apo B 48 ABCG5/G8 ACAT NPC1L1 Protein Ezetimibe blocks the absorption of cholesterol and other sterols at the brush border of the intestine. The exact mechanism is unknown but it is thought the drug affects a protein facilitiating absorption called sterol “permease”. The enterocyte has reduced amounts of cholesterol to put in the chylomicrons. Less free cholesterol & sterol absorption EZETIMIBE 依折麦布特异地与刷状缘结构蛋白高亲和地结合 X 肠细胞 淋巴管 肠腔

依折麦布通过阻断甾醇诱导的NPC1L1 内在化而发挥作用 Ge et al. Cell Metab 2008; 7, 508–519

依折麦布对肠道胆固醇吸收及胆固醇合成的影响 男性，18例， LDL-C 130 -180 mg/l Placebo Ezetimibe * vs placebo - 54 % * p < 0.001 + 89 % * p < 0.001 - 22.3 % * p < 0.001 + 1,9% 49.8% Cholesterol intake was constant during both treatment periods. On placebo the mean neutral sterol excretion was approximately 1 g per day which results in a mean cholesterol synthesis of 931 mg per day. On ezetimibe fecal excretion of total neutral sterols increased by 72% resulting in an increase of cholesterol synthesis by 89%. A small but not statistically significant increase in acidic sterol excretion was also observed. 22.7% 931 1763 - 20.4% Cholesterol Intestinal Absorption (%) Cholesterol Synthesis (mg/j) Change in LDL-C (%) Sudhop et al. Circulation 2002;106:1943-8

他汀介导的胆固醇合成抑制会导致胆固醇吸收增加吗 ?

阿托伐他汀 20mg 及 80mg 降低胆固醇合成 并增加胆固醇吸收 Atorvastatin 20mg Atorvastatin 80mg 7-烯胆甾醇 /菜油甾醇 - 79% - 86% +71% % Change +48% P<0.05 P<0.05 胆固醇合成 (7-烯胆甾醇 ) P<0.05 P<0.05 -69% 胆固醇吸收 (菜油甾醇 ) -76% Lamon Fava et al J Lipid Res 2007; 48: 1746-53

抑制胆固醇合成 LDL-C 20-60% 增加胆固醇吸收 抑制胆固醇吸收 LDL-C 20% 增加胆固醇合成 (他汀) 合成 吸收 合成 (依折麦布) 增加胆固醇合成

胆固醇吸收与生成的关联: 对临床实践的影响 ? 高合成个体 vs 高吸收个体

胆固醇的来源 吸收 合成 LIVER Acetyl-CoA Cholesterol GUT

评价胆固醇吸收的理想指标 7-烯胆甾醇 /菜油甾醇 比 吸收 合成 LIVER GUT Lathosterol Campesterol Acetyl-CoA Lathosterol Campesterol Cholesterol GUT 菜油甾醇 7-烯胆甾醇 HIGH 高吸收个体 LOW LOW 高合成个体 HIGH

依折麦布与他汀类药物联用的作用在杂合子家族性高胆固醇血症的人群中得到验证 65 例杂合子家族性高胆固醇血症的患者 • 2 步治疗 : 他汀单一治疗，然后他汀+依折麦布联合治疗 • 他汀 (辛伐他汀 20/40 mg/d, 阿托伐他汀 20/40 mg/d) 降低 LDL-C 36.7% • 联合治疗降低 LDL-C 57% Pisciotta et al. Atherosclerosis 2007; 194:e116-e122

杂合子家族性高胆固醇血症人群中，他汀及依折麦布降低LDL-C 水平的相关曲线 Pisciotta et al. Atherosclerosis 2007; 194:e116-e122

65例家族性高胆固醇血症患者中，使用辛伐他汀20/40 mg/日或阿托伐他汀20/40 mg/日降低LDL-C 的个体反应 Pisciotta et al. Atherosclerosis 2007; 194:e116-e122

他汀类单药治疗能使患者达到治疗目标吗?  现实中的情况如何 ?  达到LDL-C治疗目标的主要障碍是什么 ?  未达到他汀类治疗目标的患者的进一步治疗方案是什么?

未达到他汀类治疗目标的患者的进一步治疗方案 1. 他汀剂量加倍

他汀: “6 规则” Reduction of LDL (%) +40 mg -10 -20 -30 -40 -50 +20 mg 10 +40 mg - 6% +10 mg - 6% +20 mg - 6% Reduction of LDL (%) 10 20 40 80 mg Statin

未达到他汀类治疗目标的患者的进一步治疗方案 1.他汀剂量加倍 2. 改用更加强效的他汀 3. 使用依折麦布-他汀联合治疗

对于他汀单药治疗反应不理想的患者对 依折麦布-他汀联合治疗反应更好 假设 对于他汀单药治疗反应不理想的患者对 依折麦布-他汀联合治疗反应更好

他汀治疗不达标的患者治疗策略的比较研究 1. 他汀剂量加倍 vs. 依折麦布-他汀联合治疗  EASEGO 研究  EZ-PATH 及 TEMPO 研究 2. 换用更强效的他汀 vs. 依折麦布-他汀联合治疗  IN-CROSS 研究

他汀治疗不达标的患者治疗策略的比较研究 1. 他汀剂量加倍 vs. 依折麦布-他汀联合治疗  EASEGO 研究  EZ-PATH 及 TEMPO 研究 2. 换用更强效的他汀 vs. 依折麦布-他汀联合治疗  IN-CROSS 研究

EASEGO 研究 研究设计 入选的血脂指标 : LDL-C  2.5 mmol/L and < 5.0 mmol/L TG  4.0 mmol/L, TC  7.0 mmol/L on statin monotherapy 367 名冠心病和/或2型糖尿病患者 (n=115) (n=110) (n=74) (n=68) simvastatin 40 mg Stratum 1 : simvastatin 20 mg ezetimibe/simvastatin 10/20 mg atorvastatin 20 mg Stratum 2 : atorvastatin 10 mg ezetimibe/simvastatin 10/20 mg V1 V2 V3 Follow-up Week -1 Screening Week 0 Randomization Start study treatment Week 12 End study treatment Week +2 AE monitoring van Lennep et al. Curr Med Res Opin 2008; 24: 685-694

Mean % change from baseline EASEGO 研究 % 血脂指标改变 (与基线资料相比) # Mean % change from baseline * 17.6 % * * * * p < 0.001, # p = 0.02 for between-treatment comparison between EZE/SIMVA and doublind statin van Lennep et al. Curr Med Res Opin 2008; 24: 685-694

EASEGO 研究 LDL-C 达标的患者的比例 % of patients LDL-C < 2.5 mmol/l (< 100 mg/dL) LDL-C < 2.0 mmol/l (< 80 mg/dL) % of patients OR 5.7 (95% CI: 3.7-9.0) OR 12.9 (95% CI: 5.4-31.0) van Lennep et al. Curr Med Res Opin 2008; 24: 685-694

LDL-C < 2.5 mmol/l (< 100 mg/dL) EASEGO 研究 仅使用他汀治疗，患者 LDL-C 达标的比例 LDL-C < 2.5 mmol/l (< 100 mg/dL) Simvastatin at baseline Atorvastatin at baseline % of patients OR 8.2 (95% CI: 4.6-15.1) OR 3.4 (95% CI: 1.7-6.8) van Lennep et al. Curr Med Res Opin 2008; 24: 685-694

在阿托伐他汀（20mg）基础上加用依折麦布 vs 增加阿托伐他汀剂量（40mg）的比较： 高胆固醇血症且冠心病中高危的患者 2.5 ≤ LDL-C ≤ 4.1 mmol/l n = 98 Atorva 20 mg + Eze 10 mg Atorva 20 mg Randomization n = 98 Atorva 40 mg 6 weeks 6 weeks Run-in period Double-blind period Conard et al. Am J Cardiol 2008; 102: 1489-94 TEMPO study

% change from Baseline at week 6 在阿托伐他汀（20mg）基础上加用依折麦布 vs 增加阿托伐他汀剂量（40mg）的比较： 高胆固醇血症且冠心病中高危的患者 血脂指标及hsCRP的改变 NS % change from Baseline at week 6 NS NS 20% p<0.001 p<0.001 TEMPO study Conard et al. Am J Cardiol 2008; 102: 1489-94

在阿托伐他汀（20mg）基础上加用依折麦布 vs 增加阿托伐他汀剂量（40mg）的比较： 高胆固醇血症且冠心病中高危的患者 Patients reached LDL-C < 2.5 mmol/l LDL-C Mean % change at week 6 % patients reaching LDL-C goal p<0.001 p<0.001 A20 + E10 A40 TEMPO study Conard et al. Am J Cardiol 2008; 102: 1489-94

在阿托伐他汀（40mg）基础上加用依折麦布 vs 增加阿托伐他汀剂量（80mg）的比较： 高胆固醇血症且冠心病高危的患者 LDL-C ≥ 1.8 mmol/l and ≤ 4.1 mmol/l n = 288 Atorva 40 mg + Eze 10 mg Atorva 40 mg Randomization n = 291 Atorva 80 mg 5 weeks 6 weeks Run-in period Double-blind period Leiter et al. Am J Cardiol 2008; 102: 1495-1501 EZ-PATH study

在阿托伐他汀（40mg）基础上加用依折麦布 vs 增加阿托伐他汀剂量（80mg）的比较： 高胆固醇血症且冠心病高危的患者 Optional LDL-C goal < 1.8 mmol/l LDL-C n=279 n=277 % patients reaching LDL-C goal Mean % Change at week 6 16% * * p<0.001 p<0.001 A40 + E10 A80 EZ-PATH study Leiter et al. Am J Cardiol 2008; 102: 1495-1501

他汀治疗不达标的患者治疗策略的比较研究 1. 他汀剂量加倍 vs. 依折麦布-他汀联合治疗  EASEGO 研究  EZ-PATH 及 TEMPO 研究 2. 换用更强效的他汀vs. 依折麦布-他汀联合治疗  IN-CROSS 研究

JV Phase IV 3 Articles - NOT APPROVED FOR USE 11/19/2018 10:09 AM IN-CROSS 研究 目的 LDL-C升高的高危患者 [ ≥ 2.6 mmol/l (100 mg/dl) and ≤ 4.14 mmol/l (160 mg/dl)] ，无论之前是否接受过单一他汀治疗, 与使用罗苏伐他汀(ROSUVA) 10 mg 相比，改用依折麦布/辛伐他汀(EZE/SIMVA) 10/20 mg 能提高疗效 Reckless p1A Reckless p1B Reckless p1C Reckless p1D Slide 48 Farnier et al. IJCP 2009; 63: 547-559 Clinical Knowledge Library 48

IN-CROSS研究 :研究设计 多中心，随机，双盲，平行组研究 618 名高危患者，他汀单药治疗未达标 LDL-C ≥ 2.59 mmol/l (100 mg/dl), ≤ 4.14 mmol/l (160 mg/dl) TG ≤ 3.96 mmol/l (350 mg/dl) EZE/SIMVA 10/20 mg 6 weeks Run-in 6 weeks Stratum 1 Stratum 2 Atorva 10 Rosuva 5 Simva 20 Atorva 20 Prava 40 Simva 40 Fluva 80 ROSUVA 10 mg Farnier et al. IJCP 2009; 63: 547-559

IN-CROSS研究 : 主要终点 LDL-C改变的平均水平 他汀类治疗时的基础LDL-C水平 : 3.2 mmol/l (125 mg/dL) LDL-C改变的平均水平 10 Overall Study Population Stratum 1 Stratum 2 -10 Mean % Change from Baseline (SE) -20 - 16.9% EZE/SIMVA 10/20 mg ROSUVA 10 mg -30 - 27.7%  10.7%  7%  17% -40 p  0.001 (95% CI: -11.3, -3.2) (95% CI: -23.1, -9.9) Farnier et al. IJCP 2009; 63: 547-559

% Change from Baseline (SE) IN-CROSS 研究 : 血脂指标的改善 改变的均值 (TG的中位数) p =0.433 % Change from Baseline (SE) p =0.056 p  0.001 p  0.001 p  0.001 EZE/SIMVA 10/20 mg ROSUVA 10 mg p  0.001 Farnier et al. IJCP 2009; 63: 547-559

IN-CROSS 研究 : 研究结束时LDL-C达标的比例 JV Phase IV 3 Articles - NOT APPROVED FOR USE 11/19/2018 10:09 AM IN-CROSS 研究 : 研究结束时LDL-C达标的比例 *** p £ 0.001 EZE/SIMVA vs. ROSUVA for adjusted odds ratio. 10 20 30 40 50 60 70 80 *** 72% Reckless p10 Fig4 EZE/SIMVA 10/20 mg ROSUVA 10 mg 56% *** % Patients Reaching LDL-C Goal 38% *** Slide 52 25% 19% 11% <2.59 mmol/L (<100 mg/dL) <1.81 mmol/L (<70 mg/dL) <2.00 mmol/L (<77mg/dL) Secondary Exploratory Secondary Farnier et al. IJCP 2009; 63: 547-559 Clinical Knowledge Library 52

IN-CROSS 研究 : 数据解读 入选标准意味研究人群为在低/中剂量他汀治疗下，LDL-C未达标（对他汀类反应良好的人群被剔除） JV Phase IV 3 Articles - NOT APPROVED FOR USE 11/19/2018 10:09 AM IN-CROSS 研究 : 数据解读 入选标准意味研究人群为在低/中剂量他汀治疗下，LDL-C未达标（对他汀类反应良好的人群被剔除） 入选他汀反应差的患者可使本研究人群更为丰富（他汀低合成，因此胆固醇吸收更好的人群） Reckless p1A Reckless p1B Reckless p1C Reckless p1D Slide 53  该入选标准可以解释该研究中，组间差异比一般人群更为明显的现象  这一机制也可以解释为何在该研究中，依折麦布在高剂量组更为有效 (该组患者可能对他汀类反应更差) Farnier et al. IJCP 2009; 63: 547-559 Clinical Knowledge Library 53

JV Phase IV 3 Articles - NOT APPROVED FOR USE 11/19/2018 10:09 AM IN-CROSS 研究 : 结论 Reckless Table 4 p13 对于他汀类单药治疗未能达标的患者，目前的研究显示从他汀类单药治疗改为依折麦布/辛伐他汀10/20 mg 与罗苏伐他汀10mg相比，能更好地降低LDL-C，使得高危患者LDL-C达标率明显提高 Slide 54 Farnier et al. IJCP 2009; 63: 547-559 Clinical Knowledge Library 54

结论 (1)  多数情况下，他汀类药物仍是有效地控制LDL的 手段  然而，即使是最强效的他汀和/或采用最大的剂量， 仍然有许多高危患者无法达到治疗目标（对他汀药 物治疗的个体差异极大） 55

结论 (2)  胆固醇合成与吸收的相互作用可调节对他汀类药物 单药治疗的反应  对他汀类药物单药治疗反应较差的患者适宜接受 依折麦布-他汀联合治疗 通过对胆固醇吸收和合成途径地双重抑制能更好 地降低LDL-C 56

关键信息 降低LDL-C : 结果比手段更为重要 La Rosa J., Am J Cardiol 2007; 100: 240-242