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1、他汀类药物的副作用除了停药还能作些什么 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望Disclosure（讲前声明）No any interest was involved in this Lecture冠心病冠心病:发展中国家的严峻挑战发展中国家的严峻挑战q WHO2008年报告：心血管病死亡占 全球死亡31%，排名第一(传染病29%)q 17,00万/年死于动脉粥样硬化性疾病 q 80分布在低中等收入国家包括中国 q 我国每年死于冠心病的人数达250万CHD
2、:Severe challenge in developing countries 22.615.9/13.27.92.8安慰剂组安慰剂组5年心梗发生率（）年心梗发生率（）奠定了他汀类药物的临床广泛与强化应用的基础奠定了他汀类药物的临床广泛与强化应用的基础奠定了他汀类药物的临床广泛与强化应用的基础奠定了他汀类药物的临床广泛与强化应用的基础 5项经典他汀类里程碑临床试验项经典他汀类里程碑临床试验CAREn=4,159TC 5.4 mmol/lLIPIDn=9,014TC 5.6 mmol/lWOSn=6,595 TC 7.0 mmol/l4Sn=4,444TC 6.8 mmol/l冠心病冠心病+
3、胆固醇高胆固醇高冠心病冠心病+胆固醇不高胆固醇不高无冠心病无冠心病胆固醇高胆固醇高TexCAPSn=6,605 TC 5.7 mmol/l无冠心病无冠心病胆固醇不高胆固醇不高LDL-C降低降低35253226233424233135Landmark studies of statin-related clinical trials LDL-C降低 事件减少优化药物治疗是现代冠心病治疗主流优化药物治疗是现代冠心病治疗主流药物药物危险性减少危险性减少(%)(%)5 5年事件发生率年事件发生率(%)(%)无药物治疗无药物治疗020.0阿司匹林阿司匹林2515.0 受体阻滞剂受体阻滞剂2511.3AC
4、EIACEI258.4他汀类药物他汀类药物305.9同时使用上述同时使用上述4 4种药物，可使总的死亡危险性减少种药物，可使总的死亡危险性减少70%70%5 5年中，每治疗年中，每治疗7 7位患者，便可减少位患者，便可减少1 1例主要心血管事件例主要心血管事件Yusuf et al.Rev Cardiovasc Med.2003;4(suppl 3):537-46.Current strategies of medication therapy for coronary heart disease 他汀促进强化调脂与靶目标概念诞生他汀促进强化调脂与靶目标概念诞生 危险等级危险等级TLCTLC开
5、始开始(mg)mg)治疗开始治疗开始(mg)mg)目标值目标值(mg)mg)低危低危:（1010年危险性年危险性5%240240LDL-CLDL-C 160160TCTC 270270LDL-CLDL-C 190190TC240TC240LDL-C160LDL-C 200200LDL-CLDL-C 130130TC TC 240 240LDL-C LDL-C 160 160TC200TC200LDL-C130LDL-C 160 160LDL-C LDL-C 100 100TC TC 160 160LDL-C LDL-C 100 100TC160TC160LDL-C100LDL-C 120120
6、LDL-CLDL-C880 0TC TC 160160LDL-C LDL-C 880 0TC120TC120LDL-C80LDL-C3ALT3倍倍ULN ULN 19/213219/2132（0.90.9）8/20688/2068（0.40.4）横纹肌溶解横纹肌溶解#3/2230 3/2230（0.10.1）0/22300/2230（0 0）肌病肌病 9/22639/2263（0.40.4）1/22301/2230（0.040.04）因肌肉方面不良反应因肌肉方面不良反应而停药而停药 41/226341/2263（1.81.8）34/223034/2230（1.51.5）Rate of adve
7、rse effects occurred in A to Z study不良反应类型不良反应类型TNT研究不良事件发生率与剂量关系 La Rosa JC et al.N Engl J Med 2005;352:1425-1435.阿托伐他汀 10mg阿托伐他汀 80mgP值(n=5,006)(n=4,995)和治疗相关的副反应289(5.8)406(8.1)0.001和治疗相关的肌痛234(4.7)241(4.8)0.72 肌溶解*3(0.06)2(0.04)肝酶升高大于三倍9(0.2)60(1.2)65 yrs)with MI 接受二种降压方案治XZK or或安慰 剂治疗，随访4.5年q 结
8、果与结论：XZK（含洛伐他汀10mg 明显 降低老年心梗后高血压患者的心血管事件Li J-J,Lu Z-L,et al.J Clin Pharmacol 2009;47:947-956.Xuezhikang decrease CVE in Chinese hypertensive elderly with MI 他汀类副作用他汀类副作用:除了停药还能作些什么？除了停药还能作些什么？他汀类药物之间的转换应用他汀类药物之间的转换应用 Statin switching Statin switchingAdverse effects of statins:Strategies beyond disco
9、ntinuationStatin switching:a case reportq Case report:1 59-year-old women withCase report:1 59-year-old women with heart transplantation 4 years heart transplantation 4 years eralier.eralier.q Pravastatin 20mg/d for 4 years Pravastatin 20mg/d for 4 yearsq After switching from After switching from pr
10、avastatin topravastatin to simvastatin,simvastatin,she developed severe muscular she developed severe muscular weakness until repeat hemodialysis weakness until repeat hemodialysis Sochman J,Podzimkova M.Int J Cardiol 2005;99:145-146.Statin switching:basic mechanism辛伐他汀阿托伐他汀氟伐他汀氟伐他汀不良反应不良反应药物积聚药物积聚
11、氟伐他汀氟伐他汀较危险的途径CYP 450 3A4CYP 450 3A4CYP 450 2C9CYP 450 2C9与与CYP 450 3A4 CYP 450 3A4 相互作用常用药物相互作用常用药物 心血管药物心血管药物(钙离子拮抗剂，钙离子拮抗剂，氯吡格雷，贝特类，烟酸，地氯吡格雷，贝特类，烟酸，地高辛，华法令高辛，华法令)抗菌药抗菌药(克拉霉素、红霉素克拉霉素、红霉素)抗哮喘药物抗哮喘药物(茶碱茶碱)免疫抑制剂免疫抑制剂(环孢素环孢素)胃肠道药物胃肠道药物(奥美拉唑奥美拉唑 )Ballantyne C et al.Arch Intern Med 2003;163:553564Corsin
12、i A.Cardiovasc Drugs Ther 2003;17:257277Drug interactions between statin and other medications 相对亲水性相对亲水性*Statin switching:basic mechanism他汀药效基团他汀药效基团OONNSNOHOHOOCH3CH3CH3FCH3Ca(3R,5S)亲水的磺酸基团亲水的磺酸基团Buckett et al.,(2000);McTaggart et al.,(2001)相对亲脂性相对亲脂性*-1.0-0.50.00.51.01.52.0瑞舒伐他汀瑞舒伐他汀西立伐他汀西立伐他汀辛伐他
13、汀辛伐他汀氟伐他汀氟伐他汀阿托伐他汀阿托伐他汀普伐他汀普伐他汀*log D at pH 7.4肝外扩散肝外扩散分布少分布少肝内肝内 CYP代谢少代谢少Cell-selective action of Water-loving and water-hating statin 普伐他汀普伐他汀ML-236B静注静注CC1414标记美百乐镇标记美百乐镇 及及 ML-236B ML-236B 后大鼠全身放射显影照片后大鼠全身放射显影照片Arai M,et al.Annu Rep Sankyo Res Lab 1988;1:40.普伐他汀普伐他汀在肝脏高度选择性分布在肝脏高度选择性分布High-degr
14、ee selective action in liver following pravastatin administrationThe rate of occurrence of muscular symptoms with high dosage statin therapy varied depending on the statinLescol XL treatment was associated with a significantly lower risk of muscular symptoms compared with pravastatin,atorvastatin an
15、d simvastatin他汀类药物他汀类药物剂量剂量出现肌肉症出现肌肉症状的比例状的比例危险比危险比 95%CI 95%CIP P 值值 普伐他汀普伐他汀40 mg/40 mg/天天10.9%10.9%1 1阿托伐他汀阿托伐他汀404080 mg/80 mg/天天14.9%14.9%1.281.021.281.021.601.600.0350.035辛伐他汀辛伐他汀404080 mg/80 mg/天天18.2%18.2%1.781.391.781.392.292.290.00010.0001氟伐他汀氟伐他汀80 mg/80 mg/天天5.1%5.1%0.330.260.330.260.420
16、.420.000145U/L）应用无恶化现象 2）迄今无肌病及肌溶解报道J Gerontol Med Sci 2001;13:1-9;Curr Ther Res 1996;57:118-127.Red yeast rice（红曲）红曲）for dislipidemia in a statin-intolerant patients:a randomize trialqDesign Design（设计）设计）:Randomized,controlled trialqPatientsPatients（患者）患者）:62 名他汀肌病停药者qTherapy Therapy（治疗）治疗）:Rid yea
17、st rice 1800mg(Sylvan bioproducts,Kittanning,Pennsylvania)or placebo(n=31 respectively)BidqFollow-upFollow-up（随访）随访）:24 weeks,primary outcome:LDL-C;secondary outcome:TC,HDL-C,TG,Liver enzyme,CK,weight,qResults Results（结果）结果）:LDL-C减少:1.11mmol/L vs 0.28 mmol/L at 12 wks,0.93 mmol/L vs 0.39 mmol/L at 2
18、4 wksqConclusion Conclusion（结论）结论）:Red yeast rice may be a treatment option for dislipidemic patients who cannot tolerate statin therapyBecher DJ,et al.Ann Intern Med 2009;150:830-839.Omega-3-fatty acids(Omega-3-fatty acids(-3-3-脂肪酸脂肪酸):):an an cardiovascular agent cardiovascular agentqLipid-related
19、 effects:Lipid-related effects:dose-dependently reduce blood TGqPleiotropic effects:Pleiotropic effects:favorable effects on inflammatory process,endothelial dysfunction,platelet aggregation and arrhythmogenesisqAdministration:Administration:used alone or used in combination with statinqMACE:MACE:ne
20、ed further study and more evidenceDimitrow PP,et al.Mini Rev Med Chem 2009;9:1030-1039.他汀类副作用他汀类副作用:除了停药还能作些什么？除了停药还能作些什么？小剂量他汀与降脂药物联合应用小剂量他汀与降脂药物联合应用 Combination of low-dose statin and Combination of low-dose statin and other lipid-lowering drugs other lipid-lowering drugs Adverse effects of statin
21、s:Strategies beyond discontinuation小剂量他汀与其它调脂药物联合应用qBile acid sequestrants Bile acid sequestrants（多价螯合剂）多价螯合剂）(Cholestyramine,colestipol,colesevelam)Cholestyramine,colestipol,colesevelam)qEzetimibeEzetimibeqNiacinNiacinqPlant sterolsPlant sterols（植物固醇）植物固醇）qFibrate Fibrate (fenofibrate,bezafibrate,g
22、emfibrozil)(fenofibrate,bezafibrate,gemfibrozil)qOmega-3-fatty acids Omega-3-fatty acids（-3-3-脂肪酸）脂肪酸）Combination of low-dose statin and other lipid-lowering drugs 小剂量他汀与其它调脂药物联合应用q目的：维持达标水平,降低不良反应与事件q原则：小剂量他汀与另外一种降脂药物组成Combination of low-dose statin and other lipid-lowering drugs It has to stated t
23、hat for most of these combination therapies data on cardiovascular outcomes are still lacking.Fundam Clin Pharmacol 2009;14:88-94.临床上可供选择的联合治疗模式小剂量他汀类治疗LDL 未达到目标HDL 未达到目标TG 未达到目标*加用烟酸*加用贝特类药物 加用鱼油*=增加肌病危险性Grundy S,Am J Cardiol 2002;90:1135-38*加用烟酸*加用贝特类 加用伊折麦布*加用烟酸*加用贝特类药物Models of lipid-lowering co
24、mbination therapy依折麦布依折麦布+辛伐他汀辛伐他汀:显著降低显著降低LDL-C平均 变化%10 mg依10 mg+辛伐他汀10 mg80 mg40 mg20 mg辛伐他汀*联合治疗与单用他汀比较 p0.01Davidson,et al.J Am Coll Cardiol 2002;40:2125Davidson,et al.J Am Coll Cardiol 2002;40:2125More reduction of LDL-C levels following EZE+Simvastatin 依折麦布联合他汀治疗更有效降低CRPThomas P,et al.,Am J Ca
25、rdiol 2007;99:17061713.12 weeks therapyMore reduction of CRP levels following EZE+Simvastatin HATS:辛伐他汀与烟酸联用显著改善冠脉狭窄和心血管事件Zhao X et al.J Am Coll Cardiol.2002;39:242A;1130-73.Change in Stenosis,%CVD Event Rate,%*90%Reduction*代谢综合征n=69非代谢综合征n=7740%Reduction代谢综合征 n=77非代谢综合征 n=83*冠脉造影冠脉造影心血管事件心血管事件Place
26、boNiacin+SimvastatinMore reduction of MACE following niacin+simvastatin 他汀类副作用他汀类副作用:除了停药还能作些什么？除了停药还能作些什么？非他汀类降脂药物联合应用非他汀类降脂药物联合应用 Combination of non-statin lipid-lowering drugs Combination of non-statin lipid-lowering drugs Adverse effects of statins:Strategies beyond discontinuation非他汀降脂药物联合应用的临床
27、方向非他汀降脂药物联合应用的临床方向q Niacin-resin or fibrate-niacinq Extended-release niacin/laropipranq Squalene synthase inhibitor（角鲨烯合成 酶抑制剂）q Microsomal triglyceride transfer protein inhibitor（微粒体甘油三脂转运蛋白抑制剂）q antisense apolipoprotein B（反义载脂蛋白B）Novel nonstatin strategies to lower LDL-CCurr Atheroscler Rep 2009;1
28、1:67-70.Extended niacin/laropiprant applicationqDesign:Design:Randomized,double-blind,placebo controlled Randomized,double-blind,placebo controlled multicenter,24-week trialmulticenter,24-week trialqDrug:Drug:Combination of Niacin 2000mg/laropiprant 40mg Combination of Niacin 2000mg/laropiprant 40mg
29、qResults:Results:LDL-C 18%LDL-C 18%Incidence and intensity of flushing were significantly reduced Incidence and intensity of flushing were significantly reduced compared with Niacin 2000mg pared with Niacin 2000mg alone.qConclusion:Conclusion:Combination of Niacin/laropiprant was generally Combinati
30、on of Niacin/laropiprant was generally well tolerated by adults with dyslipidemia.well tolerated by adults with dyslipidemia.Perry CM.Drugs 2009;69:1665-1679.Raising HDL-C with niacin and fibrates:a comparative reviewqDesign:Design:A head-to-head comparative study A head-to-head comparative studyqDr
31、ug:Drug:Combination of Niacin 2,000mg/Gemfibrozil Combination of Niacin 2,000mg/Gemfibrozil 1,200mg compared with Niacin or Fibrate trial alone1,200mg compared with Niacin or Fibrate trial aloneqIndexes:TC/HDL-C,Lp(a)and fibrinogen Indexes:TC/HDL-C,Lp(a)and fibrinogen qConclusion:Conclusion:Combinat
32、ion therapies of Niacin plus a Combination therapies of Niacin plus a resin are effective,well tolerated,and safe.resin are effective,well tolerated,and safe.Sprecher D,Am J Cardiol 2001;86(suppl 1):46-50.他汀类副作用他汀类副作用:除了停药还能作些什么？除了停药还能作些什么？保护性药物的联合应用保护性药物的联合应用 Coenzyme Q10 supplementationCoenzyme Q1
33、0 supplementationAdverse effects of statins:Strategies beyond discontinuation保护性药物联合应用的临床证据保护性药物联合应用的临床证据q Br J Clin Pharmacol 1996;42:333-337.q Ann Intern Med 2002;137:581-585.q Arch of Neurol 2004;61:889-892.q Eur J Clin Invest.2005;35:251-258.q Am J Cardiol 2004;94:1306-1310.q Georgian Medical Ne
34、ws 2005(1):20-24.Clinical application of statin with preventive drugs 辅酶辅酶Q10Q10与他汀类药物的机制关系与他汀类药物的机制关系HMG-CoA甲酸戊酸甲酸戊酸异戊烯焦磷酸异戊烯焦磷酸焦磷酸法呢酯焦磷酸法呢酯辅酶辅酶Q10(CoQ10)多醇多醇胆固醇胆固醇鲨烯鲨烯HMGCoA还原酶HMGCoA还原酶抑制剂乙酰辅酶A+Possible Mechanism of Co-Q10 and statins 他汀类药物与他汀类药物与对辅酶对辅酶Q10Q10水平影响水平影响 Br J Clin Pharmacol 1996,42:33
35、3高胆固醇血症患者(21岁-76岁，n=80）40名接受他汀类药物治疗，20名接受贝特类药物，20名没有药物治疗，20名健康对照者入住及试验一周后采集血样辛伐他汀(n=40)贝特类(n=20)未治疗患者(n=20)健康对照者(n=20)辛伐他汀贝特类 未治疗组健康对照组e P0.05 vs 未治疗组 h P0.05 vs 健康对照组Decreased levels of Co-Q10 in patients treated with statinMg l-1 0.75e 0.91h 0.95h 0.96辅辅酶酶Q Q1 10 0水水平平Statin-induced myopathy is as
36、sociated with mitochondrion dysfunction 他汀性肌病与线粒体功能异常他汀性肌病与线粒体功能异常 Ann Intern Med.2002,137:581-585A,C,E服用他汀类药物肌肉活检图B、D、F 停药后肌肉活检图阿托伐他汀对辅酶阿托伐他汀对辅酶Q10Q10水平的影响水平的影响Decreased levels of Co-Q10 in patients treated with atorvastatinArchives of Neurology Vol.61(6):889-892*P0.01 与基线水平相比治疗后的天数2.01.81.61.41.21
37、.00.80.60.40.20基线 14 30 辅酶Q10的浓度(ug/mL)1.260.670.62*N=34阿托伐他汀80mg/天疗程30天辛伐他汀对辅酶辛伐他汀对辅酶Q10水平的影响水平的影响Effects of simvatstatin on plasma levels of Co-Q10 European Journal of Clinical Investigation.2005,35:251258辅酶Q10水平(nmol/L)时间（月）N=21辛伐他汀20mg/天疗程6个月，期间测定辅酶Q10的浓度停药一个月后，再测定体内辅酶Q10水平1500125010007505000 1
38、2 3 4 5 6 7*P0.05,与基线相比vs服用他汀类药物的患者 DT值,#p=0.002,$p=0.12DT值14位高脂血症患者51-79岁，他汀类药20mg/天，疗程 3-6个月10名患者出现心室舒张功能恶化再加用辅酶Q10 300mg/天(100mg/次，tid)后，患者心肺功能得到恢复Silver MA,et al.Am J Cardiol 2004,94:1306-1310 192#209$242 基线 他汀类药物他汀类药物+辅酶Q10Statin plus Co-Q10 reverse statin-induced ventricular dysfunction 辅酶辅酶Q1
39、0逆转他汀引起的心室舒张功能逆转他汀引起的心室舒张功能 基线 他汀类药物+辅酶Q10 他汀类药物组小结小结:他汀副作用他汀副作用除了停药可以选择策略除了停药可以选择策略q 减量与间断应用减量与间断应用 q 他汀类药物之间的转换应用他汀类药物之间的转换应用 q 非他汀降脂药物的替换应用非他汀降脂药物的替换应用q 小剂量他汀与降脂药物联合应用小剂量他汀与降脂药物联合应用 q 保护性药物的联合应用保护性药物的联合应用温馨提示：上述策略的循证证据十分有限，本内容仅供学术研讨Summary:Adverse effects of statins:Strategies beyond discontinuationBuilding insights,break boundaries