他汀类药物的副作用除了停药还能作些什么

1、他汀类药物的副作用除了停药还能作些什么,Adverse effects of statins: Strategies beyond discontinuation,Disclosure（讲前声明,No any interest was involved in this Lecture,冠心病:发展中国家的严峻挑战,WHO2008年报告：心血管病死亡占 全球死亡31%，排名第一 (传染病29%) 17,00万/年死于动脉粥样硬化性疾病 80分布在低中等收入国家包括中国 我国每年死于冠心病的人数达250万,CHD: Severe challenge in developing countries,

2、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,CARE n=4,159 TC 5.4 mmol/l,LIPID n=9,014 TC 5.6 mmol/l,WOS n=6,595 TC 7.0 mmol/l,4S n=4,444 TC 6.8 mmol/l,冠心病 + 胆固醇高,冠心病+ 胆固醇不高,无冠心病 胆固醇高,TexCAPS n=6,605 TC 5.7 mmol/l,无冠心病 胆固醇不高,LDL-C降低 35 25 32 26 23,34 24 23 31 35,Landmark studies of statin-related clinical tr

3、ials,LDL-C降低 事件减少,优化药物治疗是现代冠心病治疗主流,同时使用上述4种药物，可使总的死亡危险性减少70% 5年中，每治疗7位患者，便可减少1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,Target of lower-density cholesterol following lipid-lowering therapy,中国成

4、人血脂异常防治指南委员会. 中华心血管病杂志 2007; 35: 390-413,Safety Issue of Statin Therapy an long-term important issue,2002,2006,他汀应用需要格外关注药物的安全性,药物间相互作用 肌毒性与肝毒性,他汀类药物的副作用机制尚不十分清楚 严重不良反应绝对停用（Discontinuation,Special attention on safety issue of statin therapy,临床要点,他汀类药物相互作用的可能风险,合并高血压， 同时服用钙离子拮抗剂，辛伐他汀, 阿托伐他汀慎重使用（定期监测C

5、K) 合并房颤，辛伐他汀, 阿托伐他汀应在监测CK下慎用 心衰患者，辛伐他汀, 阿托伐他汀应在定期监测CK及地高辛浓度下慎重使用 PCI术后，联合使用氯吡格雷，辛伐他汀, 阿托伐他汀应在定期监测CK下慎重使用 他汀应尽量避免与烟酸类和贝特类药物合用,Possible risk of drugs when co-administration with statin,他汀类药物应用的肌毒性问题,肌病：他汀类药物最严重的不良反应 Mechanism: Gemonic variation 表现：肌痛或肌无力，伴有CK升高至正常上 限10倍以上，也可有发热和全身不适症状 发生率：大约是0.1%，且与剂量

6、有关 危害：肌病未能及时被发现，仍旧继续用药， 则可能导致横纹肌溶解和急性肾功能衰竭,Statin-associated myopathy: an important issue,他汀类药物肌毒性的临床认知,The clinician should suspect a toxic myopathy when a patient without a pre-existing muscle disease develops myalgia, fatigue, weakness or myoglobinuria, temporally connected to the administration

7、of a statin or exposure to a myotoxic substance,Dalakas MC. J Neurol Neurosurg Psychiatry 2009;80:832-838,Statin-related toxic myopathy: clinical recognition,他汀类药物肌肉症状的基本定义,1. Pasternak R et al. Circulation 2002;106:102428 2. Ucar M et al. Drug Saf 2000;22:44157,Definition of statin-associated myopa

8、thy,澳大利亚报道他汀类药物致肌病的危险因素,Australian Adverse Drug Reactions Bulletin. 2004 Feb；23（1,Risk factors of statin-related myopathy in Australia,他汀类副作用:除了停药还能作些什么,减量与间断应用 (reduce dose and nondaily dosing regimes) 他汀类药物之间的转换应用 (statin switching) 非他汀降脂药物的替换应用 (nonstatin alternatives) 他汀与降脂药物联合应用 (combination of

9、 ow-dose statin and others) 保护性药物的联合应用 (coenzyme Q10 supplementation,Adverse effects of statins: Strategies beyond discontinuation,他汀类副作用:除了停药还能作些什么,减量与间断应用 Reduce dose and nondaily dosing regimes,Adverse effects of statins: Strategies beyond discontinuation,治疗组76,359；安慰剂71,962,Law MR. Br Med J 2003

10、;326:1423,长期治疗是他汀获益的必要条件,58项他汀临床试验荟萃分析的结果,Benefits of statin therapy derived from long-term administration,他汀突然撤除会增加心血管事件,Circulation 2002; 105:1446-1542,Withdrawal of Statins: 增加ACS患者心血管事件发生率 可能机制之一 炎症因子反弹,Li J-J, et al. Med Hypo 2006; 66:478,Increased mortality after withdrawing a statin therapy,他

11、汀撤除事件增加的可能机制：炎症“反弹,_ Time Median CRP(mg/dl) Mean CRP(mg/dl) IL-6 (pg/dl) _ Baseline 0.15 0.300.10 8.4 0.6 6 weeks 0.10 0.220.09 6.7 0.4 Withdrawal Day 1 0.10 0.210.09 6.8 0.5 Day 3 0.14 0.270.14 7.7 0.6 Day 7 0.16 0.310.15 8.7 0.8 _,Li J-J, et al. Clin Chim Acta 2006;366:273-279,Increased mortality

12、after withdrawing a statin therapy,AtoZ 研究中不良事件发生率与剂量关系,de Lemos JA, et al. JAMA 2004;292:1307-1316,辛伐他汀40或80mg/日 安慰剂辛伐他汀20mg/日 AST或ALT3倍ULN 19/2132（0.9） 8/2068（0.4） 横纹肌溶解# 3/2230（0.1） 0/2230（0） 肌病 9/2263（0.4） 1/2230（0.04） 因肌肉方面不良反应 而停药 41/2263（1.8） 34/2230（1.5,Rate of adverse effects occurred in A

13、to Z study,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,不良反应类型,Safety issue of high-dose statin administration in TNT study,他汀小剂量应用有效性的证据,对象：106名高脂血症妇女 方法：Atorvastatin 10mg/d 3-6 m 指标：LDL-C, CRP, TPA/PAI-1, Sex steroid production 结论：low-dose has no influence on endocrin

14、ological status except effective in LDL-C and inflammatory markers,Evidence of reduced and nondaily dosing statin regimes,Ushiroyama T, et al. Int J Cardiol 2006;113:66-75,MEGA研究小剂量普伐他汀在日本成年人胆固醇升高一级预防治疗有效,研究背景：8214例中度高脂血症的患者，接受限制总胆固醇和饱和脂肪酸的饮食，每周吃3次鱼，一组服用10-20mg普伐他汀，一组不服用普伐他汀治疗 随访时间：5.3年 结果： 服用10mg20

15、mg普伐他汀可以使冠心病的危险约降低30,Nakamura H, et al. Lancet 2006;368:1155-1163,Mega study: low-dose pravastatin decreases CVE in Japanese,血脂康降低老年MI高血压患者CVE,研究设计：多中心、随机、安慰剂对照 对象：1530老年高血压患者（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 结果与结论： 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 Pharma

16、col 2009; 47:947-956,Xuezhikang decrease CVE in Chinese hypertensive elderly with MI,他汀类副作用:除了停药还能作些什么,他汀类药物之间的转换应用 Statin switching,Adverse effects of statins: Strategies beyond discontinuation,Statin switching: a case report,Case report: 1 59-year-old women with heart transplantation 4 years erali

17、er. Pravastatin 20mg/d for 4 years After switching from pravastatin to simvastatin, she developed severe muscular weakness until repeat hemodialysis,Sochman J, Podzimkova M. Int J Cardiol 2005;99:145-146,Statin switching: basic mechanism,Ballantyne C et al. Arch Intern Med 2003;163:553564Corsini A.

18、Cardiovasc Drugs Ther 2003;17:257277,Drug interactions between statin and other medications,相对亲水性,Statin switching: basic mechanism,Buckett et al., (2000); McTaggart et al., (2001,相对亲脂性,瑞舒伐他汀,西立伐他汀,辛伐他汀,氟伐他汀,阿托伐他汀,普伐他汀,log D at pH 7.4,肝外扩散分布少,肝内 CYP代谢少,Cell-selective action of Water-loving and water

19、-hating statin,普伐他汀,ML-236B,静注C14标记美百乐镇及 ML-236B 后大鼠全身放射显影照片,Arai M, et al. Annu Rep Sankyo Res Lab 1988;1:40,普伐他汀在肝脏高度选择性分布,High-degree selective action in liver following pravastatin administration,The rate of occurrence of muscular symptoms with high dosage statin therapy varied depending on the

20、statin Lescol XL treatment was associated with a significantly lower risk of muscular symptoms compared with pravastatin, atorvastatin and simvastatin,PRIMO研究:他汀类药物剂量和肌肉症状风险,Bruckert B et al. Cardiovasc Drugs Ther 2006;19:403-414,N=7924,Statin dosing and statin-relating myopathy in PRIMO study,FDA报道

21、他汀发生肌毒性事件,FDA report data on file,Statin-related toxic myopathy: Are all statins same,他汀类副作用:除了停药还能作些什么,非他汀降脂药物的替换应用 Nonstatin alternatives,Adverse effects of statins: Strategies beyond discontinuation,非他汀降脂药物替换应用的临床选择,烟酸 多廿烷醇 Red yeast rice （血脂康） 3- 脂肪酸 依折麦布,Clinical selection of nonstatin lipid-lo

22、wering drugs,烟酸类调脂药物的作用特点与应用,B族维生素(vitamin B3), 大剂量有降脂作用；适用高TG 血症，低HDL-C血症或以TG升高为主混合型高脂血症 速释剂烟酸不良反应明显，现已不用。缓释型烟酸不 良反应明显减轻，较易耐受 临床试验CDP,CLAS-I,FATS,HATS,ARBITER2 等证实，烟酸降低主要冠脉事件减少总死亡率 常见不良反应：颜面潮红、高血糖、高尿酸（或痛风）、上消化道不适等。绝对禁忌证为慢性肝病和严重痛风；相对禁忌证为溃疡病、肝毒性和高尿酸血症,Clinical features and application of Niacin-deriv

23、ed drugs,Study on extended niacin application,Design: Randomized, double-blind, placebo controlled multicenter, 24-week trial Drug: Combination of Niacin 2000mg/laropiprant 40mg Results: LDL-C 18% Incidence and intensity of flushing were significantly reduced compared with Niacin 2000mg alone. Concl

24、usion: Combination of Niacin/laropiprant was generally well tolerated by adults with dyslipidemia,Perry CM. Drugs 2009;69:1665-1679,多廿烷醇调脂治疗临床应用文献汇总,作用机制：通过腺苷酸激酶选择性阻断HMG-CoA还原 酶的活性（他汀完全阻断HMG-CoA合成酶） 调脂作用：10 mg/d: LDL-C 17%; HDL-C +5% 20mg/d: LDL-C 24%; HDL-C +18% 证据：1）肝酶异常者（ALT45U/L）应用无恶化现象 2）迄今无肌病及

25、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） for dislipidemia in a statin- intolerant patients: a randomize trial,Design （设计）: Randomized, controlled trial Patients（患者）: 62 名他汀肌病停药者 Therapy （治疗）: Rid yeast rice 1800mg (Sylvan bioproducts, Kittanning, Pennsyl

26、vania) or placebo (n=31 respectively) Bid Follow-up（随访）: 24 weeks, primary outcome: LDL-C; secondary outcome: TC, HDL-C, TG, Liver enzyme, CK, weight, Results （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 24 wks Conclusion （结论）: Red yeast rice may be a treatment o

27、ption for dislipidemic patients who cannot tolerate statin therapy,Becher DJ, et al. Ann Intern Med 2009;150:830-839,Omega-3-fatty acids (-3-脂肪酸): an cardiovascular agent,Lipid-related effects: dose-dependently reduce blood TG Pleiotropic effects: favorable effects on inflammatory process, endotheli

28、al dysfunction, platelet aggregation and arrhythmogenesis Administration: used alone or used in combination with statin MACE: need further study and more evidence,Dimitrow PP, et al. Mini Rev Med Chem 2009;9:1030-1039,他汀类副作用:除了停药还能作些什么,小剂量他汀与降脂药物联合应用 Combination of low-dose statin and other lipid-lo

29、wering drugs,Adverse effects of statins: Strategies beyond discontinuation,小剂量他汀与其它调脂药物联合应用,Bile acid sequestrants （多价螯合剂） (Cholestyramine, colestipol, colesevelam) Ezetimibe Niacin Plant sterols（植物固醇） Fibrate (fenofibrate, bezafibrate, gemfibrozil) Omega-3-fatty acids （-3-脂肪酸,Combination of low-dos

30、e statin and other lipid-lowering drugs,小剂量他汀与其它调脂药物联合应用,目的：维持达标水平,降低不良反应与事件 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 that for most of these combination therapies data on cardiovascular outcomes are still lacking,Fundam Clin Pharmacol 2009;14

31、:88-94,临床上可供选择的联合治疗模式,小剂量他汀类治疗,= 增加肌病危险性,Grundy S, Am J Cardiol 2002;90:1135-38,Models of lipid-lowering combination therapy,依折麦布+辛伐他汀:显著降低LDL-C,Davidson,et al. J Am Coll Cardiol 2002;40:2125,More reduction of LDL-C levels following EZE+Simvastatin,依折麦布联合他汀治疗更有效降低CRP,Thomas P, et al., Am J Cardiol 2

32、007;99:17061713,12 weeks therapy,More 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 = 77,40% Reduction,代谢综合征 n = 77,非代谢综合征 n = 83,Placebo,N

33、iacin + Simvastatin,More reduction of MACE following niacin+simvastatin,他汀类副作用:除了停药还能作些什么,非他汀类降脂药物联合应用 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方向,Niacin-resin or fibrate-niacin Extended-release niacin/laropipran Squal

34、ene synthase inhibitor （角鲨烯合成 酶抑制剂） Microsomal triglyceride transfer protein inhibitor （微粒体甘油三脂转运蛋白抑制剂） antisense apolipoprotein B （反义载脂蛋白B,Novel nonstatin strategies to lower LDL-C,Curr Atheroscler Rep 2009;11:67-70,Extended niacin/laropiprant application,Design: Randomized, double-blind, placebo c

35、ontrolled multicenter, 24-week trial Drug: Combination of Niacin 2000mg/laropiprant 40mg Results: LDL-C 18% Incidence and intensity of flushing were significantly reduced compared with Niacin 2000mg alone. Conclusion: Combination of Niacin/laropiprant was generally well tolerated by adults with dysl

36、ipidemia,Perry CM. Drugs 2009;69:1665-1679,Raising HDL-C with niacin and fibrates: a comparative review,Design: A head-to-head comparative study Drug: Combination of Niacin 2,000mg/Gemfibrozil 1,200mg compared with Niacin or Fibrate trial alone Indexes: TC/HDL-C, Lp (a) and fibrinogen Conclusion: Co

37、mbination therapies of Niacin plus a resin are effective, well tolerated, and safe,Sprecher D, Am J Cardiol 2001;86(suppl 1):46-50,他汀类副作用:除了停药还能作些什么,保护性药物的联合应用 Coenzyme Q10 supplementation,Adverse effects of statins: Strategies beyond discontinuation,保护性药物联合应用的临床证据,Br J Clin Pharmacol 1996;42:333-33

38、7. Ann Intern Med 2002;137:581-585. Arch of Neurol 2004;61:889-892. Eur J Clin Invest. 2005;35:251-258. Am J Cardiol 2004;94:1306-1310. Georgian Medical News 2005(1):20-24,Clinical application of statin with preventive drugs,辅酶Q10与他汀类药物的机制关系,HMG-CoA,甲酸戊酸,异戊烯焦磷酸,焦磷酸法呢酯,辅酶Q10(CoQ10,多醇,胆固醇,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,他汀类药物与对辅酶Q10水平影响,Br J Clin Pharmacol 1996, 42:333,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,贝特类,未治疗组,健康对