不同他汀类药物对肝功能影响的网状Meta分析

doi:10.12114/j.issn.1007-9572.2021.00.488

摘要/Abstract

摘要： 背景　他汀类药物（简称他汀）是目前最为常用的药物之一，而他汀的不良反应尤其是肝毒性也越来越引起人们的关注，但目前关于不同他汀对肝功能影响的评价不一。目的　系统评价不同他汀对肝功能的影响。方法　计算机检索Cochrane Library、PubMed、EMBase、Medline，检索干预措施为他汀、不良反应涉及肝功能异常的随机对照试验（RCTs），检索时限为建库至2020-09-10。由2位研究者进行筛选文献、提取资料、评价纳入文献的偏倚风险，采用Stata 14软件进行网状Meta分析。结果　共纳入46篇RCTs，54 499例患者，包含6种药物：阿托伐他汀（21篇）、瑞舒伐他汀（10篇）、辛伐他汀（10篇）、普伐他汀（7篇）、洛伐他汀（4篇）、匹伐他汀（3篇）。网状Meta分析结果显示，阿托伐他汀肝功能异常发生率高于瑞舒伐他汀、普伐他汀，阿托伐他汀、瑞舒伐他汀肝功能异常发生率高于安慰剂（P<0.05）。累积排序曲线（SUCRA）对不同他汀的排序结果为安慰剂（77.2%）>匹伐他汀（70.9%）>普伐他汀（64.1%）>辛伐他汀（60.7%）>瑞舒伐他汀（40.4%）>洛伐他汀（31.6%）>阿托伐他汀（5.1%）。通过细胞色素P450氧化酶（CYP450酶）进行代谢的他汀肝功能异常发生率高于安慰剂（P<0.05）。SUCRA对不同代谢途径他汀的排序结果为安慰剂（95.6%）>不通过CYP450酶进行代谢的他汀（51.9%）>通过CYP450酶进行代谢的他汀（2.6%）。脂溶性他汀肝功能异常发生率高于安慰剂（P<0.05）。SUCRA对不同性质他汀的排序结果为安慰剂（97.4%）>水溶性他汀（48.7%）>脂溶性他汀（3.9%）。高强度阿托伐他汀肝功能异常发生率高于中强度匹伐他汀、中强度普伐他汀、中强度辛伐他汀、高强度瑞舒伐他汀、中强度瑞舒伐他汀，高强度阿托伐他汀、高强度瑞舒伐他汀肝功能异常发生率高于安慰剂（P<0.05）。SUCRA对不同剂量他汀的排序结果为中强度瑞舒伐他汀（76.4%）>中强度匹伐他汀（71.6%）>安慰剂（69.1%）>中强度辛伐他汀（67.5%）>中强度普伐他汀（55.1%）>低强度普伐他汀（41.7%）>高强度瑞舒伐他汀（40.9%）>中强度阿托伐他汀（37.9%）>低强度洛伐他汀（31.0%）>高强度阿托伐他汀（8.8%）。结论　脂溶性他汀、通过CYP450酶进行代谢的他汀、高剂量他汀肝功能异常发生率较高。本研究纳入文献较多且总体质量尚可，对临床用药具有一定的指导意义，但部分文献质量不高，仍需开展更多高质量的RCTs对本研究结果进行验证。

关键词: 他汀类药物, 阿托伐他汀, 肝疾病, 肝功能, 随机对照试验, 网状Meta分析

Abstract: Background　As one of the most commonly used drugs，statins’ adverse reactions，especially hepatotoxicity，have become a growing concern. However，the assessment of the effects of different statins on liver function still varies at present. Objective　To systematically review the effects of different statins on liver function. Methods　We searched electronic databases，including Cochrane Library，PubMed，EMBase and Medline to collect randomized controlled trials （RCTs） about abnormal liver function associated with statins as the intervention from inception to September 10th 2020. Literature review，data extraction，and risk of bias evaluation were performed by two researchers. Stata 14 was used for network meta-analysis. Results　All in all，46 RCTs were included，containing 6 types of Statins as interventions for 54 499 cases，including 21 with atorvastatin，10 with rosuvastatin，10 with simvastatin，7 with pitavastatin，4 with lovastatin，and 3 with pitavastatin. The results of network meta-analysis were as follows: the incidence of liver dysfunction induced by atorvastatin was higher than that caused by rosuvastatin or pravastatin. The incidence of liver dysfunction induced by atorvastatin was higher than that by placebo，so did that induced by rosuvastatin （P<0.05）. The SUCRA value for Statins and placebo ranked from highest to lowest were: placebo（77.2%）>pitavastatin（70.9%）>pravastatin（64.1%）>simvastatin（60.7%）>rosuvastatin （40.4%）>lovastatin（31.6%）>atorvastatin（5.1%）. The incidence of liver dysfunction caused by statins metabolized by CYP450 enzyme was higher than that by placebo（P<0.05）. The ranking results of statins with different metabolic pathways and placebo by SUCRA were: placebo（95.6%）>statins not metabolized by CYP450 enzyme（51.9%）>statins metabolized by CYP450 enzyme（2.6%）. The incidence of liver dysfunction caused by liposoluble statins was higher than that by placebo（P<0.05）. The ranking results of statins with different solubilities and placebo by SUCRA were: placebo（97.4%）>hydrosoluble statins（48.7%）>liposoluble statins （3.9%）. The incidence of liver dysfunction induced by high-intensity atorvastatin was higher than that by medium-intensity pitavastatin，medium-intensity pravastatin，medium-intensity simvastatin，high-intensity rosuvastatin or medium-intensity rosuvastatin（P<0.05）. The incidence of liver dysfunction caused by high-intensity atorvastatin or high-intensity rosuvastatin was higher than that by placebo（P<0.05）. The ranking results of different doses of statins and placebo by SUCRA were: medium-intensity rosuvastatin（76.4%）>medium-intensity pitavastatin（71.6%）>placebo（69.1%）>medium-intensity simvastatin （67.5%）>medium-intensity pravastatin（55.1%）>low-intensity pravastatin（41.7%）>high-intensity rosuvastatin（40.9%）>medium-intensity atorvastatin（37.9%）>low-intensity lovastatin（31.0%）>high-intensity atorvastatin（8.8%）. Conclusion　Liposoluble statins，statins metabolized by CYP450 enzymes and high-dose statins tend to lead to a higher incidence of liver dysfunction. With an analysis of the reports of many fair-quality RCTs，this study may be used as guidance for clinical medication. However，due to some eligible RCTs with low quality，more high-quality RCTs are needed to verify our conclusion.

Key words: Statin, Atorvastatin, Liver diseases, Liver function, Randomized controlled trial, Network meta-analysis

邸钰蓉,冯英娜,杨大鸿,等. 不同他汀类药物对肝功能影响的网状Meta分析[J]. 中国全科医学, 2021, 24(18): 2331-2341. DOI: 10.12114/j.issn.1007-9572.2021.00.488.
DI Yurong,FENG Yingna,YANG Dahong, et al. Network Meta-analysis of Effects of Different Statins on Liver Function　[J]. Chinese General Practice, 2021, 24(18): 2331-2341. DOI: 10.12114/j.issn.1007-9572.2021.00.488.

参考文献

［1］GU Q，PAULOSE-RAM R，BURT V L，et al．Prescription cholesterol-lowering medication use in adults aged 40 and over：United States，2003—2012［J］．NCHS Data Brief，2014（177）：1-8.
［2］SALAMI J A，WARRAICH H，VALERO-ELIZONDO J，et al．National Trends in Statin Use and Expenditures in the US Adult Population From 2002 to 2013：Insights From the Medical Expenditure Panel Survey［J］．JAMA Cardiol，2017，2（1）：56-65．DOI：10.1001/jamacardio.2016.4700.
［3］PINAL-FERNANDEZ I，CASAL-DOMINGUEZ M，MAMMEN A L.Statins：pros and cons［J］．Med Clin，2018，150（10）：398-402．DOI：10.1016/j.medcli.2017.11.030.
［4］Cholestrol Treatment Trialists'（CTT） Collaboration，BAIGENT C，BLACKWELL L，et al．Efficacy and safety of more intensive lowering of LDL cholesterol：a meta-analysis of data from 170，000 participants in 26 randomised trials［J］．Lancet，2010，376（9753）：1670-1681．DOI：10.1016/s0140-6736（10）61350-5.
［5］CHAN D K，O'ROURKE F，SHEN Q，et al．Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins［J］．Acta Neurol Scand，2011，124（3）：188-195．DOI：10.1111/j.1600-0404.2010.01450.x.
［6］CONLY J，CLEMENT F，TONELLI M，et al．Cost-effectiveness of the use of low-and high-potency statins in people at low cardiovascular risk［J］．CMAJ，2011，183（16）：E1180-1188．DOI：10.1503/cmaj.101281.
［7］EBRAHIM S，TAYLOR F C，BRINDLE P.Statins for the primary prevention of cardiovascular disease［J］．BMJ，2014（348）：g280.
［8］MILLS E J，O'REGAN C，EYAWO O，et al．Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events：a meta-analysis of >40 000 patients［J］．Eur Heart J，2011，32（11）：1409-1415．DOI：10.1093/eurheartj/ehr035.
［9］MILLS E J，WU P，CHONG G，et al．Efficacy and safety of statin treatment for cardiovascular disease：a network meta-analysis of 170 255 patients from 76 randomized trials［J］．QJM，2011，104（2）：109-124．DOI：10.1093/qjmed/hcq165.
［10］NACI H，BRUGTS J J，FLEURENCE R，et al．Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality：a network meta-analysis of placebo-controlled and active-comparator trials［J］．Eur J Prev Cardiol，2013，20（4）：641-657．DOI：10.1177/2047487313480435.
［11］DU SOUICH P，ROEDERER G，DUFOUR R.Myotoxicity of statins：mechanism of action［J］．Pharmacol Ther，2017，175：1-16．DOI：10.1016/j.pharmthera.2017.02.029.
［12］STROES E S，THOMPSON P D，CORSINI A，et al．Statin-associated muscle symptoms：impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment，Aetiology and Management［J］．Eur Heart J，2015，36（17）：1012-1022．DOI：10.1093/eurheartj/ehv043.
［13］高海洋.他汀类药物导致肝损伤的诊断和监测［J］．心血管病学进展，2017，38（3）：271-276．DOI：10.16806/j.cnki.issn.1004-3934.2017.03.008.
［14］BJORNSSON E，JACOBSEN E I，KALAITZAKIS E．Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing［J］．J Hepatol，2012，56（2）：374-380．DOI：10.1016/j.jhep.2011.07.023.
［15］MULCHANDANI R，LYNGDOH T，KAKKAR A K.Statin use and safety concerns：an overview of the past，present，and the future［J］．Expert Opin Drug Saf，2020，19（8）：1011-1024．DOI：10.1080/14740338.2020.1796966.
［16］李伦，田金徽，姚亮，等．网状Meta分析的统计学基础、假设和证据质量评估［J］．循证医学，2015，15（3）：180-183．DOI：10.3969/j.issn.1671-5144.2015.03.015.
［17］HUTTON B，SALANTI G，CALDWELL D M，et al．The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions：checklist and explanations［J］．Ann Intern Med，2015，162（11）：777-784．DOI：10.7326/m14-2385.
［18］AITHAL G P，WATKINS P B，ANDRADE R J，et al．Case definition and phenotype standardization in drug-induced liver injury［J］．Clin Pharmacol Ther，2011，89（6）：806-815．DOI：10.1038/clpt.2011.58.
［19］CHESS L E，GAGNIER J.Risk of bias of randomized controlled trials published in orthopaedic journals［J］．BMC Med Res Methodol，2013（13）：76.
［20］HIGGINS J P T，ALTMAN D G，G?TZSCHE P C，et al．The Cochrane Collaboration's tool for assessing risk of bias in randomised trials［J］．BMJ Clin Res Ed，2011，343：d5928．DOI：10.1136/bmj.d5928.
［21］CHAIMANI A，HIGGINS J P，MAVRIDIS D，et al．Graphical tools for network meta-analysis in STATA［J］．PLoS One，2013，8（10）：e76654．DOI：10.1371/journal.pone.0076654.
［22］SALANTI G，ADES A E，IOANNIDIS J P.Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis：an overview and tutorial［J］．J Clin Epidemiol，2011，64（2）：163-171．DOI：10.1016/j.jclinepi.2010.03.016.
［23］XUE J，WU Z，GONG S，et al．High-dose atorvastatin improves vascular endothelial function in patients with leukoaraiosis［J］．J Clin Lab Anal，2020，34（3）：e23081．DOI：10.1002/jcla.23081.
［24］SAPEY E，PATEL J M，GREENWOOD H，et al．Simvastatin improves neutrophil function and clinical outcomes in pneumonia.A pilot randomized controlled clinical trial［J］．Am J Respir Crit Care Med，2019，200（10）：1282-1293．DOI：10.1164/rccm.201812-2328oc.
［25］HARI P，KHANDELWAL P，SATPATHY A，et al．Effect of atorvastatin on dyslipidemia and carotid intima-media thickness in children with refractory nephrotic syndrome：a randomized controlled trial［J］．Pediatr Nephrol，2018，33（12）：2299-2309．DOI：10.1007/s00467-018-4036-x.
［26］WANG G M，CHEN K Q，LI B，et al．Effect of lovastatin treatment on liver function in elderly hepatitis b virus carriers with coronary heart disease［J］．World Chinese Journal of Digestology，2017，25（6）：541-545.10.11569/wcjd.v25.i6.541
［27］COSTANTINE M M，CLEARY K，HEBERT M F，et al．Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women：a pilot randomized controlled trial［J］．Am J Obstet Gynecol，2016，214（6）：720，e1-17．DOI：10.1016/j.ajog.2015.12.038.
［28］ABRALDES J G，VILLANUEVA C，ARACIL C，et al．Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis［J］．Gastroenterology，2016，150（5）：1160-1170.e3．DOI：10.1053/j.gastro.2016.01.004.
［29］VIASUS D，GARCIA-VIDAL C，SIMONETTI A F，et al．The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia：a randomised，double-blind，placebo-controlled trial［J］．BMJ Open，2015，5（1）：e006251．DOI：10.1136/bmjopen-2014-006251.
［30］DEEDWANIA P C，STONE P H，FAYYAD R S，et al．Improvement in renal function and reduction in serum uric acid with intensive statin therapy in older patients：a post hoc analysis of the SAGE trial［J］．Drugs Aging，2015，32（12）：1055-1065．DOI：10.1007/s40266-015-0328-z.
［31］BRAAMSKAMP M J，STEFANUTTI C，LANGSLET G，et al．Efficacy and safety of pitavastatin in children and adolescents at high future cardiovascular risk［J］．J Pediatr，2015，167（2）：338-43.e5．DOI：10.1016/j.jpeds.2015.05.006.
［32］TERAMOTO T，TAKEUCHI M，MORISAKI Y，et al．Efficacy，safety，tolerability，and pharmacokinetic profile of evacetrapib administered as monotherapy or in combination with atorvastatin in japanese patients with dyslipidemia［J］．American Journal of Cardiology，2014，113（12）：2021-2029．DOI：10.1016/j.amjcard.2014.03.045.
［33］SPONSELLER C A，MORGAN R E，KRYZHANOVSKI V A，et al．Comparison of the lipid-lowering effects of pitavastatin 4 mg versus pravastatin 40 mg in adults with primary hyperlipidemia or mixed （combined） dyslipidemia：a PhaseⅣ，prospective，US，multicenter，randomized，double-blind，superiority trial［J］．Clin Ther，2014，36（8）：1211-1222．DOI：10.1016/j.clinthera.2014.06.009.
［34］MANDAL P，CHALMERS J D，GRAHAM C，et al．Atorvastatin as a stable treatment in bronchiectasis：a randomised controlled trial［J］．Lancet Respir Med，2014，2（6）：455-463．DOI：10.1016/s2213-2600（14）70050-5.
［35］EL GENDY H A，ELSHARNOUBY N M.Safety and vasopressor effect of rosuvastatin in septic patients［J］．Egypt J Anaesth，2014，30（3）：311-317．DOI：10.1016/j.egja.2014.02.005.
［36］KUMAR P，KENNEDY G，KHAN F，et al．Rosuvastatin might have an effect on C-reactive protein but not on rheumatoid disease activity：Tayside randomized controlled study［J］．Scottish Medical Journal，2012，57（2）：80-83．DOI：10.1258/smj.2012.012004.
［37］MUSCARI A，PUDDU G M，SANTORO N，et al．The atorvastatin during ischemic stroke study：a pilot randomized controlled trial［J］．Clin Neuropharmacol，2011，34（4）：141-147．DOI：10.1097/wnf.0b013e3182206c2f.
［38］HSIA J，MACFADYEN J G，MONYAK J，et al．Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin.The JUPITER trial （Justification for the Use of Statins in Prevention：an Intervention Trial Evaluating Rosuvastatin）［J］．J Am Coll Cardiol，2011，57（16）：1666-1675．DOI：10.1016/j.jacc.2010.09.082.
［39］GUMPRECHT J，GOSHO M，BUDINSKI D，et al．Comparative long-term efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20-40 mg in patients with type 2 diabetes mellitus and combined （mixed） dyslipidaemia［J］．Diabetes Obes Metab，2011，13（11）：1047-1055．DOI：10.1111/j.1463-1326.2011.01477.x.
［40］BAYS H E，SCHWARTZ S，LITTLEJOHN T，et al．MBX-8025，a novel peroxisome proliferator receptor-delta agonist：lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin［J］．J Clin Endocrinol Metab，2011，96（9）：2889-2897．DOI：10.1210/jc.2011-1061.
［41］CHAN K L，TEO K，DUMESNIL J G，et al．Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis：results of the aortic Stenosis progression observation：measuring effects of rosuvastatin （ASTRONOMER） trial［J］．Circulation，2010，121（2）：306-314．DOI：10.1161/circulationaha.109.900027.
［42］AVIS H J，HUTTEN B A，GAGNé C，et al．Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia［J］．J Am Coll Cardiol，2010，55（11）：1121-1126．DOI：10.1016/j.jacc.2009.10.042.
［43］RIDKER P M，DANIELSON E，FONSECA F A，et al．Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein［J］．N Engl J Med，2008，359（21）：2195-2207．DOI：10.1056/nejmoa0807646.
［44］NEWMAN C B，SZAREK M，COLHOUN H M，et al．The safety and tolerability of atorvastatin 10 mg in the collaborative atorvastatin diabetes study （CARDS）［J］．Diabetes and Vascular Disease Research，2008，5（3）：177-183．DOI：10.3132/dvdr.2008.029
［45］LEWANDOWSKI M，KORNACEWICZ-JACH Z，MILLO B，
et al．The influence of low dose atorvastatin on inflammatory marker levels in patients with acute coronary syndrome and its potential clinical value［J］．Cardiol J，2008，15（4）：357-364.
［46］CRISOSTOMO L M，SOUZA C A，MENDES C M，et al．Vascular and metabolic response to statin in the mildly hypertensive hypercholesterolemic elderly［J］．Clinics：Sao Paulo，2008，63（5）：589-594．DOI：10.1590/s1807-59322008000500004.
［47］CHUNG J，BRASS E P，ULRICH R G，et al．Effect of atorvastatin on energy expenditure and skeletal muscle oxidative metabolism at rest and during exercise［J］．Clin Pharmacol Ther，2008，83（2）：243-250．DOI：10.1038/sj.clpt.6100264.
［48］LEWIS J H，MORTENSEN M E，ZWEIG S，et al．Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease：results of a prospective，randomized，double-blind，placebo-controlled，multicenter trial［J］．Hepatology，2007，46（5）：1453-1463．DOI：10.1002/hep.21848.
［49］KYEONG H Y，PARK H Y，CHOI J H，et al．Comparison of efficacy and safety after administering high potency statin to high risk patients：rosuvastatin 10 mg versus atorvastatin 20 mg［J］．Korean Circulation Journal，2007，37（4）：154-160．DOI：10.4070/kcj.2007.37.4.154.
［50］DUMAN D，SAHIN S，ESERTAS K，et al．Simvastatin improves endothelial function in patents with subclinical hypothyroidism［J］．Heart Vessels，2007，22（2）：88-93．DOI：10.1007/s00380-006-0950-0.
［51］NISSEN S E.Halting the progression of atherosclerosis with intensive lipid lowering：results from the Reversal of Atherosclerosis with Aggressive Lipid Lowering （REVERSAL） trial［J］．Am J Med，2005，118（12 Suppl）：22-27．DOI：10.1016/j.amjmed.2005.09.020.
［52］LYNCH J R，MCGIRT M，LASKOWITZ D T，et al．Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage：results of a pilot randomized clinical trial 871［J］．Neurosurgery，2005，57（2）：420．DOI：10.1093/neurosurgery/57.2.420a.
［53］CLAUSS S B，HOLMES K W，HOPKINS P，et al．Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia［J］．Pediatrics，2005，116（3）：682-688．DOI：10.1542/peds.2004-2090.
［54］MELANI L，MILLS R，HASSMAN D，et al．Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia：a prospective，randomized，double-blind trial［J］．Eur Heart J，2003，24（8）：717-728．DOI：10.1016/S0195-668X（02）00803-5.
［55］BAYS H E，OSE L，FRASER N，et al．A multicenter，randomized，double-blind，placebo-controlled，factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia［J］．Clin Ther，2004，26（11）：1758-1773．DOI：10.1016/j.clinthera.2004.11.016.
［56］SCHNECK D W，KNOPP R H，BALLANTYNE C M，et al．Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease［J］．Am J Cardiol，2003，91（1）：33-41．DOI：10.1016/s0002-9149（02）02994-6.
［57］SAITO Y，GOTO Y，DANE A，et al．Randomized dose-response study of rosuvastatin in Japanese patients with hypercholesterolemia［J］．J Atheroscler Thromb，2003，10（6）：329-36．DOI：10.5551/jat.10.329.
［58］KADIKOYLU G，YUKSELEN V，YAVASOGLU I，et al．Hemostatic effects of atorvastatin versus simvastatin［J］．Ann Pharmacother，2003，37（4）：478-484．DOI：10.1345/aph.1c189.
［59］WU C C，SY R，TANPHAICHITR V，et al．Comparing the efficacy and safety of atorvastatin and simvastatin in Asians with elevated low-density lipoprotein-cholesterol - A multinational，multicenter，double-blind study［J］．Journal of the Formosan Medical Association，2002，101（7）：478-487.
［60］OLSSON A G，ISTAD H，LUURILA O，et al．Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia［J］．Am Heart J，2002，144（6）：1044-1051．DOI：10.1067/mhj.2002.128049.
［61］WANG K Y，TING C T.A randomized，double-blind，placebo-controlled，8-week study to evaluate the efficacy and safety of once daily atorvastatin （10 mg） in patients with elevated LDL-cholesterol［J］．Japanese Heart Journal，2001，42（6）：725-738．DOI：10.1536/jhj.42.725.
［62］SCHWARTZ G G，OLSSON A G，EZEKOWITZ M D，et al．Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes：the MIRACL study：a randomized controlled trial［J］．JAMA，2001，285（13）：1711-1718．DOI：10.1001/jama.285.13.1711.
［63］DOWNS J R，CLEARFIELD M，TYROLER H A，et al．Air Force/Texas Coronary Atherosclerosis Prevention Study （AFCAPS/TEXCAPS）：additional perspectives on tolerability of long-term treatment with lovastatin［J］．Am J Cardiol，2001，87（9）：1074-1079．DOI：10.1016/s0002-9149（01）01464-3.
［64］FONG R L，WARD H J.The efficacy of lovastatin in lowering cholesterol in African Americans with primary hypercholesterolemia［J］．American Journal of Medicine，1997，102（4）：387-391．DOI：10.1016/S0002-9343（97）00091-0.
［65］NAWROCKI J W，WEISS S R，DAVIDSON M H，et al．Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin，a new HMG-CoA reductase inhibitor［J］．Arteriosclerosis Thrombosis and Vascular Biology，1995，15（5）：678-682．DOI：10.1161/01.ATV.15.5.678.
［66］KEECH A，COLLINS R，MACMAHON S，et al．Three-year follow-up of the Oxford Cholesterol Study：assessment of the efficacy and safety of simvastatin in preparation for a large mortality study［J］．Eur Heart J，1994，15（2）：255-269．DOI：10.1093/oxfordjournals.eurheartj.a060485.
［67］BEHOUNEK B D，MCGOVERN M E，KASSLER-TAUB K B，et al．A multinational study of the effects of low-dose pravastatin in patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia［J］．Clinical Cardiology，1994，17（10）：558-562.
［68］CONTACOS C，BARTER P J，SULLIVAN D R.Effect of pravastatin and ω-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia［J］．Arteriosclerosis and Thrombosis，1993，13（12）：1755-1762.
［69］SCHACHTER M.Chemical，pharmacokinetic and pharmacodynamic properties of statins：an update［J］．Fundam Clin Pharmacol，2005，19（1）：117-125．DOI：10.1111/j.1472-8206.2004.00299.x.
［70］GRUNDY S M，STONE N J，BAILEY A L，et al．2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol：a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines［J］．Circulation，2019，139（25）：e1082-1143．DOI：10.1161/CIR.0000000000000625.
［71］RAMKUMAR S，RAGHUNATH A，RAGHUNATH S.Statin therapy：review of safety and potential side effects［J］．Acta Cardiol Sin，2016，32（6）：631-639．DOI：10.6515/acs20160611a.
［72］Cholesterol Treatment Trialists' （CTT） Collaborators，MIHAYLOVA B，EMBERSON J，et al．The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease：meta-analysis of individual data from 27 randomised trials［J］．Lancet，2012，380（9841）：581-590．DOI：10.1016/s0140-6736（12）60367-5.
［73］ADHYARU B B，JACOBSON T A.Safety and efficacy of statin therapy［J］．Nat Rev Cardiol，2018，15（12）：757-769．DOI：10.1038/s41569-018-0098-5.
［74］HO P M，MAGID D J，SHETTERLY S M，et al．Medication nonadherence is associated with a broad range of adverse outcomes in patients with coronary artery disease［J］．Am Heart J，2008，155（4）：772-779．DOI：10.1016/j.ahj.2007.12.011.
［75］NACI H，BRUGTS J，ADES T.Comparative tolerability and harms of individual statins：a study-level network meta-analysis of
246 955 participants from 135 randomized，controlled trials［J］．Circ Cardiovasc Qual Outcomes，2013，6（4）：390-399．DOI：10.1161/circoutcomes.111.000071.
［76］WARD N C，WATTS G F，ECKEL R H.Statin toxicity［J］．Circ Res，2019，124（2）：328-350．DOI：10.1161/circresaha.118.312782.
［77］MESGARPOUR B，GOUYA G，HERKNER H，et al．A population-based analysis of the risk of drug interaction between clarithromycin and statins for hospitalisation or death［J］．Lipids Health Dis，2015，14：131．DOI：10.1186/s12944-015-0134-y.
［78］ZHANG T.Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites［J］．Eur J Pharm Sci，2015，77：216-229．DOI：10.1016/j.ejps.2015.06.019.
［79］李艳芳.他汀类药物的研发及其脂溶性与水溶性［J］．中华老年心脑血管病杂志，2018，20（9）：1008.
［80］DIMMITT S B，WARREN J B，STAMPFER H G.Small increase in mortality with high dose，but not low dose，statin［J］．J Am Coll Cardiol，2020，76（7）：884-885．DOI：10.1016/j.jacc.2020.06.041.
［81］HIPPISLEY-COX J，COUPLAND C.Unintended effects of statins in men and women in England and Wales：population based cohort study using the QResearch database［J］．BMJ，2010，340：c2197．DOI：10.1136/bmj.c2197.
［82］CATAPANO A L，GRAHAM I，DE BACKER G，et al．2016 ESC/EAS guidelines for the management of dyslipidaemias［J］．Eur Heart J，2016，37（39）：2999-3058．DOI：10.1093/eurheartj/ehw272.
［83］ALLA V M，AGRAWAL V，DENAZARETH A，et al．A reappraisal of the risks and benefits of treating to target with cholesterol lowering drugs［J］．Drugs，2013，73（10）：1025-1054.

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