Pleiotropic Effects of Statins

Pleiotropic Effects of Statinsverse group of drugs that share the ability to inhibithydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase), the enzyme that controls the ratelimitingstep of cholesterol synthesis, but this inhibitionis followed by other subsequences associated with themevalonate pathway (Figure 1).The clinically beneficial effects of statins were usuallyassumed to result from their ability to reduce cholesterolsynthesis. In 1994, the landmark ScandinavianSimvastatin Survival Study (4S) established the benefitsof a HMG-CoA reductase inhibitor on mortality in patientswith atherosclerosis. 5 In accord with traditionalacceptance of atherosclerosis as a consequence of lipiddisorders, post-hoc analysis of the 4S trial suggested thatthe benefit provided by simvastatin in individual patientsindeed related to the magnitude of change in low-densitylipoprotein cholesterol. 10 Subsequent studies, however,differed with this conclusion even as they affirmed theclinical benefits of statins as a class on cardiovascularmorbidity and mortality in patients with or without establishedatherosclerotic disease. 6-9 These studies raisedquestions about additional beneficial effects of statins,because mevalonate, the product of the enzyme reaction,is the precursor not only of cholesterol but also of manynonsteroidal isoprenoid compounds, and inhibition ofHMG-CoA reductase may produce pleiotropic effects(see Figure 1).Indeed, the mevalonate pathway yields a series ofisoprenoids that are vital for diverse cellular functions. 11These isoprenoids include: isopentanyl adenosine, presentin some types of transfer RNA; dolichols, requiredfor glycoprotein synthesis; and polyisoprenoid sidechains of ubiquinone and heme A, involved in electrontransport. Several proteins have also been identified thatare post-translationally modified by the covalent attachmentof mevalonate-derived isoprenoid groups-eitherfarnesyl or geranylgeranyl pyrophosphate. These proteinsmust be prenylated as a prerequisite for membraneassociation, which is required for their function. Membersof this family are involved in a number of cellularprocesses, including cell signaling, cell differentiationand proliferation, myelination, cytoskeleton dynamics,Acetyl CoAHMG-CoAmevalonateHMG CoA reductaseisopentanyl – PP*geranyl-PP dekaprenyl-PP dekaprenyl 4OH benzoate CoQ10squalene farnesyl-PP farnesylated proteinscholesterolgeranylated proteins activation NFB** inflammationproliferation of SMC****PP – pyrophosphate**NFB – nuclear factor kappa B***SMC – smooth muscle cellsFigure 1. Cholesterol (mevalonate) synthesis pathway.191 Acta Cardiol Sin 2005;21:1908

Daniel Pella et al.and endocytotic/exocytotic transport.Hence, through the inhibition of HMG-CoA reductase,statins may affect a variety of processes; this mayhelp to explain their non-lipid-related pharmacologicproperties. Indeed, several recent in vitro and in vivo experimentshave demonstrated that HMG-CoA reductaseinhibitors have antiatherosclerotic effects that are not relatedto lipid lowering. Because of their broad effectsand their extremely low incidence of side effects, statinsmight even be seen as the new aspirin. 12The currently available statins are lovastatin, simvastatin,pravastatin, atorvastatin, fluvastatin and rosuvastatin.Cerivastatin was withdrawn from the marketin 2001 due to increased number of fatal rhabdomyolyses.13It seems that the process of metabolization of statinsis important from the safety point of view. Several ofthem are metabolized via cytochrome P450 (see Table1). 14-16 However, only a small proportion of rosuvastatinand fluvastatin are metabolized via cytochrome P4502C9, so there is no high risk of dangerous drug interactionsassociated with the use of these statins as well.Patients taking several drugs metabolized by the samecytochrome P450 are at higher risk of side effects ofstatins. Only two of the currently available statins arehydrophilic – pravastatin and rosuvastatin – this couldalso be important in prevention of “increased fluidity” ofmuscle cell membrane and then increased risk of myopathyor even rhabdomyolysis. 16 Antioxidant activitiesof statins differ (the greatest is observed in atorvastatin,with surprisingly much lower activity observed in rosuvastatin)and might be cardioprotective in two differentways. Firstly, statins decrease oxidation of LDL cholesterolparticles, and secondly, they have protective effecton myocyte membrane in ubiquinone deficiency whichmay appear during long-term statin therapy. 16,18The main action of statins is to specifically and reversiblyinhibit HMG-CoA reductase, which controls therate-limiting step in cholesterol synthesis. Several studieshave compared lipid-lowering effects of differentstatins head to head. In one of the latest, STELLARstudy, rosuvastatin in the dosage of 40 mg was moreeffective than all currently available statins in all recommendeddoses. LDL cholesterol was lowered by 55%with rosuvastatin 40 mg daily. 19These differences in efficacy were confirmed in ameta-analysis of 164 studies published in 2003. Herealso, the different statins showed a two- to three-fold differencein the extent of LDL cholesterol lowering acrossthe dosage range. 20The effect on HDL cholesterol was compared aswell in the STELLAR study. It was shown that rosuvastatinhad the greatest potency to increase HDL cholesterol,followed by simvastatin and atorvastatin (maximalincrease 9.6% vs 6.8% vs 5.7%). 21 The recent study ofBevilacqua showed different results. 22 Compared werefluvastatin extended release form 80 mg daily, whichwas superior to atorvastatin 20 mg daily. However, ingeneral, statins have much lower potency to increaseHDL in comparison with fibrates or nicotinic acid.Surprisingly, it was shown in the MIRACL trial thathigh-density lipoprotein, but not low-density lipoproteincholesterol levels, influenced short-term prognosis afteracute coronary syndrome, and this finding suggested thatthe clinical benefit of atorvastatin after acute coronarysyndrome was mediated by qualitative changes in theTable 1. Characteristics of statinsAtorvastatin Lovastatin Pravastatin Simvastatin Fluvastatin RosuvastatinDose range (mg/dL) 10-80 10-80 10-80 10-80 20-80 5-40Maximal LDL-C reduction (%) 60 40 34 47 24 55Serum triglyceride reduction (%) 29 16 24 18 10 43Serum HDL-C increased (%) 6 8.6 12 12 8 9,2Penetration to CNS No Yes No Yes No NoRenal excretion (%) 2 10 20 13 < 6 10Mechanism of hepatic metabolism Cytochromep-450 3A4Cytochromep-450 3A4Sulfation Cytochromep-450 3A4Cytochromep-450 2C9(small proportion)Cytochromep-450 2C9(small proportion)Hydro/lipophilic properties lipophilic lipophilic hydrophilic lipophilic lipophilic hydrophilicActa Cardiol Sin 2005;21:1908

Pleiotropic Effects of StatinsLDL particle and/or by non-lipid (pleiotropic) effects ofthe drug. 23PLEIOTROPIC EFFECTS – DEFINITIONDrugs usually have multiple effects; through an analogywith single genes which affect more than onesystem or determine more than one phenotype, they arecurrently referred to as “pleiotropic effects” (from theGreek “pleion,” meaning more, and “tropos,” meaningdirection or turn). These may be related or unrelated toprimary mode of action of the drug. Pleiotropic effectsmay emerge during preclinical and clinical studies indrug development, but more often than not, they are discovereda posteriori long after the therapeutic agent ismarketed (the same situation occurs in use of statins).They may be undesirable and recognized as adverse sideeffects, they may be neutral, or they may be beneficial,enhancing the desirable effect of a drug. 24ANTIATHEROGENIC PLEIOTROPICEFFECTS OF STATINSThe most important pleiotropic antiatherogenic effectsof statins are improvement of endothelial dysfunction,antioxidative properties, antiinflammatory, antiproliferativeand antithrombotic effects and neoangiogenesis.25 Statins inhibit by blocking HMG-CoA reductase,and also by blocking synthesis of geranylated proteinsresponsible for proliferation and migration of smoothmuscle cells from vessel media to intima and their conversionfrom contractile to reparatory type which arecauses growth of atherosclerotic plaque. Also, synthesisof farnesylated proteins is inhibited, that is why also activityof nuclear factor kappa B is decreased. This factorplays very important role in the initiation of inflammatoryprocess-atherosclerosis is inflammatory disease. 26Statins and Endothelial DysfunctionAbnormal endothelium-dependent vasomotor responsespredict the long-term progression of atherosclerosisand associated coronary events, as well as eventsafter vascular surgery. 27,38 Statins are able to increase nitricoxide synthesis and improve blood flow dependentupon endotheliumm, as was shown in study of Marchesiet al. with atorvastatin and other statins. 29,30Statins and Antiinflammatory EffectsRecent research has shown that inflammation plays akey role in coronary artery disease and other manifestationsof atherosclerosis. Immune cells dominate earlyatherosclerotic lesions, and activation of inflammationcan elicit acute coronary syndromes. Elevated markersfor inflammation such as CRP, interleukin-6, intercellularadhesion molecule-1 (ICAM-1), and serumamyloid A have been associated with increased risk forthe first and reccurent cardiovascular events. 31 Many experimentaland clinical studies confirmed significantreduction of CRP measured by high sensitive method (hsCRP). The higher the baseline value of CRP, the higherthe decrease that has been observed, e.g. in the PROVEIT study. 32 In that study, decrease of hs CRP achieved89% in the atorvastatin group and 85% in the pravastatingroup. Generally, the greatest decreases of hs CRP wereobserved after treatment with atorvastatin or rosuvastatin.Increased levels of CRP were associated withmore pronounced monocyte migration and increasedLDL uptake by macrophages. 33Statins and Plaque GrowthStatins have antiproliferative effects and inhibittransformation of contractile smooth muscle cells toreparatory-type cells and their migration from arterialmedia into intima. 34 Statins decrease synthesis of extracellularmatrix and proteins Rac1, Rho A as well, andby this means decrease plaque growth. 35Substantial differences have been found between thestatins. For example, in the ASAP study, it was shownthat at the highest therapeutic dose, two years of treatmentwith atorvastatin reduced the thickness of thearterial wall, while after simvastatin treatment, the thicknessof the arterial wall continued to increase. 36 Similarresults were achieved in the ARBITER study whenatorvastatin and pravastatin were compared. 37 In a veryrecent study, REVERSAL, where intravascular ultrasoundmethod was used to quantify atherosclerosis, after18 months of therapy with atorvastatin 80 mg daily, volumeof the atherosclerotic plaque slightly decreased,while the volume of the plaque continued to increaseduring therapy with pravastatin 40 mg daily. 38193 Acta Cardiol Sin 2005;21:1908

Daniel Pella et al.Statins and AngiogenesisStatins are able to activate proteinkinase Akt in endothelialcells and thereby stimulate activity of endothelialnitric oxide synthethase leading to increased NOproduction and neoangiogenesis. Stimulation of proteinkinaseAkt improves myocardial aerobic metabolism.Statins increase also the level of angiopoetine. 39Statins and Plaque RuptureStatins significantly reduce metalloproteinases activity,mainly of MMP1 and MMP3, which play importantroles in plaque rupture or fissuration. 40 Decrease ofblood pressure observed during long-term treatment withstatins lead to improvement of rheology and arterialstiffness. 41Statins and ThrombosisStatins have capacity to decrease global fibrinolyticactivity of the blood, decrease activity of PAI-1 and inhibitthrombine generation. Data regarding influence ofstatins on fibrinogen levels are not so convincing. 42Statins and Plaque StabilityThere were several pleiotropic effects of statins describedwhich should be responsible for the stability ofthe atherosclerotic plaque. Nevertheless, the most importantfinding for plaque stability is the combination oflipid-lowering effects with pleiotropic ones (especiallydecrease of plaque lipid core size and inhibition of inflammatoryreaction). 43Possible Negative Pleiotropic Effects of StatinsInhibition of HMG-CoA reductase leads not only todecreased synthesis of cholesterol but also affects synthesisof other substances. Besides these positive pleiotropiceffects, there is probably also a negative one,namely, inhibition of geranyl pyrophosphate synthesisand subsequently dekaprenyl-4-bensoate, which is a precursorof coenzyme Q10. Coenzyme Q10 (ubiquinone,ubidekarenone) is a very important substance in myocardialenergetic metabolism and the stability of cellmembrane as well; when deficient, myocytes could beprone to damage in the form of myopathy or myositis, oreven rhabdomyolysis. 44 Deficiency of coenzyme Q10will appear usually after longer duration of treatment andmay also be dependent on type of statin and its dosage.Given the fact that statins will be prescribed morewidely (“... statins to every patient with documented coronaryartery disease...” Yusuf S, Lancet 2002), it is veryimportant to consider the safety of such therapy. 45 Statintherapy is long-term (even life-long, following evidence-basedmedicine), so the risk of adverse effectsmight be increased. More clinical studies are needed inorder to confirm the beneficial effects of coenzyme Q10substitution in long-term statin therapy. The InternationalCollege of Cardiology, in its scientific statement,recommended use of statins preferably in conjunctionwith coenzyme Q10 in order to prevent possible myopathy.46The recently published hypothesis by Moosmannand Behl has identified a possible role of deficiency ofselenium and association with possible adverse effects ofstatins, namely myopathy and polyneuropathy. 47 Theynoted that the pattern of side effects associated withstatins resembled the pathology of selenium deficiency,and postulated that the mechanism lay in a wellestablishedbut often overlooked biochemical pathway –the isopentylation of selenocysteine-tRNA. A negativeeffect of statins on selenoprotein synthesis does seem toexplain many of the enigmatic effects and side effects ofstatins, in particular, statin-induced myopathy.In a recent study, Silver et al. evaluated left ventriculardiastolic function with Doppler echocardiographybefore and after statin therapy. Statin therapy worseneddiastolic parameters in most patients; coenzyme Q10supplementation in patients with worsened diastolicfunction with statin therapy improved parameters of diastolicfunction. 48Similar results were confirmed in the study ofKumar et al. in more than 100 studied subjects (the studyof Silver et al. evaluated only 14 patients). 49What is very important to say is that statins are generallyvery well tolerated drugs and a remarkably safe classof lipid lowering agents. These data probably lead to thefact that in the United Kingdom simvastatin is now availablein pharmacies without medical prescription. 50PLEIOTROPIC EFFECTS OF STATINS INNON-ATHEROSCLEROTIC DISEASEAntiproliferative and antiinflammatory effects ofActa Cardiol Sin 2005;21:1908

Pleiotropic Effects of StatinsTable 2. Possible beneficial pleiotropic effects of statins in non-atherosclerotic diseasesfibrosclerotic aortic stenosissudden cardiac death preventionarterial hypertensiondeep venous thrombosisAlzheimer’s dementiaregression of left ventricular hypertrophyrheumatic diseases (rheumatoid arthritis)osteoporosissclerosis multiplexvitiligostatins have raised questions about possible use of statinsin diseases other than atherosclerosis, cardiovascular andnon-cardiovascular. Many clinical studies are in progresswhich probably should enlighten us on their relativeclinical relevance and importance. Some of the diseasesinvolved in this research are listed in Table 2. 51CONCLUSIONSStatins have the same mode of action via inhibitionof HMG-CoA reductase activity but differ between eachother in the extent of this inhibition, which leads to differentlevels of LDL cholesterol lowering. Due to thisfact, not only cholesterol synthesis inhibited is but alsoformation of inflammatory proteins, substances associatedwith smooth muscle cells proliferation and endogenoussynthesis of coenzyme Q10.Although the possibility that statins might havepleiotropic effects was met at first with healthy scepticism,the vast amount of knowledge accrued over thepast few years has moved these effects into the spotlight.Pleiotropic effects of statins are numerous and varied,they may add to the desirable effect of a drug or be undesirableand interfere with the treatment. As the list ofpleiotropic effects effects of statins is expanding rapidly,it will become essential to establish their relative biologicalsignificance and clinical relevance.LDL cholesterol indubitably represents a modifiablekey risk factor for atherosclerosis, and lowering LDL-Cblood levels certainly diminishes cardiovascular risk inthe long term. The current flurry of interest in the socalledpleiotropic effects of statins should in no waydeter practitioners from aggressive management of dyslipidemia,a long established risk factor, as mandated bycurrent guidelines. Nevertheless, it will be important totake action on the new indications which have emergedfrom consideration of possible pleiotropic effects.Further study of pleiotropic functions of statins mayprovide insights into the biology of atherosclerosis (andother diseases e.g. osteoporosis, rheumatoid arthritis,connective tissue diseases, etc.) that could yield benefitsin terms of targeting and developing novel strategies thatwill address the residual burden of atherosclerotic complicationsthat plague even those individuals who achievedcurrent lipid goals.REFERENCES1. World Health Organization. The World Health Report 2002:Reducing risks, promoting healthy life. Geneva: World HealthOrganization; 2002.2. American Heart Association. Statistical fact sheet — populations.International Disease Statistics. Dallas, T: American HeartAssociation; 2003.3. Endo A, Kuroda M, Tanarawa K. Competitive inhibition of3-HMG-CoA reductase by ML 236 A and ML 236 B. Febs Lett1976;72:323-6.4. Roberts JR. Lipid-lowering drugs in atherosclerosis. Am JCardiol 1996;89:682.5. Simvastatin Survival Study Group. Randomized trial ofcholesterol lowering in 4444 patients with coronary heart disease:the Scandinavian Simvastatin Survival Study (4S). Lancet1994;334:1383-9.6. Sacks FM, Pfeffer MA, Moye LA. The effect of pravastatin oncoronary events after myocardial infarction in patients withaverage cholesterol levels. N Eng J Med 1996;335:1001-9.7. The Long-term Intervention with Pravastatin in IschaemicDisease (LIPID) Study Group. Prevention of cardiovascularevents and death with pravastatin in patients with coronary heartdisease and broad range of initial cholesterol levels. N Eng J Med1998;339:1349-57.8. West of Scotland Coronary Prevention Group. West of ScotlandCoronary Prevention Study: identification of High-risk Groupsand Comparison with Other Cardiovascular Intervention Trials.Lancet 1996;346:1339-42.9. Downs JR, Clearfield M, Weis S. Primary prevention of acutecoronary events with lovastatin in men and women with averagecholesterol levels. N Eng J Med 1999;339:1615-22.195 Acta Cardiol Sin 2005;21:1908

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Review ArticleActa Cardiol Sin 2005;21:190−8高 血 脂 治 療 藥 物 STATIN 的 多 重 作 用Daniel Pella Rafael Rybar Viola Mechirova1st Internal Clinic, Faculty of Medicine PJ Safarik University Kosice, Slovakia近 十 年 來 , 對 於 改 善 血 脂 肪 異 常 與 預 防 缺 血 性 心 臟 病 之 間 的 研 究 逐 漸 開 展 。 對 於 建 立新 的 治 療 標 的 與 研 發 新 的 高 血 脂 治 療 藥 物 也 拓 展 臨 床 治 療 的 選 擇 。 不 論 病 人 是 否 具 有 冠 狀動 脈 心 臟 病 ,STATIN 已 成 為 降 低 血 膽 固 醇 值 與 心 血 管 疾 病 併 發 症 最 主 要 及 最 有 效 的 藥 物 。最 近 研 究 指 出 ,STATIN 在 治 療 心 血 管 疾 病 的 好 處 , 不 僅 僅 只 從 降 低 血 膽 固 醇 值 方 面 解釋 。 一 些 改 善 血 脂 肪 異 常 以 外 的 效 果 , 如 抗 發 炎 、 抗 增 生 及 抗 血 栓 效 果 , 以 及 改 善 內 皮 細胞 功 能 等 , 也 扮 演 部 份 角 色 , 本 文 將 對 這 些 改 善 血 脂 肪 異 常 外 之 多 重 作 用 (extra-lipidpleiotropic effects) 作 概 略 介 紹 。關 鍵 詞 : 高 血 脂 治 療 藥 物 、 降 血 脂 外 多 重 作 用 、 冠 狀 動 脈 心 臟 病 。198