Statin 178197 222807040 2008-07-01T05:35:46Z 64.229.168.249 /* Cholesterol lowering */ [[Image:lovastatin.png|frameright|thumb|[[Lovastatin]], the first statin to be marketed]] The '''statins''' (or '''HMG-CoA reductase inhibitors''') form a class of [[hypolipidemic agent|hypolipidemic drug]]s used to lower [[cholesterol]] levels in people with or at risk of [[cardiovascular disease]]. They lower cholesterol by inhibiting the enzyme [[HMG-CoA reductase]], which is the [[rate-limiting step|rate-limiting]] enzyme of the mevalonate pathway of [[cholesterol]] synthesis. Inhibition of this enzyme in the [[liver]] stimulates [[LDL receptor]]s, resulting in an increased [[clearance (medicine)|clearance]] of [[low-density lipoprotein]] (LDL) from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks. ==History== {{seealso|Statin development}} [[Akira Endo (biochemist)|Akira Endo]] and Masao Kuroda of [[Tokyo]], [[Japan]] commenced research into inhibitors of HMG-CoA reductase in [[1971]] (Endo 1992). This team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as [[mevalonate]] is a precursor of many substances required by organisms for the maintenance of their cell wall ([[ergosterol]]) or [[cytoskeleton]] ([[isoprenoid]]s).<ref name="Endo1992">{{cite journal |author=Endo A |title=The discovery and development of HMG-CoA reductase inhibitors |journal=J. Lipid Res. |volume=33 |issue=11 |pages=1569–82 |year=1992 |pmid=1464741 |url=http://www.jlr.org/cgi/reprint/33/11/1569|format=PDF}}</ref> The first agent isolated was [[mevastatin]] (ML-236B), a molecule produced by ''[[Penicillium citrinum]]''. The [[pharmaceutical company]] [[Merck & Co.]] showed an interest in the Japanese research in [[1976]], and isolated [[lovastatin]] (mevinolin, MK803), the first commercially marketed statin, from the mold ''[[Aspergillus terreus]]''. Dr Endo was awarded the 2006 [[Japan Prize]] for his work on the development of statins. ==Indications and uses== Statins, the most potent cholesterol-lowering agents available, lower [[LDL cholesterol]] (so-called "bad cholesterol") by 1.8 mmol/l. This translates in a 60% decrease in the number of cardiac events (heart attack, sudden cardiac death), and a 17% reduced risk of [[stroke]].<ref>{{cite journal |author=Law MR, Wald NJ, Rudnicka AR |title=Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis |journal=BMJ |volume=326 |issue=7404 |pages=1423 |year=2003 |month=June |pmid=12829554 |pmc=162260 |doi=10.1136/bmj.326.7404.1423 |url=http://www.bmj.com/cgi/content/full/326/7404/1423}}</ref> They have less effect than the [[fibrate]]s or [[niacin]] in reducing [[triglyceride]]s and raising [[HDL-cholesterol]] ("good cholesterol"). Professional guidelines generally require that the patient has tried a cholesterol-lowering diet before statin use is considered; statins or other pharmacologic agents may then be recommended for patients who do not meet their lipid-lowering goals through diet and lifestyle approaches. The indications for the prescription of statins have broadened over the years. Initial studies, such as the [[Scandinavian Simvastatin Survival Study]] (4S), supported the use of statins in [[secondary prevention]] for cardiovascular disease, or as primary prevention only when the risk for cardiovascular disease was significantly raised (as indicated by the [[Framingham Heart Study|Framingham risk score]]).<ref name="Wilson-etal">{{cite journal |author=Wilson P, D'Agostino R, Levy D, Belanger A, Silbershatz H, Kannel W |title=Prediction of coronary heart disease using risk factor categories |journal=Circulation |volume=97 |issue=18 |pages=1837–47 |year=1998 |pmid=9603539|url=http://circ.ahajournals.org/cgi/content/full/97/18/1837}}</ref> Indications were broadened considerably by studies such as the [[Heart Protection Study]] (HPS), which showed preventative effects of statin use in specific risk groups, such as [[diabetes mellitus|diabetics]]. The [[ASTEROID trial]], published in 2006, using only a statin at high dose, achieved lower than usual target calculated LDL values and showed disease regression within the [[coronary artery|coronary arteries]] using [[IVUS|intravascular ultrasonography]].<ref name="Nissen2006">{{cite journal | author = Nissen S, Nicholls S, Sipahi I, Libby P, Raichlen J, Ballantyne C, Davignon J, Erbel R, Fruchart J, Tardif J, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu E | title = Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. | journal = JAMA | volume = 295 | issue = 13 | pages = 1556–65 | year = 2006 | url=http://jama.ama-assn.org/cgi/content/full/295/13/1556 | pmid=16533939 | doi = 10.1001/jama.295.13.jpc60002}}</ref> Based on clinical trials, the [[National Cholesterol Education Program]] guidelines, and the increasing focus on aggressively lowering LDL-cholesterol, the statins continue to play an important role in both the primary and secondary prevention of [[coronary heart disease]], [[myocardial infarction]], [[stroke]] and [[peripheral artery disease]]. Research continues into other areas where statins also appear to have a favorable effect: [[inflammation]], [[dementia]],<ref>{{cite journal | last =Wolozin | first =B | coauthors =Wang SW, Li NC, Lee A, Lee TA, Kazis LE | title =Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease | journal =BMC Medicine | volume =5 | pages =20 | date =[[July 19]] [[2007]] | doi =10.1186/1741-7015-5-20 | pmid=17640385 | url=http://www.biomedcentral.com/1741-7015/5/20}} {{PMC|1955446}}</ref> [[cancer]],<ref name="Khurana">{{cite journal | last=Khurana | first=V | authorlink = | coauthors =Bejjanki HR, Caldito G, Owens MW | title=Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans |journal=Chest |volume=131 |issue=5 |pages=1282–1288 | date=May 2007 | url=http://www.chestjournal.org/cgi/content/full/131/5/1282 | pmid=17494779 | doi=10.1378/chest.06-0931}}</ref> [[cataracts|nuclear cataracts]],<ref name="Klein2006">{{cite journal |author=Klein BE, Klein R, Lee KE, Grady LM |title=Statin use and incident nuclear cataract |journal=JAMA |volume=295 |issue=23 |pages=2752–8 |year=2006 |month=June |pmid=16788130 |doi=10.1001/jama.295.23.2752 |url=http://jama.ama-assn.org/cgi/content/full/295/23/2752}}</ref> and [[hypertension]].<ref>{{cite journal |author=Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH |title=Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial |journal=Arch. Intern. Med. |volume=168 |issue=7 |pages=721–7 |year=2008 |month=April |pmid=18413554 |doi=10.1001/archinte.168.7.721}}</ref> ==Members== ===Fermentation-derived and synthetic=== The statins are divided into two groups: [[fermentation (biochemistry)|fermentation]]-derived and [[chemical synthesis|synthetic]]. The statins include, in alphabetical order (brand names vary in different countries): {| class="wikitable" | '''Statin''' || '''Brand name''' || '''Derivation''' |- | [[Atorvastatin]] || Lipitor, Torvast || Synthetic |- | [[Cerivastatin]] || Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious [[Adverse drug reaction|adverse effects]]) || Synthetic |- | [[Fluvastatin]]|| Lescol, Lescol XL || Synthetic |- | [[Lovastatin]] || Mevacor, Altocor|| Fermentation-derived |- | [[Mevastatin]] || - || Naturally-occurring compound. Found in [[Monascus purpureus|red yeast rice]]. |- | [[Pitavastatin]] || Livalo, Pitava || Synthetic |- | [[Pravastatin]] || Pravachol, Selektine, Lipostat|| Fermentation-derived |- | [[Rosuvastatin]] || Crestor || Synthetic |- | [[Simvastatin]] || Zocor, Lipex || Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product) |- | [[Simvastatin]]+[[Ezetimibe]] || [[Vytorin]] || Combination therapy |- | [[Lovastatin]]+[[Niacin]] extended-release || [[Advicor]] || Combination therapy |- | [[Atorvastatin]]+[[Amlodipine]] Besylate || [[Caduet]] || Combination therapy - Cholesterol+Blood Pressure |} [[Low density lipoprotein|LDL]]-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.<ref>{{cite journal |author=Shepherd J, Hunninghake DB, Barter P, McKenney JM, Hutchinson HG |title=Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals |journal=Am. J. Cardiol. |volume=91 |issue=5A |pages=11C–17C; discussion 17C–19C |year=2003 |pmid=12646338 |doi=10.1016/S0002-9149(03)00004-3}}</ref> The relative potency of pitavastatin has not yet been fully established. ===Comparative effectiveness=== No large scale comparison exists that examines the relative effectiveness of the various statins against one another for preventing hard cardiovascular outcomes, such as death or myocardial infarction. An independent analysis has been done to compare atorvastatin, pravastatin and simvastatin, based on their effectiveness against [[placebo]]s. It found that, at commonly prescribed doses, there are no [[statistical significance|statistically significant]] differences in reducing cardiovascular morbidity and mortality.<ref>{{cite journal |author=Zhou Z, Rahme E, Pilote L |title=Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention |journal=Am. Heart J. |volume=151 |issue=2 |pages=273–81 |year=2006 |pmid=16442888 |doi=10.1016/j.ahj.2005.04.003}}</ref> The CURVES study, which compared the efficacy of different doses of atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin for reducing LDL and total cholesterol in patients with hypercholesterolemia, found that atorvastatin was more effective without increasing adverse events.<ref name="Jones1998">{{cite journal |author=Jones P, Kafonek S, Laurora I, Hunninghake D |title=Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) |journal=Am J Cardiol |volume=81 |issue=5 |pages=582–7 |year=1998 |pmid=9514454 |doi=10.1016/S0002-9149(97)00965-X}}</ref> ==Safety== ===Adverse effects=== While some patients on statin therapy report [[myalgia]]s, [[muscle cramps]], or far less-frequent gastrointestinal or other symptoms, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose. [[Liver enzyme]] derangements may also occur, typically in about 0.5%,{{fact|date=January 2008}} are also seen at similar rates with placebo use and repeated enzyme testing, and generally return to normal either without discontinuance over time or after briefly discontinuing the drug. Multiple other side-effects occur rarely; typically also at similar rates with only placebo in the large statin safety/efficacy trials. A clearer major safety concern, [[myositis]], [[myopathy]], rarely with [[rhabdomyolysis]] (the pathological breakdown of [[skeletal muscle]]) may lead to [[acute renal failure]] when muscle breakdown products damage the kidney. [[Coenzyme Q10]] (ubiquinone) levels are decreased in statin use;<ref>{{cite journal |author=Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G |title=Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study |journal=J Clin Pharmacol |volume=33 |issue=3 |pages=226–9 |year=1993 |pmid=8463436}}</ref> Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking.<ref>{{cite journal |author=Marcoff L, Thompson PD |title=The role of coenzyme Q10 in statin-associated myopathy: a systematic review |journal=J. Am. Coll. Cardiol. |volume=49 |issue=23 |pages=2231–7 |year=2007 |pmid=17560286 |doi=10.1016/j.jacc.2007.02.049}}</ref> One [[2004]] study found that of 10,000 patients treated for one year, 0.44 will develop rhabdomyolysis. [[Cerivastatin]], which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x).<ref name="Graham2004">{{cite journal |author=Graham DJ, Staffa JA, Shatin D, ''et al'' |title=Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs |journal=JAMA |volume=292 |issue=21 |pages=2585–90 |year=2004 |pmid=15572716 |doi=10.1001/jama.292.21.2585| url=http://jama.ama-assn.org/cgi/content/full/292/21/2585}}</ref> All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological [[elimination half-life|half-lives]] and more cellular specificity, have had a better ratio of [[efficacy]] to lower adverse effect rates. The risk of myopathy is lowest with [[pravastatin]] and [[fluvastatin]] probably because they are more hydrophillic and as a result have less muscle penetration. [[Lovastatin]] induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.<ref name="pmid17992259">{{cite journal |author=Hanai J, Cao P, Tanksale P, ''et al'' |title=The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity |journal=J. Clin. Invest. |volume=117 |issue=12 |pages=3940–51 |year=2007 |pmid=17992259 |doi=10.1172/JCI32741}}</ref> Despite initial concerns that statins might increase the risk of [[cancer]], various studies concluded later that statins have no influence on cancer risk (including the [[heart protection study]] and a 2006 [[meta-analysis]]<ref name="Dale2006">{{cite journal |author=Dale KM, Coleman CI, Henyan NN, Kluger J, White CM |title=Statins and cancer risk: a meta-analysis |journal=JAMA |volume=295 |issue=1 |pages=74–80 |year=2006 |pmid=16391219 |doi=10.1001/jama.295.1.74|url=http://jama.ama-assn.org/cgi/content/full/295/1/74}}</ref>). Indeed, a 2005 trial showed that patients taking statins for over 5 years ''reduced'' their risk of [[colorectal cancer]] by 50%; this effect was not exhibited by [[fibrate]]s. The trialists warn that the [[number needed to treat]] would approximate 5000, making statins unlikely tools for primary prevention.<ref name="Poynter2005">{{cite journal |author=Poynter JN, Gruber SB, Higgins PD, ''et al'' |title=Statins and the risk of colorectal cancer |journal=N. Engl. J. Med. |volume=352 |issue=21 |pages=2184–92 |year=2005 |pmid=15917383 |doi=10.1056/NEJMoa043792|url=http://content.nejm.org/cgi/content/full/352/21/2184}}</ref> However, in a recent meta-analysis of 23 statin treatment arms with 309,506 person-years of follow-up, there was an inverse relationship between achieved LDL-cholesterol levels and rates of newly diagnosed cancer that the authors claim requires further investigation.<ref>{{cite journal |author=Alsheikh-Ali AA |title=Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer: Insights From Large Randomized Statin Trials |journal=Journal of the American College of Cardiology |volume=50 |issue=5 |pages=409–418 |year=2007 |pmid=17662392 |doi=10.1016/j.jacc.2007.02.073}}</ref> ===Drug interactions=== Combining any statin with a [[fibrate]], another category of lipid-lowering drugs, increases the risks for [[rhabdomyolysis]] to almost 6.0 per 10,000 person-years.<ref name="Graham2004"/> Most physicians have now abandoned routine monitoring of liver enzymes and [[creatine kinase]], although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in [[renal function]]. Consumption of [[grapefruit]] or [[grapefruit juice]] inhibits the metabolism of statins&mdash;[[furanocoumarin]]s in grapefruit juice inhibit the [[Cytochrome P450 oxidase|cytochrome P450]] enzyme [[CYP3A4]], which is involved in the metabolism of most statins (however it is a major inhibitor of only atorvastatin, lovastatin and simvastatin) and some other medications<ref name="Kane2000">{{cite journal |author=Kane GC, Lipsky JJ |title=Drug-grapefruit juice interactions |journal=Mayo Clin. Proc. |volume=75 |issue=9 |pages=933–42 |year=2000 |pmid=10994829 |doi=}}</ref> (it had been thought that [[flavonoid]]s were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins. This is not recommended as a result of the increased risk and potential for statin toxicity. ==Pharmacogenomics== A 2004 study showed that patients with one of two common [[single nucleotide polymorphisms]] (small genetic variations) in the [[HMG-CoA reductase]] gene were less responsive to statins.<ref name="Chasman 2004">{{cite journal |author=Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP, Ridker PM |title=Pharmacogenetic study of statin therapy and cholesterol reduction |journal=JAMA |volume=291 |issue=23 |pages=2821–7 |year=2004 |pmid=15199031 |doi=10.1001/jama.291.23.2821|url= http://jama.ama-assn.org/cgi/content/full/291/23/2821}}</ref> ==Mode of action== ===Cholesterol lowering=== [[Image:HMG-CoA reductase pathway.png|thumb|right|280px|The HMG-CoA reductase pathway]] {{Main|Cholesterol|Lipoprotein}} Most circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, via [[steroid biosynthesis]] through the [[HMG-CoA reductase pathway]]. Cholesterol, both from dietary intake and secreted into the [[duodenum]] as [[bile]] from the liver, is typically absorbed at a rate of 50% by the [[small intestine]]s. The typical diet in the United States and many other Western countries is estimated as adding about 200–300&nbsp;mg/day to intestinal intake, an amount much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor. Cholesterol is not water-soluble, and is therefore carried in the blood in the form of [[lipoprotein]]s, the type being determined by the [[apoprotein]], a protein coating that acts as an [[emulsifier]]. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, and [[insulin resistance]]. [[Low density lipoprotein]] (LDL) and [[very low density lipoprotein]] (VLDL) carry cholesterol toward tissues, and elevated levels of these lipoproteins are associated with [[atheroma]] formation (fat-containing deposits in the arterial wall) and [[cardiovascular disease]]. Conversely, [[High density lipoprotein]] (HDL), carries cholesterol back to the liver and is associated with protection against cardiovascular disease. Statins act by [[competitive inhibitor|competitively inhibiting]] [[HMG-CoA reductase]], the first committed [[enzyme]] of the [[HMG-CoA reductase pathway]]. By reducing intracellular cholesterol levels, they cause [[hepatocyte|liver cell]]s to make more [[LDL receptor]]s, leading to increased clearance of low-density lipoprotein from the bloodstream.<ref name="Ma1986">{{cite journal |author=Ma PT, Gil G, Südhof TC, Bilheimer DW, Goldstein JL, Brown MS |title=Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue=21 |pages=8370–4 |year=1986 |pmid=3464957 |url=http://www.pnas.org/cgi/reprint/83/21/8370|format=PDF |doi=10.1073/pnas.83.21.8370}} {{PMC|386930}}</ref> Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the [[ASTEROID trial]], which demonstrated regression of [[atheroma]] employing [[intravascular ultrasound]].<ref name="Nissen2006"/> ===Non-cholesterol related actions=== Statins exhibit action beyond lipid-lowering activity in the prevention of [[atherosclerosis]]. Researchers hypothesize that statins prevent [[cardiovascular disease]] via four proposed mechanisms (all subjects of a large body of biomedical research):<ref name="Furberg">{{cite journal |author=Furberg CD |title=Natural Statins and Stroke Risk |url=http://circ.ahajournals.org/cgi/content/full/99/2/185|journal=Circulation |volume=99|year=1999|pages=185–188|pmid=9892578}}</ref> # Improving [[endothelium|endothelial]] function # Modulate [[inflammation|inflammatory]] responses # Maintain [[atherosclerosis|plaque]] stability # Prevent [[thrombosis|thrombus]] formation ==Controversy== Some scientists take a skeptical view of the need for many people to require statin treatment. Given the wide indications for which statins are prescribed, and the declining benefit in groups at lower baseline risk of cardiovascular events, the evidence base for expanded statin use has been questioned by some researchers.<ref name="Abramson2007">{{cite journal |author=Abramson J, Wright J |title=Are lipid-lowering guidelines evidence-based? |journal=Lancet |volume=369 |issue=9557 |pages=168–9 |year=2007 |pmid=17240267| doi=10.1016/S0140-6736(07)60084-1}}</ref> A much smaller minority, exemplified by [[The International Network of Cholesterol Skeptics]], question the "[[lipid hypothesis]]" itself and argue that elevated cholesterol has not been adequately linked to heart disease. These groups claim that statins are not as beneficial or safe as suggested.<ref>{{cite journal |author=Ravnskov U, Rosch P, Sutter M, Houston M |title=Should we lower cholesterol as much as possible? |journal=BMJ |volume=332 |issue=7553 |pages=1330–2 |year=2006 |pmid=16740566|doi=10.1136/bmj.332.7553.1330|url=http://www.bmj.com/cgi/content/full/332/7553/1330}}</ref> ==References== {{Reflist|2}} ==External links== * [http://www.jr2.ox.ac.uk/bandolier/booth/booths/statin.html Statin page] at ''[[Bandolier (journal)|Bandolier]]'', an [[evidence-based medicine]] journal {{Statins}} [[Category:Statins]] [[de:Statin]] [[es:Estatina]] [[fr:Statine]] [[it:statina]] [[nl:Statine]] [[ja:スタチン]] [[pl:Statyny]] [[pt:Estatina]] [[fi:Statiini]] [[sv:Statiner]] [[th:สแตติน]] [[tr:Statinler]] [[zh:羟甲戊二酰辅酶A还原酶抑制剂]]