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Combining any statin with a [[fibrate]] or niacin, 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]].
Combining any statin with a [[fibrate]] or niacin, 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. [[Bitter orange]]s may have a similar effect.<ref>[http://www.mayoclinic.com/health/food-and-nutrition/AN00413 Mayo clinic: article on interference between grapefruit and medication]</ref> Furanocoumarins in grapefruit juice (i.e. [[bergamottin]] and [[dihydroxybergamottin]]) 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 lovastatin, simvastatin and to a lesser degree atorvastatin) 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=10.4065/75.9.933}}</ref> (it had been thought that flavonoids (i.e. [[naringin]]) were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including [[myopathy]]/[[rhabdomyolysis]]). An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins; this increases risk and the potential for statin toxicity.
Consumption of [[grapefruit]] or [[grapefruit juice]] inhibits the metabolism of statins. [[Bitter orange]]s may have a similar effect.<ref>[http://www.mayoclinic.com/health/food-and-nutrition/AN00413 Mayo clinic: article on interference between grapefruit and medication]</ref> Furanocoumarins in grapefruit juice (i.e. [[bergamottin]] and [[dihydroxybergamottin]]) 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 lovastatin, simvastatin and to a lesser degree atorvastatin) 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=10.4065/75.9.933}}</ref> (it had been thought that flavonoids (i.e. [[naringin]]) were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including [[myopathy]]/[[rhabdomyolysis]]).


==Mechanism of action==
==Mechanism of action==

Revision as of 09:16, 20 December 2011

This article is about the group of cholesterol lowering drugs. For the amino acid, see Statine.
Statin
Drug class
Lovastatin, a compound isolated from Aspergillus terreus, was the first statin to be marketed.
Class identifiers
UseHigh cholesterol
ATC codeC10AA
Biological targetHMG-CoA reductase
Clinical data
Drugs.comhmg-coa-reductase-inhibitors
External links
MeSHD019161
Legal status
In Wikidata

Statins (or HMG-CoA reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases,[1] and statins are therefore used in the prevention of these diseases. Evidence has found that they are most effective in those with cardiovascular disease (secondary prevention), with questionable benefit in those without previous CVD but with elevated cholesterol levels.[2][3] Statins have rare but severe adverse effects, particularly muscle damage, and some doctors believe they are overprescribed.

The best-selling of the statins is atorvastatin, marketed as Lipitor and manufactured by Pfizer. By 2003 it had become the best-selling pharmaceutical in history,[4] with Pfizer reporting sales of US$12.4 billion in 2008.[5] As of 2010, a number of statins are on the market: atorvastatin (Lipitor and Torvast), fluvastatin (Lescol), lovastatin (Mevacor, Altocor, Altoprev), pitavastatin (Livalo, Pitava), pravastatin (Pravachol, Selektine, Lipostat), rosuvastatin (Crestor) and simvastatin (Zocor, Lipex).[6] Several combination preparations of a statin and another agent—such as ezetimibe/simvastatin are available.

Medical uses

Clinical practice guidelines generally recommend that the people have tried "lifestyle modification", including a cholesterol-lowering diet and physical exercise, before statin use is considered; statins or other pharmacologic agents may then be recommended for those who do not meet their lipid-lowering goals through diet and lifestyle approaches.[7][8]

Primary prevention

There is debate over whether or not statins are effective in those with high cholesterol but no other health problems.[9] One review did not find a mortality benefit in those at high-risk but without prior cardiovascular disease.[9] Other reviews concluded that there is a mortality and morbidity benefit[10][11] but there was concerns regarding the quality of the evidence.[3] With respect to quality of life there is limited evidence of improvement when statins are used for primary prevention.[3] No studies as of 2010 show improved clinical outcomes in children with high cholesterol even though statins decrease cholesterol levels.[12]

Secondary prevention

Statins are effective in decreasing mortality in people with preexisting cardiovascular disease. They are also currently advocated for use in patients at high risk of developing heart disease.[2] On average, statins can lower LDL cholesterol by 1.8 mmol/l (70 mg/dl), which translates into a 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduced risk of stroke after long-term treatment.[13] They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").

Comparative effectiveness

While no direct comparison exists all statins appear equally effective regardless of potency or degree of cholesterol reduction.[11]

A comparison of atorvastatin, pravastatin and simvastatin, based on their effectiveness against placebos, found that, at commonly prescribed doses, there are no statistically significant differences among agents in reducing cardiovascular morbidity and mortality.[14]

Adverse effects

The most common adverse side effects are raised liver enzymes and muscle problems. In randomized clinical trials, reported adverse effects are low; but they are "higher in studies of real world use", and more varied.[15] In randomized trials statins increased the risk of an adverse effect by 39% compared to placebo (odds ratios 1.4); two-thirds of these were myalgia or raised liver enzymes with serious adverse effects similar to placebo.[16] However, reliance on clinical trials can be misleading indications of real-world adverse effects – for example, the statin cerivastatin was withdrawn from the market in 2001 due to cases of rhabdomyolysis (muscle breakdown), although rhabdomyolysis did not occur in a meta-analysis of cerivastatin clinical trials.[15] Other possible adverse effects include cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction.[15]

Some patients on statin therapy report myalgias,[17] muscle cramps,[17] or, less frequently, gastrointestinal or other symptoms. Liver enzyme derangements may also occur, typically in about 0.5%,[citation needed] 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. Two randomized clinical trials found cognitive issues while two did not; recurrence upon reintroduction suggests that these are causally related to statins in some individuals.[18] A Danish case-control study published in 2002 suggested a relation between long term statin use and increased risk of nerve damage or polyneuropathy[19] but suggested this side effect is "rare, but it does occur";[20] other researchers have pointed to studies of the effectiveness of statins in trials involving 50,000 people which have not shown nerve damage as a significant side effect.[21]

Rare reactions include myositis and myopathy, with the potential for rhabdomyolysis (the pathological breakdown of skeletal muscle) leading to acute renal failure. Coenzyme Q10 (ubiquinone) levels are decreased in statin use;[22] Q10 supplements are sometimes used to treat statin-associated myopathy, though there was no evidence of their effectiveness as of 2007.[23] A common variation in the SLCO1B1 gene, which participates in the absorption of statins, has been shown to significantly increase the risk of myopathy.[24]

Graham et al. (2004) reviewed records of over 250,000 patients treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.[25] The incidence of rhabdomyolyis was 0.44 per 10,000 patients treated with statins other than cerivastatin. However, the risk was over tenfold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) were combined with fibrate (fenofibrate or gemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001.

All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological half-lives and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates.[citation needed] Some researchers have suggested that hydrophilic statins such as fluvastatin, rosuvastatin, and pravastatin are less toxic than lipophilic statins such as atorvastatin, lovastatin, and simvastatin, but other studies have not found a connection;[26] it is suggested that the risk of myopathy is lowest with pravastatin and fluvastatin probably because they are more hydrophillic and as a result have less muscle penetration.[citation needed] Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.[26]

Although there have been concerns that statins might increase cancer, several meta-analyses have found no relationship to cancer, the largest of which as of 2006 included nearly 87,000 participants.[27] However, in 2007 a meta-analysis of 23 statin treatment arms with 309,506 person-years of follow-up found that the risk of cancer was significantly associated with lower achieved LDL-C levels; the authors say that this requires further investigation.[28]

Several case-control studies have found that statins reduce cancer incidence,[27] including one[29] which showed that patients taking statins for over 5 years reduced their risk of colorectal cancer by 50%; this effect was not exhibited by fibrates although the trialists warned that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.[29]

Drug interactions

Combining any statin with a fibrate or niacin, another category of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years.[25] 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. Bitter oranges may have a similar effect.[30] Furanocoumarins in grapefruit juice (i.e. bergamottin and dihydroxybergamottin) inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however it is a major inhibitor of only lovastatin, simvastatin and to a lesser degree atorvastatin) and some other medications[31] (it had been thought that flavonoids (i.e. naringin) were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis).

Mechanism of action

The HMG-CoA reductase pathway, which is blocked by statins via inhibiting the rate limiting enzyme HMG-CoA reductase.
Main article: Cholesterol homeostasis

Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. Because statins are similar to HMG-CoA on a molecular level they take the place of HMG-CoA in the enzyme and reduce the rate by which it is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol, as well as a number of other compounds. This ultimately reduces cholesterol via several mechanisms.

Inhibiting cholesterol synthesis

By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night,[32] so statins with short half-lives are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-acting simvastatin taken at night rather than the morning,[33][34] but have shown no difference in the long-acting atorvastatin.[35]

Increasing LDL uptake

Liver cells sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation.[36] This is accomplished via protease enzymes that cleave a protein called "membrane-bound sterol regulatory element binding protein", which migrates to the nucleus and causes increased production of various other proteins and enzymes, including the LDL receptor. The LDL receptor then relocates to the liver cell membrane and binds to passing LDL and VLDL particles (the "bad cholesterol" linked to disease). LDL and VLDL are drawn out of circulation into the liver where the cholesterol is reprocessed into bile salts. These are excreted, and subsequently recycled mostly by an internal bile salt circulation.

Other effects

Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. The ASTEROID trial showed direct ultrasound evidence of atheroma regression during statin therapy.[37] Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):[38]

  1. Improve endothelial function
  2. Modulate inflammatory responses
  3. Maintain plaque stability
  4. Prevent thrombus formation

Statins may even benefit those without high cholesterol. In 2008 the JUPITER study showed fewer stroke, heart attacks, and surgeries even for patients who had no history of high cholesterol or heart disease, but only elevated C-reactive protein levels. There were also 20% fewer deaths (mainly from reduction in cancer deaths) though deaths from cardiovascular causes were not reduced.[39]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|alt=Statin pathway edit]]
Statin pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Pharmacogenomics

A 2004 study showed that patients with one of two common single-nucleotide polymorphisms (SNP) (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins.[40] A 2008 study showed that carriers of the KIF6 genetic mutation were more responsive to statin treatment.[41]

Likewise, a 2008 study demonstrated a link between an increased risk of myopathy at higher doses of statins (40 – 80 mg) and a SNP in SLCO1B1, a gene encoding for the organic anion transporter peptide OADP1B1.[24]

History

Main article: Statin development

In 1971, Akira Endo, a Japanese biochemist working for the drug company Sankyo, began the search for a cholesterol-lowering drug. Research had already shown that cholesterol is mostly manufactured by the body in the liver, using an enzyme known as HMG-CoA reductase.[4] Endo and his 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 (isoprenoids).[42] The first agent they identified was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum.

Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs. P. Roy Vagelos, chief scientist and later CEO of Merck & Co, was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the fungus Aspergillus terreus, first marketed in 1987 as Mevacor.[4]

A link between cholesterol and cardiovascular disease, known as the lipid hypothesis, had already been suggested. Cholesterol is the main constituent of atheroma, the fatty lumps in the wall of arteries that occur in atherosclerosis and, when ruptured, cause the vast majority of heart attacks. Treatment consisted mainly of dietary measures such as a low-fat diet, and poorly tolerated medicines such as clofibrate, cholestyramine and nicotinic acid. Cholesterol researcher Daniel Steinberg writes that while the Coronary Primary Prevention Trial of 1984 demonstrated that cholesterol lowering could significantly reduce the risk of heart attacks and angina, physicians, including cardiologists, remained largely unconvinced.[43]

To market statins effectively, Merck had to convince the public about the dangers of high cholesterol, and doctors that statins were safe and would extend lives. As a result of public campaigns, people became familiar with their cholesterol numbers and the difference between "good" and "bad" cholesterol, and rival pharmaceutical companies began producing their own statins, such as pravastatin (Pravachol), manufactured by Sankyo and Bristol-Myers Squibb. In April 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study or "4S", were announced. Researchers tested simvastatin, later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded that patients saw a 35-percent reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42 percent.[4][44] In 1995, Zocor and Mevacor both made Merck over US$1 billion.[4] Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008.

Available forms

The statins are divided into two groups: fermentation-derived and synthetic. They include, along with brand names, which may vary between countries:

Statin Image Brand name Derivation Metabolism[45]
Atorvastatin
Lipitor, Torvast Synthetic CYP3A4
Cerivastatin
Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis) Synthetic various CYP3A isoforms [46]
Fluvastatin
Lescol, Lescol XL Synthetic CYP2C9
Lovastatin
Mevacor, Altocor, Altoprev Fermentation-derived. Naturally-occurring compound. Found in oyster mushrooms and red yeast rice. CYP3A4
Mevastatin
Compactin Naturally-occurring compound. Found in red yeast rice. CYP3A4
Pitavastatin
Livalo, Pitava Synthetic
Pravastatin
Pravachol, Selektine, Lipostat Fermentation-derived. (A fermentation product of bacterium Nocardia autotrophica). Non CYP[47]
Rosuvastatin
Crestor Synthetic CYP2C9 and CYP2C19
Simvastatin
Zocor, Lipex Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product ofAspergillus terreus.) CYP3A4
Simvastatin+Ezetimibe Vytorin Combination therapy
Lovastatin+Niacin extended-release Advicor Combination therapy
Atorvastatin+Amlodipine Besylate Caduet Combination therapy - Cholesterol+Blood Pressure
Simvastatin+Niacin extended-release Simcor Combination therapy

LDL-lowering potency varies between agents. Cerivastatin is the most potent, (withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis) followed by (in order of decreasing potency), rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.[48] The relative potency of pitavastatin has not yet been fully established.

The oyster mushroom, a culinary mushroom, naturally contains lovastatin.

Some types of statins are naturally occurring, and can be found in such foods as oyster mushrooms and red yeast rice. Randomized controlled trials found them to be effective, but the quality of the trials was low.[49] Most of the block-buster branded statins will be generic by 2012,including atorvastatin, the largest selling branded drug.

Statin Equivalent Dosages
% LDL Reduction (approx.) Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin
10-20% -- 20 mg 10 mg 10 mg -- 5 mg
20-30% -- 40 mg 20 mg 20 mg -- 10 mg
30-40% 10 mg 80 mg 40 mg 40 mg 5 mg 20 mg
40-45% 20 mg -- 80 mg 80 mg 5–10 mg 40 mg
46-50% 40 mg -- -- -- 10–20 mg 80 mg*
50-55% 80 mg -- -- -- 20 mg --
56-60% -- -- -- -- 40 mg --
* 80mg dose no longer recommended due to increased risk of rhabdomyolysis
Starting dose
Starting dose 10–20 mg 20 mg 10–20 mg 40 mg 10 mg; 5 mg if hypothyroid, >65 yo, Asian 20 mg
If higher LDL reduction goal 40 mg if >45% 40 mg if >25% 20 mg if >20% -- 20 mg if LDL >190 mg/dL (4.87 mmol/L) 40 mg if >45%
Optimal timing Anytime Evening With evening meals Anytime Anytime Evening


Research

Research continues into other areas where statins also appear to have a favorable effect, including dementia,[50] lung cancer,[51]nuclear cataracts,[52] hypertension,[53] prostate cancer [54]

Controversy

Some scientists believe that statins are overused. Their use has expanded into groups with lesser benefit, and lesser evidence of benefit. The lower the risk of cardiovascular events, the lower the ratio is of benefits to costs.[55]

A smaller group of scientists, The International Network of Cholesterol Skeptics, question the lipid hypothesis and argue that elevated cholesterol has not been adequately linked to heart disease. These organizations maintain that statins are not as beneficial or safe as suggested.[56]

References

  1. ^ Lewington S, Whitlock G, Clarke R; et al. (2007). "Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths". Lancet. 370 (9602): 1829–39. doi:10.1016/S0140-6736(07)61778-4. PMID 18061058. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b National Institute for Health and Clinical Excellence (May 2008, reissued March 2010). "Lipid modification - Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease - Quick reference guide" (PDF). Retrieved 2010-08-25. {{cite web}}: Check date values in: |date= (help)
  3. ^ a b c Taylor F, Ward K, Moore TH; et al. (2011). Taylor, Fiona (ed.). "Statins for the primary prevention of cardiovascular disease". Cochrane Database Syst Rev (1): CD004816. doi:10.1002/14651858.CD004816.pub4. PMID 21249663. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  4. ^ a b c d e Simons, John. "The $10 billion pill", Fortune magazine, January 20, 2003.
  5. ^ "Doing Things Differently", Pfizer 2008 Annual Review, April 23, 2009, p. 15.
  6. ^ Sweetman, Sean C., ed. (2009). "Cardiovascular drugs". Martindale: the complete drug reference (36th ed.). London: Pharmaceutical Press. pp. 1155–434. ISBN 978-0-85369-840-1.
  7. ^ National Cholesterol Education Program (2001). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Executive Summary. Bethesda, MD: National Institutes of Health. National Heart, Lung, and Blood Institute. p. 40. NIH Publication No. 01-3670.
  8. ^ National Collaborating Centre for Primary Care (2010). NICE clinical guideline 67: Lipid modification (PDF). London: National Institute for Health and Clinical Excellence. p. 38.
  9. ^ a b Ray; Seshasai, S. R. K.; Erqou, S.; Sever, P.; Jukema, J. W.; Ford, I.; Sattar, N.; et al. (2010). "Statins and All-Cause Mortality in High-Risk Primary Prevention: A Meta-analysis of 11 Randomized Controlled Trials Involving 65 229 Participants". Arch Intern Med. 170 (12): 1024. doi:10.1001/archinternmed.2010.182. PMID 20585067. Retrieved 2010-11-04. {{cite journal}}: Explicit use of et al. in: |author= (help); More than one of |pages= and |page= specified (help)
  10. ^ Mills, EJ (2011 Feb). "Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials". QJM : monthly journal of the Association of Physicians. 104 (2): 109–24. doi:10.1093/qjmed/hcq165. PMID 20934984. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ a b Tonelli, M (2011 Nov 8). "Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis". CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 183 (16): E1189–E1202. PMID 21989464. {{cite journal}}: Check date values in: |date= (help); Missing pipe in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ Lebenthal Y, Horvath A, Dziechciarz P, Szajewska H, Shamir R (2010). "Are treatment targets for hypercholesterolemia evidence based? Systematic review and meta-analysis of randomised controlled trials". Arch Dis Child. 95 (9): 673–80. doi:10.1136/adc.2008.157024. PMID 20515970.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Law MR, Wald NJ, Rudnicka AR (2003). "Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis". BMJ. 326 (7404): 1423. doi:10.1136/bmj.326.7404.1423. PMC 162260. PMID 12829554. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Zhou Z, Rahme E, Pilote L (2006). "Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention". Am. Heart J. 151 (2): 273–81. doi:10.1016/j.ahj.2005.04.003. PMID 16442888.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ a b c Golomb BA, Evans MA (2008). "Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism". Am J Cardiovasc Drugs. 8 (6): 373–418. doi:10.2165/0129784-200808060-00004. PMC 2849981. PMID 19159124.
  16. ^ Silva MA, Swanson AC, Gandhi PJ, Tataronis GR (2006). "Statin-related adverse events: a meta-analysis". Clin Ther. 28 (1): 26–35. doi:10.1016/j.clinthera.2006.01.005. PMID 16490577. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ a b Anne Harding (August 28, 2007). "Docs often write off patient side effect concerns". Reuters. Retrieved 2009-10-06.
  18. ^ Holman JR. (2007). Some Docs in Denial About Statin Side Effects. Doc News.
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