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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/12 13:57:46」(JST)

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This article is about the group of cholesterol-lowering drugs. For the amino acid, see Statine.

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 disease,^[1] and statins have been found to prevent cardiovascular disease in those who are at high risk. Research has found that statins are most effective for treating cardiovascular disease (CVD) as a secondary prevention strategy, with questionable benefit in those with elevated cholesterol levels but without previous CVD.^[2]^[3] Statins have some side effects including a small increased risk of diabetes, a liver difficulties.^[4] Additionally they have rare but severe adverse effects, particularly muscle damage, and some doctors believe they are over-prescribed.

As of 2010, a number of statins are on the market including: simvastatin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and rosuvastatin.^[5] There are a number of differences between them with simvastatin and pravastatin appearing superior.^[4] The best-selling statin is atorvastatin which in 2003 became the best-selling pharmaceutical in history,^[6] with Pfizer reporting sales of US$12.4 billion in 2008.^[7] Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available but have not been found to be better than simvastatin alone.

1 Medical uses
- 1.1 Primary prevention
- 1.2 Secondary prevention
- 1.3 Comparative effectiveness
2 Controversy
3 Adverse effects
- 3.1 Myositis and myopathy
- 3.2 Diabetes
- 3.3 Cancer
- 3.4 Drug interactions
4 Mechanism of action
- 4.1 Inhibiting cholesterol synthesis
- 4.2 Increasing LDL uptake
- 4.3 Other effects
5 Pharmacogenomics
6 History
7 Available forms
8 Research
9 References
10 External links

Medical uses[edit]

Clinical practice guidelines generally recommend people to try "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.^[8]^[9]

Primary prevention[edit]

There is debate over whether or not statins are effective in those with high cholesterol, but no history of heart disease.^[10] The best meta-analysis (with individual patient data) did not find a mortality benefit in those at high risk but without prior cardiovascular disease.^[10] Other reviews concluded there is a mortality and morbidity benefit,^[11]^[12] but there were concerns regarding the quality of the evidence.^[3] With respect to quality of life, evidence of improvement is limited when statins are used for primary prevention.^[3] No studies as of 2010 show improved clinical outcomes in children with high cholesterol though statins decrease cholesterol levels.^[13]

Secondary prevention[edit]

Statins are effective in decreasing mortality in people with pre-existing CVD. 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 an estimated 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduced risk of stroke after long-term treatment.^[14] They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").

Comparative effectiveness[edit]

While no direct comparison exists and all statins appear effective regardless of potency or degree of cholesterol reduction.^[12] There does appear to be some differences between them with simvastatin and pravastatin appearing superior.^[4]

A comparison of atorvastatin, pravastatin and simvastatin, based on their effectiveness against placebos, found, at commonly prescribed doses, no statistically significant differences among agents in reducing cardiovascular morbidity and mortality.^[15]

Controversy[edit]

Some scientists believe the statins are overused. Their use has expanded into areas where they provide lesser benefit, and lesser evidence of benefit. The lower the risk of cardiovascular events, the lower the ratio is of benefits to costs. The US market for statins nearly tripled when the National Cholesterol Education Program revised its guidelines to recommend statins as primary prevention. Although the panel cited randomized trials to support statin therapy for primary prevention of occlusive cardiovascular disease, a report in Lancet notes, "not one of the studies provides such evidence." ^[16] Journalists have questioned the interests of the doctors who made such recommendations, as eight of the 9 doctors on the panel were discovered to have been paid by statin manufacturers.^[17]

A smaller group of scientists, The International Network of Cholesterol Skeptics, question the lipid hypothesis and argue that elevated cholesterol has not been adequately shown to cause heart disease. These organizations maintain that statins are not as beneficial or safe as suggested.^[18] The beneficial effects of statins are suggested to be due to their working as vitamin D analogues.^[19]

Adverse effects[edit]

Choosing a statin for people with special considerations^[20]
Condition	Commonly recommended statins	explanation
kidney transplantation recipients taking ciclosporin	Pravastatin or Fluvastatin	Drug interactions are possible, but studies have not shown that these statins increase exposure to ciclosporin.^[21]
HIV-positive people taking protease inhibitors	Atorvastatin, Pravastatin or Fluvastatin	Significant negative interactions are more likely with other choices^[22]
persons taking gemfibrozil, a non-statin cholesterol-lowering drug	Atorvastatin	Combining gemfibrozil and a statin increases risk of Rhabdomyolysis and subsequently renal failure^[23]^[24]
persons taking the anticoagulant warfarin	any statin	The statin use may require that the warfarin dose be changed, as some statins increase the effect of warfarin.^[25]

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.^[26] 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.^[27] 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.^[26] Other possible adverse effects include cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction.^[26]

Some patients on statin therapy report myalgias,^[28] muscle cramps,^[28] or, less frequently, gastrointestinal or other symptoms. Liver enzyme derangements, 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 these are causally related to statins in some individuals.^[29] A Danish case-control study published in 2002 suggested a relationship between long-term statin use and increased risk of nerve damage or polyneuropathy,^[30] but suggested this side effect is "rare, but it does occur";^[31] 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.^[32]

Myositis and myopathy[edit]

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;^[33] CoQ10 supplements are sometimes used to treat statin-associated myopathy, though there was not enough evidence of their effectiveness despite their ability to raise the circulating levels of CoQ10 in blood plasma as of 2007^[update].^[34] The gene SLCO1B1 (Solute carrier organic anion transporter family member 1B1) codes for an organic anion-transporting polypeptide that is involved in the regulation of the absorption of statins. A common variation in this gene was found in 2008 to significantly increase the risk of myopathy.^[35]

Graham et al. (2004) reviewed records of over 250,000 patients treated from 1998–2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.^[36] The incidence of rhabdomyolyis was 0.44 per 10,000 patients treated with statins other than cerivastatin. However, the risk was over 10-fold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, or 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, but 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 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;^[37] the risk of myopathy was suggested to be lowest with pravastatin and fluvastatin, probably because they are more hydrophilic 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.^[37]

Diabetes[edit]

Statins may slightly increase the risk of diabetes,^[38] with higher doses appearing to have a larger effect.^[39]

Cancer[edit]

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.^[40] In 2007, though, a meta-analysis of 23 statin treatment arms with 309,506 person-years of follow-up found the risk of cancer was significantly associated with lower achieved LDL-C levels; the authors said this requires further investigation.^[41]

Several case-control studies have found statins reduce cancer incidence,^[40] including one^[42] which showed patients taking statins for over five years reduced their risk of colorectal cancer by 50%; this effect was not exhibited by fibrates, although the trialists warned the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.^[42]

Drug interactions[edit]

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.^[36] 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 certain statins. Bitter oranges may have a similar effect.^[43] 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^[44] (flavonoids (i.e. naringin) were thought to be responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). The absolute proscription of grapefruit juice consumption for users of some statins is controversial.^[45]

The FDA notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.^[46]

Mechanism of action[edit]

Avorstatin bound to HMG-CoA reductase: PDB entry 1hwk^[47]

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[edit]

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,^[48] 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,^[49]^[50] but have shown no difference in the long-acting atorvastatin.^[51]

Increasing LDL uptake[edit]

In rabbits, hepatocytes (liver cells) sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation.^[52] 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[edit]

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.^[53] Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):^[54]

Improve endothelial function
Modulate inflammatory responses
Maintain plaque stability
Prevent thrombus formation

Statins may even benefit those without high cholesterol. In 2008, the JUPITER study showed fewer strokes, 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.^[55]

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

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Statin Pathway edit

^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Pharmacogenomics[edit]

A 2004 study showed patients with one of two common single-nucleotide polymorphisms (SNPs) (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins.^[56] A 2008 study showed carriers of the KIF6 genetic mutation were more responsive to statin treatment.^[57]

Likewise, a 2008 study demonstrated a link between an increased risk of myopathy at higher doses of statins (40–80 mg) and aa SNP in SLCO1B1, a gene encoding for the organic anion transporter peptide OADP1B1.^[35]

History[edit]

Main article: Statin development

In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, began the search for a cholesterol-lowering drug. Research had already shown cholesterol is mostly manufactured by the body in the liver, using the enzyme HMG-CoA reductase.^[6] 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 walls (ergosterol) or cytoskeleton (isoprenoids).^[58] The first agent they identified was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum.

A British group isolated the same compound from Penicillium brevicompactum, named it compactin, and published their report in 1976.^[59] The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition.

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.^[6]

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 cholesterol lowering could significantly reduce the risk of heart attacks and angina, physicians, including cardiologists, remained largely unconvinced.^[60]

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, 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 the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%.^[6]^[61] In 1995, Zocor and Mevacor both made Merck over US$1 billion.^[6] Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008.

Available forms[edit]

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

Statin	Brand name	Derivation	Metabolism^[62]
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 ^[63]
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^[64]
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.^[65] 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.^[66] 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	--
* 80-mg 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[edit]

Research continues into other areas where specific statins also appear to have a favorable effect, including dementia,^[67] lung cancer,^[68] nuclear cataracts,^[69] hypertension,^[70] and prostate cancer.^[71]

References[edit]

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^ ^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.
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^ "Doing Things Differently", Pfizer 2008 Annual Review, April 23, 2009, p. 15.
^ 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.
^ National Collaborating Centre for Primary Care (2010). NICE clinical guideline 67: Lipid modification (PDF). London: National Institute for Health and Clinical Excellence. p. 38.
^ ^a ^b Ray 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): 1024–31. doi:10.1001/archinternmed.2010.182. PMID 20585067. Retrieved 2010-11-04.
^ Mills, EJ; Wu, P, Chong, G, Ghement, I, Singh, S, Akl, EA, Eyawo, O, Guyatt, G, Berwanger, O, Briel, M (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.
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^ Law MR, Wald NJ, Rudnicka AR (June 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.
^ 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.
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^ table adapted from the following source, but check individual references for technical explanations
- Consumer Reports; Drug Effectiveness Review Project (March 2013), "Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price", Best Buy Drugs (Consumer Reports): 9, retrieved 27 March 2013
^ Asberg, A. (2003). "Interactions between cyclosporin and lipid-lowering drugs: Implications for organ transplant recipients". Drugs 63 (4): 367–378. doi:10.2165/00003495-200363040-00003. PMID 12558459. edit
^ Food and Drug Administration (1 March 2012). "Drug Safety and Availability; FDA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury". fda.gov. Retrieved 3 April 2013.
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^ Sandra G. Boodman (September 10, 2002). "Study links statins to nerve damage". Pittsburgh Post-Gazette. The Washington Post. Retrieved 2009-10-06.
^ Julie Appleby; Steve Sternberg (2002-08-18). "Statin side effect rare, but be aware". USA Today. Retrieved 2009-10-06.
^ Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G (1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol 33 (3): 226–9. PMID 8463436.
^ Marcoff L, Thompson PD (2007). "The role of coenzyme Q10 in statin-associated myopathy: a systematic review". J. Am. Coll. Cardiol. 49 (23): 2231–7. doi:10.1016/j.jacc.2007.02.049. PMID 17560286.
^ ^a ^b The SEARCH Collaborative Group (2008). "SLCO1B1 Variants and Statin-Induced Myopathy - A Genomewide Study". NEJM 359 (8): 789–799. doi:10.1056/NEJMoa0801936. PMID 18650507.
^ ^a ^b Graham DJ, Staffa JA, Shatin D et al. (2004). "Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs". JAMA 292 (21): 2585–90. doi:10.1001/jama.292.21.2585. PMID 15572716.
^ ^a ^b Hanai J, Cao P, Tanksale P et al. (2007). "The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity". J. Clin. Invest. 117 (12): 3940–51. doi:10.1172/JCI32741. PMC 2066198. PMID 17992259.
^ Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ et al. (2010). "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials". Lancet 375 (9716): 735–42. doi:10.1016/S0140-6736(09)61965-6. PMID 20167359.
^ Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD et al. (2011). "Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis". JAMA 305 (24): 2556–64. doi:10.1001/jama.2011.860. PMID 21693744.
^ ^a ^b Dale KM, Coleman CI, Henyan NN, Kluger J, White CM (2006). "Statins and cancer risk: a meta-analysis". JAMA 295 (1): 74–80. doi:10.1001/jama.295.1.74. PMID 16391219.
^ Alsheikh-Ali AA; Maddukuri, PV; Han, H; Karas, RH (2007). "Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer: Insights From Large Randomized Statin Trials". Journal of the American College of Cardiology 50 (5): 409–418. doi:10.1016/j.jacc.2007.02.073. PMID 17662392.
^ ^a ^b Poynter JN, Gruber SB, Higgins PD et al. (2005). "Statins and the risk of colorectal cancer". N. Engl. J. Med. 352 (21): 2184–92. doi:10.1056/NEJMoa043792. PMID 15917383.
^ Mayo clinic: article on interference between grapefruit and medication
^ Kane GC, Lipsky JJ (2000). "Drug-grapefruit juice interactions". Mayo Clin. Proc. 75 (9): 933–42. doi:10.4065/75.9.933. PMID 10994829.
^ Reamy, Brian V.; Stephens, Mark B. (July 15, 2007). "Letters to the Editor: The Grapefruit-Drug Interaction Debate: Role of Statins". American Family Physician 76 (2): 190–192.
^ FDA Website Statins and HIV or Hepatitis C Drugs: Drug Safety Communication - Interaction Increases Risk of Muscle Injury
^ Istvan, E. S.; Deisenhofer, J. (2001). "Structural Mechanism for Statin Inhibition of HMG-CoA Reductase". Science 292 (5519): 1160–1164. doi:10.1126/science.1059344. PMID 11349148. edit
^ Miettinen TA (March 1982). "Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins". Journal of Lipid Research 23 (3): 466–73. PMID 7200504.
^ Saito Y; Yoshida S; Nakaya N; Hata Y; Goto Y (Jul-Aug 1991). "Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects. A double-blind comparative study". Arterioscler Thromb 11 (4): 816–26. doi:10.1161/01.ATV.11.4.816. PMID 2065035.
^ Wallace A; Chinn D; Rubin G (4 October 2003). "Taking simvastatin in the morning compared with in the evening: randomised controlled trial". British Medical Journal 327 (7418): 788. doi:10.1136/bmj.327.7418.788. PMC 214096. PMID 14525878.
^ Cilla DD Jr; Gibson DM; Whitfield LR; Sedman AJ (July 1996). "Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening". Journal of Clinical Pharmacology 36 (7): 604–9. PMID 8844442.
^ Ma PT, Gil G, Südhof TC, Bilheimer DW, Goldstein JL, Brown MS (1986). "Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits" (PDF). Proc. Natl. Acad. Sci. U.S.A. 83 (21): 8370–4. Bibcode:1986PNAS...83.8370M. doi:10.1073/pnas.83.21.8370. PMC 386930. PMID 3464957.
^ 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 (2006). "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial". JAMA 295 (13): 1556–65. doi:10.1001/jama.295.13.jpc60002. PMID 16533939.
^ Furberg CD (19 January 1999). "Natural Statins and Stroke Risk". Circulation 99 (2): 185–188. doi:10.1161/01.CIR.99.2.185. PMID 9892578.
^ Ridker PM, Danielson E, Fonseca FAH et al. (2008). "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein". NEJM 359 (21): 2195–207. doi:10.1056/NEJMoa0807646. PMID 18997196.
^ Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP, Ridker PM (2004). "Pharmacogenetic study of statin therapy and cholesterol reduction". JAMA 291 (23): 2821–7. doi:10.1001/jama.291.23.2821. PMID 15199031.
^ Iakoubova, O. A.; Sabatine, M. S.; Rowland, C. M.; Tong, C. H.; Catanese, J. J.; Ranade, K.; Simonsen, K. L.; Kirchgessner, T. G. et al. (2008). "Polymorphism in KIF6 Gene and Benefit from Statins After Acute Coronary Syndromes: Results from the PROVE IT-TIMI 22 Study". Journal of the American College of Cardiology 51 (4): 449–55. doi:10.1016/j.jacc.2007.10.017. PMID 18222355. |displayauthors= suggested (help) edit
^ Endo A (1 November 1992). "The discovery and development of HMG-CoA reductase inhibitors" (PDF). J. Lipid Res. 33 (11): 1569–82. PMID 1464741.
^ "Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium brevicompactum." Alian G. Brown, Terry C. Smale, Trevor J. King, Rainer Hasenkamp and Ronald H. Thompson. J. Chem. Soc., Perkin Trans. 1, 1976, 1165-1170. DOI: 10.1039/P19760001165
^ Steinberg, Daniel. The Cholesterol Wars: The Skeptics vs. The Preponderance of Evidence. Academic Press, 2007, pp. 6–9.
^ Scandinaviansimvastatinsurvival (November 1994). "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". Lancet 344 (8934): 1383–9. doi:10.1016/S0140-6736(94)90566-5. PMID 7968073.
^ Safety of Statins: Focus on Clinical Pharmacokinetics and Drug Interactions" Circulation 2004:109:III-50-IIIi-57
^ Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P450 isozymes involved. Drug Metab Dispos. 1997 Mar;25(3): 321-31.
^ Comparison of Cytochrome P-450-Dependent Metabolism and Drug Interactions of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Lovastatin and Pravastatin in the Liver. DMD February 1, 1999 vol. 27 no. 2 173-179
^ Shepherd J, Hunninghake DB, Barter P, McKenney JM, Hutchinson HG (2003). "Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals". Am. J. Cardiol. 91 (5A): 11C–17C; discussion 17C–19C. doi:10.1016/S0002-9149(03)00004-3. PMID 12646338.
^ Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V (2006). "Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials". Chin Med 1: 4. doi:10.1186/1749-8546-1-4. PMC 1761143. PMID 17302963.
^ Wolozin, B; Wang SW, Li NC, Lee A, Lee TA, Kazis LE (July 19, 2007). "Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease". BMC Medicine 5: 20. doi:10.1186/1741-7015-5-20. PMC 1955446. PMID 17640385.
^ Khurana V, Bejjanki HR, Caldito G, Owens MW (May 2007). "Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans". Chest 131 (5): 1282–1288. doi:10.1378/chest.06-0931. PMID 17494779.
^ Klein BE, Klein R, Lee KE, Grady LM (June 2006). "Statin use and incident nuclear cataract". JAMA 295 (23): 2752–8. doi:10.1001/jama.295.23.2752. PMID 16788130.
^ Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH (April 2008). "Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial". Arch. Intern. Med. 168 (7): 721–7. doi:10.1001/archinte.168.7.721. PMID 18413554.
^ Mondul AM, Han M, Humphreys EB, Meinhold CL, Walsh PC, Platz EA (February 2011). "Association of statin use with pathological tumor characteristics and prostate cancer recurrence after surgery". Journal of Urology 185 (4): 1268–1273. doi:10.1016/j.juro.2010.11.089. PMID 21334020.

External links[edit]

Statin page at Bandolier, an evidence-based medicine journal (little content after 2004)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. スタチン：作用、副作用、および投与 statins actions side effects and administration
2. スタチン誘発性ミオパチー statin myopathy
3. スタチンと慢性腎臓病 statins and chronic kidney disease
4. 冠動脈疾患または同等の冠動脈リスクを有する患者におけるコレステロール低下に関する
臨床試験 clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents
5. 小児の脂質異常症ののマネージメント management of pediatric dyslipidemia

Japanese Journal

Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation : The Kumamoto Intervention Conference Study (KICS) Registry

Ishii Masanobu,Hokimoto Seiji,Akasaka Tomonori [他]
Circulation journal : official journal of the Japanese Circulation Society 79(5), 1115-1124, 2015-05
NAID 40020437201

Prognostic Impact of Statin Use in Patients With Heart Failure and Preserved Ejection Fraction : A Report From the CHART-2 Study

Nochioka Kotaro,Sakata Yasuhiko,Miyata Satoshi [他]
Circulation journal : official journal of the Japanese Circulation Society 79(3), 574-582, 2015-03
NAID 40020375084

Fluvastatin Upregulates the Expression of Tissue Factor Pathway Inhibitor in Human Umbilical Vein Endothelial Cells

Sekiya Akiko,Morishita Eriko,Maruyama Keiko,Torishima Hiroki,Ohtake Shigeki
Journal of Atherosclerosis and Thrombosis 22(7), 660-668, 2015
… Aim: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are cholesterol-lowering drugs with a variety of pleiotropic effects including antithrombotic properties. … This study revealed unknown mechanisms of the anticoagulant effect of statins and gave a new insight to its therapeutic potential for the prevention of thrombotic diseases. …
NAID 130005089136

Related Pictures

★リンクテーブル★

「statin」

Statin
	Drug class
	; Lovastatin, a compound isolated from Aspergillus terreus, was the first statin to be marketed.
Use	High cholesterol
Biological target	HMG-CoA reductase
ATC code	C10AA
External links
MeSH	D019161
AHFS/Drugs.com	Drug Classes

　　[★] HMG-CoA還元酵素阻害薬

[WikiPathways-56] The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

[1] Lewington S, Whitlock G, Clarke R et al. (December 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.

[NICEquick-2] 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.

[Cochrane11-3] Taylor F, Ward K, Moore TH et al. (2011). "Statins for the primary prevention of cardiovascular disease". In Taylor, Fiona. Cochrane Database Syst Rev (1): CD004816. doi:10.1002/14651858.CD004816.pub4. PMID 21249663.

[Naci2013-4] Naci, H.; Brugts, J.; Ades, T. (9 July 2013). "Comparative Tolerability and Harms of Individual Statins: A Study-Level Network Meta-Analysis of 246 955 Participants From 135 Randomized Controlled Trials". Circulation: Cardiovascular Quality and Outcomes. doi:10.1161/CIRCOUTCOMES.111.000071.

[Martindale-5] 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.

[Simons-6] Simons, John. "The $10 billion pill", Fortune magazine, January 20, 2003.

[7] "Doing Things Differently", Pfizer 2008 Annual Review, April 23, 2009, p. 15.

[ATPIII-8] 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.

[NICE-9] National Collaborating Centre for Primary Care (2010). NICE clinical guideline 67: Lipid modification (PDF). London: National Institute for Health and Clinical Excellence. p. 38.

[AIM2010-10] Ray 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): 1024–31. doi:10.1001/archinternmed.2010.182. PMID 20585067. Retrieved 2010-11-04.

[11] Mills, EJ; Wu, P, Chong, G, Ghement, I, Singh, S, Akl, EA, Eyawo, O, Guyatt, G, Berwanger, O, Briel, M (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.

[CMAJ11-12] Tonelli, M; Lloyd, A, Clement, F, Conly, J, Husereau, D, Hemmelgarn, B, Klarenbach, S, McAlister, FA, Wiebe, N, Manns, B, for the Alberta Kidney Disease, Network (2011 Nov 8). "Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis". CMAJ : Canadian Medical Association 183 (16): E1189–E1202. doi:10.1503/cmaj.101280. PMC 3216447. PMID 21989464.

[Leben2010-13] 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.

[14] Law MR, Wald NJ, Rudnicka AR (June 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.

[15] 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.

[Abramson2007-16] Abramson J, Wright J (2007). "Are lipid-lowering guidelines evidence-based?". Lancet 369 (9557): 168–9. doi:10.1016/S0140-6736(07)60084-1. PMID 17240267.

[USATodayCholesterolGuidelines-17] Associated Press (16 October 2004). "Cholesterol guidelines become a morality play". USA Today.

[18] Ravnskov U, Rosch P, Sutter M, Houston M (2006). "Should we lower cholesterol as much as possible?". BMJ 332 (7553): 1330–2. doi:10.1136/bmj.332.7553.1330. PMC 1473073. PMID 16740566.

[19] Grimes, D. (2006). "Are statins analogues of vitamin D?". The Lancet 368 (9529): 83–82. doi:10.1016/S0140-6736(06)68971-X. edit

[BBDstatins2-20] table adapted from the following source, but check individual references for technical explanations

Consumer Reports; Drug Effectiveness Review Project (March 2013), "Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price", Best Buy Drugs (Consumer Reports): 9, retrieved 27 March 2013

[22] Consumer Reports; Drug Effectiveness Review Project (March 2013), "Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price", Best Buy Drugs (Consumer Reports): 9, retrieved 27 March 2013

[21] Asberg, A. (2003). "Interactions between cyclosporin and lipid-lowering drugs: Implications for organ transplant recipients". Drugs 63 (4): 367–378. doi:10.2165/00003495-200363040-00003. PMID 12558459. edit

[22] Food and Drug Administration (1 March 2012). "Drug Safety and Availability; FDA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury". fda.gov. Retrieved 3 April 2013.

[23] Bellosta, S. (2004). "Safety of Statins: Focus on Clinical Pharmacokinetics and Drug Interactions". Circulation 109 (23_suppl_1): III–I50. doi:10.1161/01.CIR.0000131519.15067.1f. edit

[24] Omar, M. A.; Wilson, J. P. (2002). "FDA Adverse Event Reports on Statin-Associated Rhabdomyolysis". The Annals of Pharmacotherapy 36 (2): 288–295. doi:10.1345/aph.1A289. PMID 11847951. edit

[25] Armitage, J. (2007). "The safety of statins in clinical practice". The Lancet 370 (9601): 1781–1790. doi:10.1016/S0140-6736(07)60716-8. edit

[GolombEvans2008-26] 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.

[27] Silva MA, Swanson AC, Gandhi PJ, Tataronis GR (January 2006). "Statin-related adverse events: a meta-analysis". Clin Ther 28 (1): 26–35. doi:10.1016/j.clinthera.2006.01.005. PMID 16490577.

[tws06oct01-28] Anne Harding (August 28, 2007). "Docs often write off patient side effect concerns". Reuters. Retrieved 2009-10-06.

[Holman2007-29] Holman JR. (2007). Some Docs in Denial About Statin Side Effects. Doc News.

[twsOCT21-30] Gaist D, Jeppesen U, Andersen M, García Rodríguez LA, Hallas J, Sindrup SH (2002). "Statins and risk of polyneuropathy—a case-control study". Neurology 58 (9): 1333–1337. doi:10.1212/WNL.58.9.1333. PMID 12011277. Lay summary – USA Today (2002-08-20).

[tws06oct11-31] Sandra G. Boodman (September 10, 2002). "Study links statins to nerve damage". Pittsburgh Post-Gazette. The Washington Post. Retrieved 2009-10-06.

[tws06oct09-32] Julie Appleby; Steve Sternberg (2002-08-18). "Statin side effect rare, but be aware". USA Today. Retrieved 2009-10-06.

[33] Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G (1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol 33 (3): 226–9. PMID 8463436.

[34] Marcoff L, Thompson PD (2007). "The role of coenzyme Q10 in statin-associated myopathy: a systematic review". J. Am. Coll. Cardiol. 49 (23): 2231–7. doi:10.1016/j.jacc.2007.02.049. PMID 17560286.

[The_SEARCH_Collaborative_Group-35] The SEARCH Collaborative Group (2008). "SLCO1B1 Variants and Statin-Induced Myopathy - A Genomewide Study". NEJM 359 (8): 789–799. doi:10.1056/NEJMoa0801936. PMID 18650507.

[Graham2004-36] Graham DJ, Staffa JA, Shatin D et al. (2004). "Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs". JAMA 292 (21): 2585–90. doi:10.1001/jama.292.21.2585. PMID 15572716.

[Hanaietal2007-37] Hanai J, Cao P, Tanksale P et al. (2007). "The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity". J. Clin. Invest. 117 (12): 3940–51. doi:10.1172/JCI32741. PMC 2066198. PMID 17992259.

[pmid20167359-38] Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ et al. (2010). "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials". Lancet 375 (9716): 735–42. doi:10.1016/S0140-6736(09)61965-6. PMID 20167359.

[pmid21693744-39] Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD et al. (2011). "Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis". JAMA 305 (24): 2556–64. doi:10.1001/jama.2011.860. PMID 21693744.

[Dale2006-40] Dale KM, Coleman CI, Henyan NN, Kluger J, White CM (2006). "Statins and cancer risk: a meta-analysis". JAMA 295 (1): 74–80. doi:10.1001/jama.295.1.74. PMID 16391219.

[41] Alsheikh-Ali AA; Maddukuri, PV; Han, H; Karas, RH (2007). "Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer: Insights From Large Randomized Statin Trials". Journal of the American College of Cardiology 50 (5): 409–418. doi:10.1016/j.jacc.2007.02.073. PMID 17662392.

[Poynter2005-42] Poynter JN, Gruber SB, Higgins PD et al. (2005). "Statins and the risk of colorectal cancer". N. Engl. J. Med. 352 (21): 2184–92. doi:10.1056/NEJMoa043792. PMID 15917383.

[43] Mayo clinic: article on interference between grapefruit and medication

[Kane2000-44] Kane GC, Lipsky JJ (2000). "Drug-grapefruit juice interactions". Mayo Clin. Proc. 75 (9): 933–42. doi:10.4065/75.9.933. PMID 10994829.

[45] Reamy, Brian V.; Stephens, Mark B. (July 15, 2007). "Letters to the Editor: The Grapefruit-Drug Interaction Debate: Role of Statins". American Family Physician 76 (2): 190–192.

[46] FDA Website Statins and HIV or Hepatitis C Drugs: Drug Safety Communication - Interaction Increases Risk of Muscle Injury

[47] Istvan, E. S.; Deisenhofer, J. (2001). "Structural Mechanism for Statin Inhibition of HMG-CoA Reductase". Science 292 (5519): 1160–1164. doi:10.1126/science.1059344. PMID 11349148. edit

[48] Miettinen TA (March 1982). "Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins". Journal of Lipid Research 23 (3): 466–73. PMID 7200504.

[49] Saito Y; Yoshida S; Nakaya N; Hata Y; Goto Y (Jul-Aug 1991). "Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects. A double-blind comparative study". Arterioscler Thromb 11 (4): 816–26. doi:10.1161/01.ATV.11.4.816. PMID 2065035.

[50] Wallace A; Chinn D; Rubin G (4 October 2003). "Taking simvastatin in the morning compared with in the evening: randomised controlled trial". British Medical Journal 327 (7418): 788. doi:10.1136/bmj.327.7418.788. PMC 214096. PMID 14525878.

[51] Cilla DD Jr; Gibson DM; Whitfield LR; Sedman AJ (July 1996). "Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening". Journal of Clinical Pharmacology 36 (7): 604–9. PMID 8844442.

[Ma1986-52] Ma PT, Gil G, Südhof TC, Bilheimer DW, Goldstein JL, Brown MS (1986). "Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits" (PDF). Proc. Natl. Acad. Sci. U.S.A. 83 (21): 8370–4. Bibcode:1986PNAS...83.8370M. doi:10.1073/pnas.83.21.8370. PMC 386930. PMID 3464957.

[Nissen2006-53] 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 (2006). "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial". JAMA 295 (13): 1556–65. doi:10.1001/jama.295.13.jpc60002. PMID 16533939.

[Furberg-54] Furberg CD (19 January 1999). "Natural Statins and Stroke Risk". Circulation 99 (2): 185–188. doi:10.1161/01.CIR.99.2.185. PMID 9892578.

[Ridker2008-55] Ridker PM, Danielson E, Fonseca FAH et al. (2008). "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein". NEJM 359 (21): 2195–207. doi:10.1056/NEJMoa0807646. PMID 18997196.

[Chasman_2004-57] Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP, Ridker PM (2004). "Pharmacogenetic study of statin therapy and cholesterol reduction". JAMA 291 (23): 2821–7. doi:10.1001/jama.291.23.2821. PMID 15199031.

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