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The statins (or HMG-CoA reductase inhibitors) are a class of drug used to lower plasma cholesterol level.

They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream. The first results can be seen after one week of use and the effect is maximal after four to six weeks.

History

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 (isoprenoids).

The first agent isolated was mevastatin (ML-236B), a molecule produced by the fungus 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 fungus Aspergillus terreus. Dr. Endo was awarded the 2006 Japan Prize for his work on the development of statins, and the Clinical Medical Research Award from the Lasker Foundation in 2008.

Mechanism of action

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, 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, but have shown no difference in the long-acting atorvastatin.

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

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.

Statins have been linked to a marked reduction in prostate cancer, benign prostate enlargement, incontinence and impotence in older men.

Indications and uses

Well statins are effective in decreasing mortality in those who have had previous cardiovascular disease there is not a mortality benefit in those at high-risk but without prior cardiovascular disease. 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. They have less effect than the fibrates or niacin in reducing triglycerides 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 risk score). 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 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 arteries using intravascular ultrasonography.

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: colon cancer , inflammation, dementia, lung cancer, nuclear cataracts, and hypertension.

Members

Fermentation-derived and synthetic

The statins are divided into two groups: fermentation-derived and synthetic.

The statins include, in alphabetical order (brand names vary in different countries):

Statin	Image	Brand name	Derivation
Atorvastatin		Lipitor, Torvast	Synthetic
Cerivastatin		Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis)	Synthetic
Fluvastatin		Lescol, Lescol XL	Synthetic
Lovastatin		Mevacor, Altocor, Altoprev	Fermentation-derived. Naturally-occurring compound. Found in oyster mushrooms and red yeast rice.
Mevastatin		-	Naturally-occurring compound. Found in red yeast rice.
Pitavastatin		Livalo, Pitava	Synthetic
Pravastatin	File:Pravastatine.png	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
Simvastatin+Niacin extended-release		Simcor	Combination therapy

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. The relative potency of pitavastatin has not yet been fully established.

Naturally-occurring statins

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..

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 placebos. It found that, at commonly prescribed doses, there are no statistically significant differences amongst statins in reducing cardiovascular morbidity and mortality. 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.

Statin equivalence

Statins differ in their ability to reduce cholesterol levels. Doses should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or dose changes, lipid levels should be analyzed within 1–3 months and dosage adjusted accordingly, then every 6–12 months afterwards.

Safety

Adverse effects

Statins are generally perceived as well-tolerated. The most common adverse side effects are raised liver enzymes and muscle problems. In clinical trials, reported adverse effects are low; but "higher in studies of real world use", and more varied. 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.

Some patients on statin therapy report myalgias, muscle cramps, or, less frequently, gastrointestinal or other symptoms. Liver enzyme derangements may also occur, typically in about 0.5%, 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. One Danish study in 2002 suggested a relation between long term statin use and increased risk of nerve damage or polyneuropathy but suggested this side effect is "rare, but it does occur"; 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.

More serious but 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; Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking. A common variation in the SLCO1B1 gene, which participates in the absorption of statins, has been shown to significantly increase the risk of myopathy.

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. 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. 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.

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). 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 fibrates. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention. 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.

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. 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. 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 (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). 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.

A 2008 study showed that carriers of the KIF6 genetic mutation were more responsive to statin treatment.

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. A smaller group of scientists, such as 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 organizations maintain that statins are not as beneficial or safe as suggested.

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External links

• Statin page at Bandolier, an evidence-based medicine journal (little content after 2004)
• Statins at Medpedia, for clinicians, maintained by clinicians

Template:Link GA

• Statins