Lovastatin, a compound isolated from Aspergillus terreus, was the first statin to be marketed.
|Biological target||HMG-CoA reductase|
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, and statins are therefore used in the prevention of these diseases. Research has found that statins are most effective for treating cardiovascular disease (CVD) (secondary prevention), with questionable benefit in those without previous CVD, but with elevated cholesterol levels. Statins have rare but severe adverse effects, particularly muscle damage, and some doctors believe they are overprescribed.
The best-selling statin is atorvastatin, marketed as Lipitor (manufactured by Pfizer) and Torvast. By 2003, atorvastatin became the best-selling pharmaceutical in history, with Pfizer reporting sales of US$12.4 billion in 2008. 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). Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available.
Medical uses 
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.
Primary prevention 
There is debate over whether or not statins are effective in those with high cholesterol, but no history of heart disease. The best meta-analysis (with individual patient data) did not find a mortality benefit in those at high risk but without prior cardiovascular disease. Other reviews concluded there is a mortality and morbidity benefit, but there were concerns regarding the quality of the evidence. With respect to quality of life, evidence of improvement is limited when statins are used for primary prevention. No studies as of 2010 show improved clinical outcomes in children with high cholesterol though statins decrease cholesterol levels.
Secondary prevention 
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. 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. 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.
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.
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."  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.
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. The beneficial effects of statins are suggested to be due to their working as vitamin D analogues.
Adverse effects 
|Choosing a statin for people with special considerations|
|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.|
|HIV-positive people taking protease inhibitors||Atorvastatin, Pravastatin or Fluvastatin||Significant negative interactions are more likely with other choices|
|persons taking gemfibrozil, a non-statin cholesterol-lowering drug||Atorvastatin||Combining gemfibrozil and a statin increases risk of Rhabdomyolysis and subsequently renal failure|
|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.|
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. 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. 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. Other possible adverse effects include cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction.
Some patients on statin therapy report myalgias, muscle cramps, or, less frequently, gastrointestinal or other symptoms. Liver enzyme derangements, 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 these are causally related to statins in some individuals. A Danish case-control study published in 2002 suggested a relationship 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.
Myositis and myopathy 
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; 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]. 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.
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. 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. 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; 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. Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.
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. 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.
Several case-control studies have found statins reduce cancer incidence, including one 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.
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. 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. 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 (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.
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.
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 
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. 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):
- 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.
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
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. A 2008 study showed carriers of the KIF6 genetic mutation were more responsive to statin treatment.
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.
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. 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). 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. 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.
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.
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%. In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008.
Available forms 
|Cerivastatin||Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis)||Synthetic||various CYP3A isoforms |
|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|
|Pravastatin||Pravachol, Selektine, Lipostat||Fermentation-derived. (A fermentation product of bacterium Nocardia autotrophica).||Non CYP|
|Rosuvastatin||Crestor||Synthetic||CYP2C9 and CYP2C19|
|Simvastatin||Zocor, Lipex||Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product ofAspergillus terreus.)||CYP3A4|
|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. The relative potency of pitavastatin has not yet been fully established.
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. 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||--|
|* 80-mg dose no longer recommended due to increased risk of rhabdomyolysis|
|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 continues into other areas where specific statins also appear to have a favorable effect, including dementia, lung cancer, nuclear cataracts, hypertension, and prostate cancer.
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