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 (CVD), and statins are therefore used in the prevention of these diseases. Randomized controlled trials have shown that they are most effective in those already suffering from cardiovascular disease (secondary prevention), but they are also advocated and used extensively in those without previous CVD but with elevated cholesterol levels and other risk factors (such as diabetes and high blood pressure) that increase a person's risk. 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, 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, sold as Vytorin—are also available.

Therapeutic uses

On average, statins can lower LDL cholesterol (so-called "bad 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. They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). There is limited evidence to support the use of statins for primary prevention in people with low cardiovascular risk. Clinical practice guidelines generally recommend that the patient has 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 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. A 2010 Cochrane review highlighted the shortcomings in the published trials and recommended that caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.

Statins are generally accepted as 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, but the evidence for this is questioned. A 2010 meta-analysis of studies found no benefit in terms of all-cause mortality when statins were used as a high-risk primary prevention intervention.

Most of the block-buster branded statins will be generic by 2012,including Lipitor, the largest selling branded drug.

Research continues into other areas where statins also appear to have a favorable effect, including dementia, lung cancer, nuclear cataracts, hypertension., prostate cancer

Available forms

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

Image >Cerivastatin >Pitavastatin >Simvastatin+Ezetimibe

Statin	|	Brand name	Derivation	Metabolism<
Atorvastatin
| center|150px ||	Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis)	Synthetic	various CYP3A isoforms <
Fluvastatin
Lovastatin
Mevastatin
| center|150px ||	Livalo, Pitava	Synthetic
Pravastatin	>center|150px ||	Pravachol, Selektine, Lipostat	Fermentation-derived. (A fermentation product of bacterium ''Nocardia autotrophica'').	Non CYP<
Rosuvastatin
Simvastatin
|		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. 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.

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.

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. {| class=wikitable |- !colspan=7 | 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 || -- |- !colspan=7 | * 80mg dose no longer reccomended due to increased risk for rhabdomyolysis |- !colspan=7 | 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 |}

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. 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 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. A Danish case-control study published 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.

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 there was no evidence of their effectiveness . 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. 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; 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. 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. 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.

Several case-control studies have found that statins reduce cancer incidence, including one 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.

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 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 (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.

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): # 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 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.

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. A 2008 study showed that 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 a SNP in SLCO1B1, a gene encoding for the organic anion transporter peptide OADP1B1.

History

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. 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). 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.

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.

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. 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.

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.

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.

References

External links

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

ca:Estatina cs:Statin de:Statin es:Estatina fr:Statine hr:Statin it:Statina he:סטטין lt:Statinai nl:Statine ja:スタチン no:Statiner pl:Statyny pt:Estatina ru:Статины fi:Statiini sv:Statin th:สแตติน tr:Statinler zh:羟甲戊二酰辅酶A还原酶抑制剂

Coordinates	34°03′″N118°15′″N
Name	Russell L. Blaylock
Birth date	November 15, 1945
Death date
Resting place coordinates
Nationality	American
Education	Doctor of Medicine, fellowship in neurology
Alma mater	LSU School of Medicine, Medical University of South Carolina
Occupation	Neurosurgeon (retired), writer, lecturer
Website	http://www.russellblaylockmd.com/

Russell L. Blaylock, MD is a retired neurosurgeon and author. He is a former clinical assistant professor of neurosurgery at the University of Mississippi Medical Center and is currently a visiting professor in the biology department at Belhaven College. He is the author of a number of books and papers, including ''Excitotoxins: The Taste That Kills'' (1994), ''Health and Nutrition Secrets That Can Save Your Life'' (2002), and ''Natural Strategies for Cancer Patients'' (2003), and writes a monthly newsletter, the ''Blaylock Wellness Report''.

Blaylock has endorsed views inconsistent with the scientific consensus, including that food additives such as aspartame and monosodium glutamate (MSG) are excitotoxic in normal doses and that the H1N1 influenza (swine flu) vaccine carries more risk than swine flu itself.

Education and career

According to his website, Blaylock completed his general surgical internship and neurosurgical residency at the Medical University of South Carolina in Charleston, SC. He was licensed to practice Neurological Surgery in North Carolina between May 6, 1977 and December 15, 2006. Along with Ludwig G. Kempe, Blaylock published a novel transcallosal approach to excising intraventricular meningiomas of the trigone. He is retired as a clinical assistant professor of neurosurgery from the University of Mississippi Medical Center, and is currently a visiting professor in the biology department at Belhaven University, a Christian university in Mississippi. He is associated with the Association of American Physicians and Surgeons and was on the editorial board of their journal.

Allegations of health dangers

Blaylock has been quoted several times in media outlets regarding his position that MSG is toxic to the brain. He also states that the widely-used artificial sweetener aspartame is toxic and may be the cause of multiple sclerosis. He has additionally cautioned against heavy use of the artificial sweetener Splenda (sucralose). These positions are not supported by scientific consensus or regulatory bodies, as extensive studies support the safety of aspartame, sucralose, and MSG.

Blaylock has also urged avoidance of the swine flu (H1N1) vaccination, which he claims is more dangerous than the infection itself. In various alternative media outlets, Blaylock has given advice on what he feels an individual should do if faced with mandatory vaccination. Current research indicates that an effective vaccine is a vital tool in protecting the public and that the new H1N1 vaccine is both safe and effective. Advertisements selling the 'Blaylock Wellness Report' at newsmax.com contain claims of additional health dangers, including fluoridated drinking water, fluoridated toothpaste, vaccines, dental amalgam, cholesterol drugs, pesticides, and aluminum cookware.

Views on politics

Blaylock wrote that the Medical University of South Carolina (where he did his internship) was "deeply embroiled in a leftist-initiated war on Western Culture". He called the American medical system 'collectivist', and blamed this collectivism for the retirement of his friend Miguel Faria. Blaylock wrote that it was around this time that he began "exploring for the first time some of the classics of liberty", including Frédéric Bastiat's ''The Law'', Friedrich Hayek's ''The Road to Serfdom'' and ''The Constitution of Liberty'', and works by Ludwig von Mises, and Murray Rothbard.

Media

Television and radio

Blaylock has appeared on the Christian Broadcasting Network (CBN), including on the network's ''The 700 Club'', a talk show started by televangelist Pat Robertson. Blaylock states that he has also been a guest on over fifty syndicated radio programs.

Books

''Excitotoxins: The Taste That Kills'' Health Press, 1994. ISBN 0929173147

''Health and Nutrition Secrets That Can Save Your Life'' Health Press, 2002. ISBN 0929173422

''Natural Strategies for The Cancer Patient'' New York : Twin Streams, 2003. ISBN 0758202210

Articles

Blaylock is the author or co-author of two case reports in the Journal of Neurosurgery, and a 32-page report entitled ''Multiple Sclerosis'' (Pritchett & Hull, 1988).

He has written for, and been on the editorial board of the journal of the politically conservative non-profit organization Association of American Physicians and Surgeons. This journal was entitled ''Medical Sentinel'' until 2003, when it became the ''Journal of American Physicians and Surgeons'' (JPandS). He also authors ''The Blaylock Wellness Report'' for the conservative website NewsMax.

References

External links

Russell Blaylock's website

Category:Louisiana State University alumni Category:American physicians Category:Neurosurgeons Category:American nutritionists Category:People in alternative medicine Category:1945 births Category:Living people Category:Place of birth missing (living people)