The statins (or HMG-CoA reductase inhibitors) are a class of drug used to lower plasma cholesterol Cholesterol is a waxy steroid metabolite found in the cell membranes and transported in the blood plasma of all animals. It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile level.

They lower cholesterol by inhibiting the enzyme HMG-CoA reductase HMG-CoA reductase is the rate controlling enzyme (EC 1.1.1.88) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. This enzyme is the target of the widely available cholesterol lowering drugs known collectively as the statins. HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum,, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol Cholesterol is a waxy steroid metabolite found in the cell membranes and transported in the blood plasma of all animals. It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile synthesis. Inhibition of this enzyme in the liver The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion. The liver is necessary for survival; there is currently no way to compensate for the absence of liver function results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors The Low-Density Lipoprotein Receptor is a mosaic protein that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL), resulting in an increased clearance In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics. Clearance is a function of glomerular of low-density lipoprotein LDL-density lipoprotein is one of the five major groups of lipoproteins (chylomicrons, VLDL, IDL, HDL, LDL) that enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream. Medically, estimates of cholesterol content carried by LDL particles are used as part of a cholesterol blood test; direct LDL (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 Tokyo , officially Tokyo Metropolis (東京都, Tōkyō-to?), is one of the 47 prefectures of Japan. It is located on the eastern side of the main island Honshū and includes the Izu Islands and Ogasawara Islands. Tokyo Metropolis was formed in 1943 from the merger of the former Tokyo Prefecture (Tokyo-fu) and the city of Tokyo. Tokyo is the, Japan Japan is an island country in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south. The characters that make up Japan's name mean "sun-origin", which is why Japan is 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 Ergosterol , a sterol, is a biological precursor (a provitamin) to vitamin D2. It is turned into viosterol by ultraviolet light, and is then converted into ergocalciferol, which is a form of vitamin D) or cytoskeleton The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within the cytoplasm and is made out of protein. The cytoskeleton is present in both plant and animal cells. The cytoskeleton was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton. It is a dynamic (isoprenoids The terpenoids , sometimes called isoprenoids, are a large and diverse class of naturally-occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in functional groups but also in their basic carbon).^[2]

The first agent isolated was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum. The pharmaceutical company The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies can deal in generic and/or brand medications. They are subject to a variety of laws and regulations regarding the patenting, testing and marketing of drugs Merck & Co. Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The headquarters of the company is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township. It was established in 1891 as the United States 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 Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the enzyme prevents binding of the substrate and vice versa HMG-CoA reductase HMG-CoA reductase is the rate controlling enzyme (EC 1.1.1.88) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. This enzyme is the target of the widely available cholesterol lowering drugs known collectively as the statins. HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum,, the first committed enzyme Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at significant rates. Since enzymes are selective for their 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 The mevalonate pathway or HMG-CoA reductase pathway or mevalonate-dependent route or isoprenoid pathway, is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria. It is important for the production of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), which serve as the basis for the, 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,^[3] so statins with short half-lives Half-life is the period of time it takes for a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but may apply to any quantity which follows a set-rate decay 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,^[4][5] but have shown no difference in the long-acting atorvastatin.^[6]

Increasing LDL uptake

Liver cells A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass. These cells are involved in: sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors The Low-Density Lipoprotein Receptor is a mosaic protein that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL) to draw cholesterol out of the circulation.^[7] This is accomplished via protease A protease breaks down proteins. A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein. Proteases work best in acidic conditions except alkaline proteases. Its optimal activity is shown in alkaline(basic) enzymes that cleave a protein called "membrane-bound sterol regulatory element binding protein", which migrates to the nucleus In cell biology, the nucleus , also sometimes referred to as the "control center", is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes and causes increased production of various other proteins and enzymes, including the LDL receptor The Low-Density Lipoprotein Receptor is a mosaic protein that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL). The LDL receptor then relocates to the liver cell membrane The cell membrane is one biological membrane separating the interior of a cell from the outside environment and binds to passing LDL LDL-density lipoprotein is one of the five major groups of lipoproteins (chylomicrons, VLDL, IDL, HDL, LDL) that enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream. Medically, estimates of cholesterol content carried by LDL particles are used as part of a cholesterol blood test; direct LDL and VLDL Very-low-density lipoprotein is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density lipoprotein, high-density lipoprotein) that enable fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the 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 Atherosclerosis is a condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by low-density. The ASTEROID trial showed direct ultrasound evidence of atheroma In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells (mostly macrophage cells), or cell debris, that contain lipids (cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous regression during statin therapy.^[8] Researchers hypothesize that statins prevent cardiovascular disease Heart disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system (as used in MeSH C14), it is usually used to refer to those related to atherosclerosis (arterial disease). These conditions have similar causes, via four proposed mechanisms (all subjects of a large body of biomedical research):^[9]

1. Improve endothelial The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary. These cells reduce function
2. Modulate inflammatory Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. Inflammation is not a synonym for infection. Even in cases where inflammation is responses
3. Maintain plaque Atherosclerosis is a condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by low-density stability
4. Prevent thrombus Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss. If the clotting is too severe and the clot breaks free, the traveling clot is now know as an 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 Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the presence of raised or abnormal levels of any or all lipids and/or lipoproteins in the blood. It is the most common form of dyslipidemia (which also includes any decreased lipid levels) or heart disease, but only elevated C-reactive protein C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation (an acute-phase protein). Its physiological role is to bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1Q complex levels. There were also 20% fewer deaths (mainly from reduction in cancer deaths) though deaths from cardiovascular causes were not reduced.^[10]

Statins have been linked to a marked reduction in prostate cancer, benign prostate enlargement, incontinence and impotence in older men.^[11]

Indications and uses

While statins 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 are effective in decreasing mortality in those who have had previous cardiovascular disease Heart disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system (as used in MeSH C14), it is usually used to refer to those related to atherosclerosis (arterial disease). These conditions have similar causes, there is not a mortality benefit in those at high-risk but without prior cardiovascular disease.^[12] Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol Low-density lipoprotein is a type of lipoprotein that transports cholesterol and triglycerides from the liver to peripheral tissues. LDL is one of the five major groups of lipoproteins; these groups include chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein, and high-density (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 A stroke (sometimes called a cerebrovascular accident ) is the rapidly developing loss of brain function(s) due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a hemorrhage (leakage of blood). As a result, the affected area of the brain is.^[13] They have less effect than the fibrates In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents or niacin Niacin is an organic compound with the formula C5H4NCO2H and, depending on the definition used, one of the between forty to eighty essential human nutrients. This colourless, water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B3 include the corresponding amide, nicotinamide (& in reducing triglycerides Triglyceride is an ester composed of a glycerol bound to three fatty acids. It is the main constituent of vegetable oil and animal fats and raising HDL-cholesterol High-density lipoprotein is one of the five major groups of lipoproteins (chylomicrons, VLDL, IDL, LDL, HDL) that enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream. In healthy individuals, about thirty percent of blood cholesterol is carried by HDL ("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 Preventive medicine or preventive care refers to measures taken to prevent diseases, rather than curing them or treating their symptoms. The term contrasts in method with curative and palliative medicine, and in scope with public health methods (which work at the level of population health rather than individual health) for cardiovascular disease, or as primary prevention only when the risk for cardiovascular disease was significantly raised (as indicated by the Framingham risk score Thomas Royle Dawber was Director of the study from 1949 to 1966. He was appointed as chief epidemiologist shortly after the start of the project, when it was not progressing well. The study had been intended to last 20 years, but at that time Dawber moved to Boston and became chairman of preventive medicine, raising funds to continue the project).^[14] 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 Diabetes mellitus —often simply referred to as diabetes—is a condition in which a person has a high blood sugar (glucose) level, either because the body doesn't produce enough insulin, or because body cells don't properly respond to the insulin that is produced. Insulin is a hormone produced in the pancreas which enables body cells to absorb. 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 Coronary circulation is the circulation of blood in the blood vessels of the heart muscle. Although blood fills the chambers of the heart, the muscle tissue of the heart is so thick that it requires coronary blood vessels to deliver blood deep into it. The vessels that deliver oxygen-rich blood to the myocardium are known as coronary arteries. The using intravascular ultrasonography.^[8]

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 ^[15] , inflammation, dementia,^[16] lung cancer,^[17] nuclear cataracts,^[18] and hypertension.^[19]

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):

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.^[20] 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^[21] and red yeast rice. Randomized controlled trials found them to be effective, but the quality of the trials was low.^[22].

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.^[23] 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.^[24]

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. ^{[25] [26] [27] [28]}

Safety

Adverse effects

Statins are generally perceived^[29] 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.^[29] 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.^[30]

Some patients on statin therapy report myalgias,^[31] muscle cramps,^[31] or, less frequently, gastrointestinal or other symptoms. Liver enzyme derangements may also occur, typically in about 0.5%,^{[citation needed]} are also seen at similar rates with placebo use and repeated enzyme testing, and generally return to normal either without discontinuance over time or after briefly discontinuing the drug. Multiple other side-effects occur rarely; typically also at similar rates with only placebo in the large statin safety/efficacy trials. Two randomized clinical trials found cognitive issues while two did not; recurrence upon reintroduction suggests that these are causally related to statins in some individuals.^[32] One Danish study in 2002^[33] suggested a relation between long term statin use and increased risk of nerve damage or polyneuropathy^[34] but suggested this side effect is "rare, but it does occur";^[35] 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.^[36]

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;^[37] Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking.^[38] A common variation in the SLCO1B1 gene, which participates in the absorption of statins, has been shown to significantly increase the risk of myopathy.^[39]

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.^[40] 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.^[41]

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^[42]). 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.^[43] 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.^[44]

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.^[40] 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^[45] (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.^[46]

A 2008 study showed that carriers of the KIF6 genetic mutation were more responsive to statin treatment.^[47]

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.^[48] 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.^[49] In 2010 a meta analysis of studies found no benefit in terms of all-cause mortality when statins were used as a high-risk primary prevention intervention.^[12]

References

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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

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