Lovastatin, the first statin to be marketed

The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic drugs used to lower cholesterol levels in people with or at risk of cardiovascular disease. 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 stimulates LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks. Lovastatin, a statin drug drawn in bkchem and GIMP by Mykhal. ... Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. ... Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. ... Cholesterol is a sterol (a combination steroid and alcohol). ... Cardiovascular disease refers to the class of diseases that involve the heart or blood vessels (arteries and veins). ... HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) is the first enzyme (EC 1. ... The rate-determining step is a chemistry term for the slowest step in a chemical reaction. ... Cholesterol is a sterol (a combination steroid and alcohol). ... The liver is the largest internal organ in the human body, and is an organ present in vertebrates and some other animals. ... Brown and Goldstein won a Nobel Prize for their identification of the Low Density Lipoprotein (LDL) receptor 30 years ago whilst they were studying the disease familiar hypercholesterolaemia. ... In medicine, the clearance, also renal clearance or renal plasma clearance (when referring to the function of the kidney), of a substance is the inverse of the time constant that describes its removal rate from the body divided by its volume of distribution (or total body water). ... Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying somewhat in their size and contents, which carry cholesterol in the blood and around the body, for use by various cells. ...

History

See also: Statin development

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).^[1] The discovery of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, called statins, was a breaktrough in the prevention of hypercholesterolemia and related diseases. ... Dr. Endo Dr Akira Endo (born 14 November 1933) is a Japanese biochemist whose work on fungi and cholesterol led to the development of the highly successful class of statin drugs. ... For other uses, see Tokyo (disambiguation). ... Year 1971 (MCMLXXI) was a common year starting on Friday (link will display full calendar) of the 1971 Gregorian calendar, known as the year of cyclohexanol. ... Mevalonic acid is a key organic compound in biochemistry. ... Ergosterol (ergosta-5,7,22-trien-3β-ol), a sterol, is the biological precursor to Vitamin D2. ... The eukaryotic cytoskeleton. ... The terpenoids, sometimes referred to as isoprenoids, are a class of naturally occurring chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. ...

The first agent isolated was mevastatin (ML-236B), a molecule produced by 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 mold Aspergillus terreus. Dr Endo was awarded the 2006 Japan Prize for his work on the development of statins. Mevastatin molecular structure Mevastatin, compactin, ML-236B is a hypolipidemic agent that belongs to the statins class. ... A pharmaceutical company, or drug company, is a commercial business whose focus is to research, develop, market and/or distribute drugs, most commonly in the context of healthcare. ... Merck & Co. ... Year 1976 Pick up sticks(MCMLXXVI) was a leap year starting on Thursday (link will display full calendar) of the Gregorian calendar. ... Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. ... Aspergillus terreus is a fungus, noteworthy for its refractoriness to amphotericin B therapy [1]. It was also the initial source for the drug mevinolin (lovastatin), a drug for lowering serum cholesterol. ... The Japan Prize is awarded to people from all parts of the world whose original and outstanding achievements in science and technology are recognized as having advanced the frontiers of knowledge and served the cause of peace and prosperity for mankind. ...

Indications and uses

Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (so-called "bad cholesterol") by 30–50%.^[2] However, 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. Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying somewhat in their size and contents, which carry cholesterol in the blood and around the body, for use by various cells. ... Clofibrate Clofibride Etofibrate Aluminium clofibrate In pharmacology, the fibrates are a class of amphipathic carboxylic acids. ... Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitamin whose derivatives such as NADH, NAD, NAD+, and NADP play essential roles in energy metabolism in the living cell and DNA repair. ... {{refimprove|date=October 2007} Ausra yra maza mergaite. ... High density lipoproteins (HDL) form a class of lipoproteins, varying somewhat in their size and contents, that carry cholesterol from the bodys tissues to the liver. ...

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).^[3] 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.^[4] The Scandinavian Simvastatin Survival Study (also known under the abbreviation 4S) is a multicenter clinical trial that was performed in 1990s in Scandinavia. ... In medicine, prevention is any effort to avoid the development of a disease or condition (primary prevention), to avoid its recurrence (secondary prevention) or to avoid its worsening or complications (tertiary prevention). ... The Framingham Heart Study is a cardiovascular study based in Framingham, Massachusetts. ... The Heart Protection Study is a large randomized controlled trial by the Medical Research Council (MRC) in the United Kingdom. ... For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. ... The ASTEROID trial was a clinical trial published in 2006 that shows the effects of statins (drugs that inhibit the enzyme HMG-CoA reductase) on atherosclerosis. ... The coronary circulation consists of the blood vessels that supply blood to, and remove blood from, the heart. ... Intravascular ultrasound (IVUS) is an medical imaging methodology using (a) specially designed long thin complex manufactured catheters attached to (b) computerized ultrasound equipment. ...

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. The National Cholesterol Education Program is a program managed by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. ... Coronary heart disease (CHD), also called coronary artery disease (CAD), ischaemic heart disease, atherosclerotic heart disease, is the end result of the accumulation of atheromatous plaques within the walls of the arteries that supply the myocardium (the muscle of the heart) with oxygen and nutrients. ... Heart attack redirects here. ... For other uses, see Stroke (disambiguation). ... In medicine (vascular surgery), Peripheral artery occlusive disease (PAOD) is a collator for all disease caused by the obstruction of large peripheral arteries, which can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or thrombus formation. ...

Research continues into other areas where statins also appear to have a favorable effect: inflammation, dementia,^[5] cancer,^[6] nuclear cataracts,^[7] and pulmonary hypertension.^{[citation needed]} An abscess on the skin, showing the redness and swelling characteristic of inflammation. ... For other uses, see Dementia (disambiguation). ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... Cataract is also used to mean a waterfall or where the flow of a river changes dramatically. ... In medicine, pulmonary hypertension (PH) is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion. ...

Members

The statins are divided into two groups: fermentation-derived and synthetic. For other uses, see Fermentation. ... In chemistry, chemical synthesis is purposeful execution of chemical reactions in order to get a product, or several products. ...

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.^[8] The relative potency of pitavastatin has not yet been fully established. Atorvastatin (INN) (IPA: ) is a member of the drug class known as statins, used for lowering cholesterol and thereby reducing cardiovascular disease. ... In pharmacology, cerivastatin (Baycol®, Lipobay®) is a synthetic member of the class of statins, used to lower cholesterol and prevent cardiovascular disease. ... An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted, negative consequences associated with the use of given medications. ... Fluvastatin (Lescol®, Canef®) is a member of the drug class of statins, used to treat hypercholesterolemia and to prevent cardiovascular disease. ... Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. ... Mevastatin molecular structure Mevastatin, compactin, ML-236B is a hypolipidemic agent that belongs to the statins class. ... Binomial name Monascus purpureus (Went, 1895) Monascus purpureus (syn. ... Pitavastatin (usually as a calcium salt) is a novel member of the medication class of statins[1]. Like the other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis. ... Pravastatin (marketed as Pravachol or Selektine) is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. ... Rosuvastatin is a member of the drug class of statins, used to treat hypercholesterolemia and related conditions, and to prevent cardiovascular disease. ... Simvastatin (INN) (IPA: ) is a hypolipidemic drug belonging to the class of pharmaceuticals called statins. It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease. ... Simvastatin (INN) (IPA: ) is a hypolipidemic drug belonging to the class of pharmaceuticals called statins. It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease. ... Ezetimibe (IPA: ) is an anti-hyperlipidemic medication which is used to lower cholesterol levels. ... Vytorin is a drug that combines Ezetimibe (eh-ZET-eh-mib) and Simvastatin (SIM-va-stat-in) and is used to treat high cholesterol. ... Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. ... Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitamin whose derivatives such as NADH, NAD, NAD+, and NADP play essential roles in energy metabolism in the living cell and DNA repair. ... Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. ... Atorvastatin (INN) (IPA: ) is a member of the drug class known as statins, used for lowering cholesterol and thereby reducing cardiovascular disease. ... Amlodipine (as besylate or malleate) is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina. ... Caduet is a medication approved by the US FDA for the treatment of high cholesterol and high blood pressure. ... Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. ...

Comparative effectiveness

No large scale comparison exists that examines the effectiveness of the various statins against one another.

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 in reducing cardiovascular morbidity and mortality.^[9] For other uses, see Placebo (disambiguation). ... In statistics, a result is significant if it is unlikely to have occurred by chance, given that a presumed null hypothesis is true. ...

Safety

Adverse effects

While some patients on statin therapy report myalgias, muscle cramps, or far less-frequent gastrointestinal or other symptoms, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose. 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. Myalgia means muscle pain and is a symptom of many diseases and disorders. ... This article is about muscular pain. ... Liver function tests (LFTs or LFs), are groups of clinical biochemistry laboratory blood assays designed to give a doctor or other health professional information about the state of a patients liver. ...

A clearer major safety concern, myositis, myopathy, rarely with rhabdomyolysis (the pathological breakdown of skeletal muscle) may lead to acute renal failure when muscle breakdown products damage the kidney. Coenzyme Q10 (ubiquinone) levels are decreased in statin use;^[10] Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking.^[11] In medicine, a myopathy is a neuromuscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. ... Rhabdomyolysis is the rapid breakdown of skeletal muscle tissue due to traumatic injury, either mechanical, physical or chemical. ... A top-down view of skeletal muscle Skeletal muscle is a type of striated muscle, usually attached to the skeleton. ... Coenzyme Q (CoQ), also known as ubiquinone or ubiquinol, is a biologically active quinone with an isoprenoid side chain, related in structure to vitamin K and vitamin E. The oxidized structure of CoQ, or Q, is given here: The various kinds of Coenzyme Q can be distinguished by the number...

One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop rhabdomyolysis. Cerivastatin, which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x).^[12] 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.^[13] Year 2004 (MMIV) was a leap year starting on Thursday of the Gregorian calendar. ... In pharmacology, cerivastatin (Baycol®, Lipobay®) is a synthetic member of the class of statins, used to lower cholesterol and prevent cardiovascular disease. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... Efficacy is the ability to produce a desired amount of a desired effect. ... Pravastatin (marketed as Pravachol or Selektine) is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. ... Fluvastatin (Lescol®, Canef®) is a member of the drug class of statins, used to treat hypercholesterolemia and to prevent cardiovascular disease. ... Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. ...

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^[14]). 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.^[15] 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.^[16] Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... The Heart Protection Study is a large randomized controlled trial by the Medical Research Council (MRC) in the United Kingdom. ... A meta-analysis is a statistical practice of combining the results of a number of studies. ... Colorectal cancer, also called colon cancer or bowel cancer, includes cancerous growths in the colon, rectum and appendix. ... Clofibrate Clofibride Etofibrate Aluminium clofibrate In pharmacology, the fibrates are a class of amphipathic carboxylic acids. ... The number needed to treat (NNT) is an epidemiological measure that indicates how many patients would require treatment with a form of medication to reduce the expected number of cases of a defined endpoint by one. ...

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.^[12] 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. Clofibrate Clofibride Etofibrate Aluminium clofibrate In pharmacology, the fibrates are a class of amphipathic carboxylic acids. ... Rhabdomyolysis is the rapid breakdown of skeletal muscle tissue due to traumatic injury, either mechanical, physical or chemical. ... Creatine Kinase Creatine kinase (CK), also known as phosphocreatine kinase or creatine phosphokinase (CPK) is an enzyme (EC 2. ... In medicine (nephrology) renal function is an indication of the state of the kidney and its role in physiology. ...

Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins—furanocoumarins in grapefruit juice inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however it is a major inhibitor of only atorvastatin, lovastatin and simvastatin) and some other medications^[17] (it had been thought that flavonoids 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. Binomial name Macfad. ... Grapefruit juice is the fruit juice coming from grapefruits. ... Furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. ... Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ... Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ... Molecular structure of the flavone backbone (2-phenyl-1,4-benzopyrone) The term flavonoid refers to a class of plant secondary metabolites. ...

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.^[18] A Single Nucleotide Polymorphism or SNP (pronounced snip) is a DNA sequence variation, occurring when a single nucleotide: adenine (A), thymine (T), cytosine (C) or guanine (G) - in the genome is altered. ... HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) is the first enzyme (EC 1. ...

Mode of action

Cholesterol lowering

The HMG-CoA reductase pathway

Main articles: Cholesterol and Lipoprotein

Most circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, via steroid biosynthesis through the HMG-CoA reductase pathway. Cholesterol, both from dietary intake and secreted into the duodenum as bile from the liver, is typically absorbed at a rate of 50% by the small intestines. The typical diet in the United States and many other Western countries is estimated as adding about 200–300 mg/day to intestinal intake, an amount much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor. Download high resolution version (534x695, 17 KB) HMG-CoA reductase pathway ( cholesterol) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... Download high resolution version (534x695, 17 KB) HMG-CoA reductase pathway ( cholesterol) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... Cholesterol is a sterol (a combination steroid and alcohol). ... A lipoprotein is a biochemical assembly that contains both proteins and lipids. ... Simplified version of latter part of steroid synthesis pathway, where the intermediates isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) form geranyl pyrophosphate (GPP), squalene and, finally, lanosterol, the first steroid in the pathways. ... The HMG-CoA reductase pathway, also known as MVA pathway or mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in virtually all organisms. ... In anatomy of the digestive system, the duodenum is a hollow jointed tube about 25-30 cm long connecting the stomach to the jejunum. ... Bile (or gall) is a bitter, yellow or green alkaline fluid secreted by hepatocytes from the liver of most vertebrates. ... In biology the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine and includes the duodenum, jejunum, and ileum. ...

Cholesterol is not water-soluble, and is therefore carried in the blood in the form of lipoproteins, the type being determined by the apoprotein, a protein coating that acts as an emulsifier. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, and insulin resistance. Low density lipoprotein (LDL) and very low density lipoprotein (VLDL) carry cholesterol toward tissues, and elevated levels of these lipoproteins are associated with atheroma formation (fat-containing deposits in the arterial wall) and cardiovascular disease. High density lipoprotein, in contrast, carries cholesterol back to the liver and is associated with protection against cardiovascular disease. A lipoprotein is a biochemical assembly that contains both proteins and lipids. ... An apoprotein is a protein without its characteristic prosthetic group. ... An emulsion is a mixture of two immiscible substances. ... Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. ... Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. ... Very Low Density Lipoprotein (VLDL) is a lipoprotein subclass. ... In pathology, an atheroma (plural: atheromata) is an accumulation and swelling (-oma) in artery walls that is made up of cells, or cell debris, that contain lipids (cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue. ... Cardiovascular disease refers to the class of diseases that involve the heart or blood vessels (arteries and veins). ... High-density lipoproteins (HDL) form a class of lipoproteins, varying somewhat in their size (8–11 nm in diameter), that carry cholesterol from the bodys tissues to the liver. ...

Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, they cause liver cells to make more LDL receptors, leading to increased clearance of low-density lipoprotein from the bloodstream.^[19] In biochemistry there are three ways in which certain chemical substances may reduce or prevent the activities of enzymes: competitive, non-competitive and uncompetitive inhibition. ... HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) is the first enzyme (EC 1. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... The HMG-CoA reductase pathway, also known as MVA pathway or mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in virtually all organisms. ... Sinusoid of a rat liver with fenestrated endothelial cells. ... Brown and Goldstein won a Nobel Prize for their identification of the Low Density Lipoprotein (LDL) receptor 30 years ago whilst they were studying the disease familiar hypercholesterolaemia. ...

Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the ASTEROID trial, which demonstrated regression of atheroma employing intravascular ultrasound.^[4] The ASTEROID trial was a clinical trial published in 2006 that shows the effects of statins (drugs that inhibit the enzyme HMG-CoA reductase) on atherosclerosis. ... In pathology, an atheroma (plural: atheromata) is an accumulation and swelling (-oma) in artery walls that is made up of cells, or cell debris, that contain lipids (cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue. ... Intravascular ultrasound (IVUS) is an medical imaging methodology using (a) specially designed long thin complex manufactured catheters attached to (b) computerized ultrasound equipment. ...

Non-cholesterol related actions

Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):^[20] Cardiovascular disease refers to the class of diseases that involve the heart or blood vessels (arteries and veins). ...

1. Improving endothelial function
2. Modulate inflammatory responses
3. Maintain plaque stability
4. Prevent thrombus formation

The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ... An abscess on the skin, showing the redness and swelling characteristic of inflammation. ... Atherosclerosis is a disease affecting arterial blood vessels. ... Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ...

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.^[21] A much smaller minority, exemplified by 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 groups claim that statins are not as beneficial or safe as suggested.^[22] A recent clinical trial found that incremental reductions in levels of LDL cholesterol achieved by adding ezetimibe, a cholesterol-absorption inhibitor, to statin treatment does not produce measurable medical benefits. This supports the argument that lowering cholesterol is not the key to preventing heart attacks.^[23] The International Network of Cholesterol Skeptics (or THINCS) is a group of scientists, physicians, and other academicians from around the world who oppose regarding the lipid hypothesis as proven fact. ... The lipid hypothesis was one of two hypotheses developed in the 1850s to explain the pathogenesis of atherosclerosis. ...

References

is the 200th day of the year (201st in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... PubMed Central grew from the online Entrez PubMed biomedical literature search system. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... PubMed Central grew from the online Entrez PubMed biomedical literature search system. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ...

External links

• Statin page at Bandolier, an evidence-based medicine journal