Statins , also known as HMG-CoA reductase inhibitor , is a class of lipid-lowering drugs. Statins have been found to reduce cardiovascular disease (CVD) and death in those at high risk of cardiovascular disease. Strong evidence that statins are effective for treating CVD in the early stages of disease (secondary prevention) and in those at high risk but without CVD (primary prevention).
Statin side effects include muscle pain, increased risk of diabetes mellitus, and abnormalities in liver enzyme tests. In addition, they have rare but severe side effects, especially muscle damage. They inhibit the HMG-CoA reductase enzyme that plays a central role in the production of cholesterol. High cholesterol levels have been linked to cardiovascular disease (CVD).
In 2010, some statins are on the market: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Some combination preparations of statins and other agents, such as ezetimibe/simvastatin, are also available. In 2005, sales were estimated at US $ 18.7 billion, in the United States. The best-selling statin is atorvastatin, also known as Lipitor, which in 2003 became the best-selling drug in history. The Pfizer manufacturer reported US $ 12.4 million in sales in 2008. Due to patent expiration, some statins became available in 2016 as a cheaper generic drug.
Video Statin
Medical use
Clinical practice guidelines generally recommend people try "lifestyle modifications", including cholesterol-lowering and physical exercise, prior to statin use. Statins or other pharmacological agents can be recommended for those who do not meet their lipid-lowering goals through diet and lifestyle changes. Statins seem to work well in men and women.
Primary prevention
By 2016, the United States Prevention Task Force recommends statins for those who have at least one risk factor for coronary heart disease, aged between 40 and 75 years, and have at least 10% 10-year risk of heart disease. Risk factors for coronary heart disease include abnormal lipid levels in the blood, diabetes mellitus, high blood pressure, and smoking. The risk of heart disease is estimated using the Pooled/AHA Cohort equation. They recommend the selective use of low to moderate doses of statins in the same adult who have 10 years of CVD incidence at 7.5-10% or greater.
Most evidence suggests that statins are effective in preventing heart disease in those with high cholesterol, but no history of heart disease. The 2013 Cochrane Review found a decrease in the risk of death and other adverse outcomes without hazard proof. For every 138 people treated for 5 years one died less and for every 49 treated one fewer had episodes of heart disease. The 2011 review reached a similar conclusion. And the 2012 review found good benefits in women and men. A 2010 review concluded that treating people with no history of cardiovascular disease may reduce cardiovascular events in men but not women, and do not provide death benefits in both sexes. Two other meta-analyzes published that year, one of which used data exclusively obtained from women, found no mortality benefit in primary prevention.
The National Institute for Health and Clinical Excellence (NICE) recommends statin treatment for adults with an estimated 10-year risk of developing cardiovascular disease greater than 10%. Guidelines by the American College of Cardiology and the American Heart Association recommend statin treatment for primary prevention of cardiovascular disease in adults with LDL cholesterol> = 190 mg/dL or those with diabetes, age 40-75 with LDL-C 70-190 mg/dl; or in those with a 10-year risk of a heart attack or stroke of 7.5% or more. In this latter group, statin assignment is not automatic, but it is recommended to be performed only after discussion of physician-patient risk by joint decision making where other risk and lifestyle factors are addressed, the potential benefits of statins are weighed against potential side effects or drug interactions and preferences the informed patient is infected. In addition, if risk decisions are uncertain, factors such as family history, coronary calcium score, ankle-brachial index, and inflammatory test (hs-CRP> = 2.0 mg/L) are advised to inform risk decisions. Additional factors that can be used are LDL-C> = 160 or a very high lifetime risk. However, critics such as Steven E. Nissen said that the AHA/ACC guidelines were not properly validated, exaggerating the risk by at least 50%, and recommending statins for patients who would not benefit, based on populations at lower-than-expected risk. by guidance. The European Society of Cardiology and the European Atherosclerosis Society recommend the use of statins for primary prevention, depending on the expected early cardiovascular scores and LDL thresholds.
Secondary Prevention
Statins are effective in reducing mortality in people with pre-existing CVD. They are also recommended for use in people at high risk for coronary heart disease. On average, statins can lower LDL cholesterol by 1.8 mmol/l (70 mg/dl), which translates to about 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduction in Stroke risk after long treatment long. They have less effect than fibrate or niacin in reducing triglycerides and increasing HDL-cholesterol ("good cholesterol").
Statins have been studied to improve surgical results in cardiac and vascular surgery. Mortality and adverse cardiovascular events are reduced in the statin group.
Comparative effectiveness
Although there is no direct comparison, all statins appear to be effective regardless of the potential or level of cholesterol reduction. There seems to be some difference between them, with simvastatin and pravastatin appearing superior in terms of side effects.
Comparisons of simvastatin, pravastatin, and atorvastatin, based on their effectiveness against placebo, were found, at the usual dose prescribed, there was no difference between statins in reducing cardiovascular morbidity and mortality, and lipids.
Children
In children statins are effective for lowering cholesterol levels in those with familial hypercholesterolaemia. However, their long-term security is unclear. Some recommend that if lifestyle changes are not enough statins should start at 8 years of age.
Familial hypercholesterolemia
Statins may be less effective in reducing LDL cholesterol in people with familial hypercholesterolaemia, especially those with homozygous deficiency. These people have defects usually either in LDL receptors or apolipoprotein B genes, both of which are responsible for clearing LDL from the blood. Statins remain the first-line treatment of familial hypercholesterolaemia, although other cholesterol-lowering measures may be necessary. In people with homozygous deficiency, statins may still prove useful, albeit at high doses and in combination with other cholesterol-lowering drugs.
Contrast induced nephropathy
A 2014 meta-analysis found that statins may reduce the risk of contraction-induced nephropathy by 53% in people undergoing coronary angiography/percutaneous intervention. The effect was found to be stronger among those with existing renal dysfunction or diabetes mellitus.
Maps Statin
Adverse effects
The most important side effects are muscle problems, increased risk of diabetes mellitus, and elevated liver enzymes in the blood due to liver damage. Over 5 years of statin treatment resulted in 75 cases of diabetes, 7.5 cases of bleeding strokes, and 5 cases of muscle damage per 10,000 people treated. This may be because, as statins inhibit the enzyme (HMG-CoA reductase) that makes cholesterol, statins also inhibit other processes of this enzyme, such as CoQ 10 production, and CoQ 10 production is important for muscle cells and blood sugar regulation.
Other possible side effects include neuropathy, pancreas and liver dysfunction, and sexual dysfunction. The rate at which such events occur has been widely debated, in part because the statin risk/benefit ratio in low-risk populations is highly dependent on the extent of adverse events. A Cochrane meta-analysis of statin clinical trials in primary prevention found no evidence of excessive side effects among those treated with statins compared with placebo. Other meta-analyzes found a 39% increase in adverse events in statin-treated individuals relative to those receiving placebo, but no serious adverse events. The authors of one study argue that side effects are more common in clinical practice than in randomized clinical trials. A systematic review concluded that while meta-analysis of clinical trials underestimated the degree of muscle pain associated with statin use, the rate of rhabdomyolysis was still "low assured" and similar to that seen in clinical trials (about 1-2 per 10,000 person years). A systematic review co-authored by Ben Goldacre concluded that only a small proportion of the adverse events reported by people in statins are actually caused by statins.
Cognitive effects
There are reports of cognitive decline with statins. In 2012, in recognition of the increase in reports and rising concerns over the relationship between statins and memory loss (including interim global amnesia reports), forgetfulness and confusion, the Food and Drug Administration (FDA) is added to the label required on statin drug warnings about possible impacts cognitive. The effect is described as rare, not serious, and reversible after discontinuation of treatment.
Several systematic reviews and meta-analyzes have concluded that the available evidence does not support the association between statin use and cognitive impairment.
Muscle
In observational studies 10-15% of people taking statins had muscle problems; in most cases it consists of muscle pain. This number, which is much higher than seen in randomized clinical trials, has become a topic of widespread debate and discussion.
Rare reactions include myopathies such as myositis (inflammation of the muscle) or even rhabdomyolysis (destruction of muscle cells), which in turn can lead to life-threatening kidney injury. The risk of statin-induced rhabdomyolysis increases with older age, the use of interacting drugs such as fibrates, and hypothyroidism. The level of coenzyme Q10 (ubiquinone) decreases in the use of statins; CoQ10 supplements are sometimes used to treat statin-related myopathy, although evidence of its efficacy is lacking in 2007. The SLCO1B1 gene ( Organic anion transport code of 1B1 family members ) for transport of polypeptide organic anions involved in statin absorption settings. A common variation in this gene was found in 2008 to significantly increase the risk of myopathy.
Note there were more than 250,000 people treated from 1998 to 2001 with atorvastatin static drugs, 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 risks are more than 10-fold when using serivastatin, or if standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) are combined with fibrate treatment (fenofibrate or gemfibrozil). Cerivastatin was withdrawn by its manufacturer in 2001.
Some researchers have suggested hydrophilic statins, such as fluvastatin, rosuvastatin, and pravastatin, less toxic than lipophilic statins, such as atorvastatin, lovastatin, and simvastatin, but other studies have not found a relationship. Lovastatin induces the expression of the atrogin-1 gene, which is believed to be responsible for promoting damage to muscle fibers. Tendon rupture does not seem to happen. Diabetes
The association between statin use and the risk of developing diabetes remains unclear and results of systematic review and meta-analysis are mixed. Higher doses have a greater effect, but the decrease in cardiovascular disease is greater than the risk of developing diabetes. Use in postmenopausal women is associated with an increased risk of diabetes. The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with the use of statins is unclear. Statins are thought to reduce the absorption of glucose from the bloodstream in response to the hormone insulin. One way that is thought to occur is to disrupt the cholesterol synthesis required for the production of certain proteins that are responsible for the uptake of glucose into cells such as GLUT1.
Cancer
Some meta-analyzes did not find an increased risk of cancer, and some meta-analyzes have found reduced risk.
Statins can reduce the risk of esophageal cancer, colorectal cancer, gastric cancer, liver cancer, and possibly prostate cancer. They appear to have no effect on the risk of lung cancer, kidney cancer, breast cancer, pancreatic cancer, or bladder cancer.
Drug interactions
Combining statins with fibrate or niacin (another category of lipid-lowering drugs) increases the risk of rhabdomyolysis to nearly 6.0 per 10,000 person-years. Liver enzyme monitoring and creatine kinase are very prudent in those who use high-dose statins or in those who use statin/fibrate combinations, and are obliged in cases of muscle cramps or impaired renal function.
Consumption of grapefruit or grapefruit juice inhibits certain statin metabolism. Bitter oranges can have the same effect. Furanocoumarin in grapefruit juice (ie, bergamottin and dihydroxybergamottin) inhibits the cytochrome P450 CYP3A4 enzyme, which is involved in the metabolism of most statins (however, it is the only major inhibitor of lovastatin, simvastatin, and to a lesser extent, atorvastatin) and some other drugs (flavonoids ie naringin) is considered responsible). It increases statin levels, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Absolute prohibition of grapefruit juice consumption for users of some controversial statins.
The FDA notifies health care professionals about updates to information governing the interaction between protease inhibitors and certain statin drugs. Unified protease inhibitors and statins can increase statin levels in the blood and increase the risk of muscle injury (myopathy). The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and cause kidney failure, which can be fatal.
Action mechanism
Statins act by inhibiting HMG-CoA reductase in a competitive, mevalonate-rate limiting enzyme. Because statins are similar in HMG-CoA structures at the molecular level, they will enter the enzyme's active site and compete with the original substrate (HMG-CoA). This competition reduces the rate at which HMG-CoA reductase is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol. Various natural statins are produced by Penicillium and Aspergillus fungus as secondary metabolites. This natural statin may serve to inhibit the HMG-CoA reductase enzyme in bacteria and fungi that compete with manufacturers.
Inhibits cholesterol synthesis
By inhibiting HMG-CoA reductase, statins block the pathway to synthesize cholesterol in the liver. This is important because most circulating cholesterol comes from internal manufacturing rather than diet. When the liver can no longer produce cholesterol, cholesterol levels in the blood will go down. Cholesterol synthesis seems to occur mostly at night, so statin with a short half-life is usually taken at night to maximize its effect. Studies have shown greater LDL and total cholesterol reduction in simvastatin short-acting taken at night than in the morning, but showed no difference in long-acting atorvastatin.
Increases LDL uptake
In rabbits, liver cells feel a decrease in liver cholesterol levels and try to compensate by synthesizing LDL receptors to pull cholesterol out of the circulation. This is done through a protease that divides the bound protein binding protein of the bound sterol, which then migrates to the nucleus and binds to the sterol response element. The sterol response elements then facilitate increased transcription of various other proteins, in particular, LDL receptors. LDL receptors are transported to the liver cell membrane and bind through LDL and VLDL particles (everyday language, "bad cholesterol"), mediate their absorption to the liver, where cholesterol is reprocessed into bile salts and other byproducts. This results in the net effect of less LDL circulating in the blood.
Decreased protein specific prenilation
Statins, by inhibiting the HMG CoA reductase pathway, simultaneously inhibit the production of cholesterol and specific prenylation proteins (see diagram). The inhibitory effect on this protein prenilation may be involved, at least in part, in the improvement of endothelial function, immune modulation. function and other pleiotropic cardiovascular benefits of statins, as well as the fact that a number of other drugs that lower LDL have not shown the same cardiovascular risk benefits in the study as statins, and may also explain certain benefits seen in cancer. reduction with statins. In addition, the inhibitory effect on protein prenylation may also be involved in a number of unwanted side effects associated with statins, including muscle pain (myopathy) and increased blood sugar (diabetes).
Other effects
As noted above, statins show action beyond lipid-lowering activity in the prevention of atherosclerosis. ASTEROID trials show evidence of ultrasound directly from atheroma regression during statin therapy. Researchers hypothesize that statins prevent cardiovascular disease through four proposed mechanisms (all subjects from large biomedical research bodies):
- Increase endothelial function
- Modify the inflammatory response
- Maintaining placard stability
- Prevents the formation of blood clots
In 2008, the JUPITER study showed benefits in those without a history of high cholesterol or heart disease, but only increased levels of C-reactive protein. The conclusions of this study, however, are controversial.
Click on the genes, proteins and metabolites below to link to each article.
Available form
Statins are divided into two groups: fermentation-derived and synthetic. They include, along with brand names, which may vary among countries:
The potential for lowering LDL varies between agents. Cerivastatin is the most potent, (withdrawn from the market in August, 2001 due to the risk of serious rhabdomyolysis) followed by (in order to reduce its potential), rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potential of pitavastatin has not been fully established.
Some types of statins are naturally occurring, and can be found in foods such as oyster mushrooms and red yeast rice. Randomized controlled trials have found these ingredients to reduce circulating cholesterol, but the quality of trials has been underestimated. Due to patent expiry periods, most of the block-buster-branded statins have been common since 2012, including atorvastatin, the best-selling branded drug.
Histori
In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, began looking for cholesterol-lowering drugs. Studies have shown that most cholesterol is produced by the body in the liver, using the HMG-CoA reductase enzyme. Endo and his team argue that certain microorganisms can produce enzyme inhibitors to defend themselves against other organisms, because mevalonate is the precursor of many substances needed 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 mentioned the antifungal properties, without mentioning the inhibition of HMG-CoA reductase.
Mevastatin has never been marketed, because of its adverse effects from tumors, muscle damage, and sometimes deaths in laboratory dogs. P. Roy Vagelos, chief scientist and then CEO of Merck & amp; Co., interested, and made several trips to Japan starting in 1975. In 1978, Merck isolated lovastatin (mevinolin, MK803) from the Aspergillus terreus fungus, first marketed in 1987 as Mevacor.
The association between cholesterol and cardiovascular disease, known as the lipid hypothesis, has been suggested. Cholesterol is a major constituent of atheroma, a fatty lump in the artery wall that occurs in atherosclerosis and, when ruptured, causes most heart attacks. Treatment consists primarily of dietary measures, such as low-fat diets, and less-tolerated drugs, such as clofibrate, cholestyramine, and nicotinic acid. Cholesterol researcher Daniel Steinberg writes that while the 1984 Prophylactic Prevention Trial of cholesterol significantly reduced the risk of heart attack and angina, doctors, including cardiologists, remain largely unsure.
Society and culture
To market statins effectively, Merck should convince the public about the dangers of high cholesterol, and doctors that statins are safe and will prolong life. As a result of the public campaign, people in the United States became familiar with their cholesterol count and the difference between "good" and "bad" cholesterol, and rival pharmaceutical companies began to produce their own statins, such as pravastatin (Pravachol), produced by Sankyo and Bristol-Myers Squibb. In April 1994, research results sponsored by Merck, Scandinavian Simvastatin Survival Study, were announced. Researchers tested simvastatin, then sold by Merck as Zocor, in 4444 patients with high cholesterol and heart disease. After five years, the study concluded that patients saw a 35% reduction in their cholesterol, and their chances of dying from a heart attack decreased by 42%. In 1995, Zocor and Mevacor made Merck over US $ 1 Ã, billion. Endo was awarded the 2006 Japanese Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008. For his "pioneering research into a new class of molecules" to "lower cholesterol," Endo was inaugurated as the National Inventors Hall of Fame in Alexandria. , Virginia in 2012. Michael C. Brown and Joseph Goldstein, who won the Nobel Prize for cholesterol-related work, said of Endo: "Millions of people whose lives will be extended through statin therapy owe it all to Akira Endo."
Research
Research continues into other areas where specific statins also appear to have beneficial effects, including dementia, lung cancer, nuclear cataracts, hypertension, and prostate cancer.
Controversy
Statins may be the most commonly prescribed drug, and related patents are beginning to expire.
In 2014, the Federal Drug Administration (FDA) issued a report on the side effects of statin use, which found that some patients reported cognitive problems, including problems with forgetfulness, memory loss, and confusion. Other patients, who run the risk of elevated blood sugar levels that statins can cause Type-2 Diabetic Mellitus are also a concern. There are further reports released in March 2015, which states Finnish researchers have determined that patients taking statins have a significant risk of developing type 2 diabetes mellitus.
The publication of a report titled "Cholesterol Confusion and Statin Controversy" by Robert DuBroff (a cardiologist researcher, University Of New Mexico) and Michel de Lorgeril (a medical researcher at the French Center National de Recherche Scientifique specialized in cardiology and nutrition - and a member of the European Society of Cardiology) presented to the World Congress of Cardiology is recommended only than the relationship between cholesterol levels does not necessarily indicate the cause of Coronary Heart Disease, but may also be just a coincidence or incidental consequence.
The public controversy over the use of cholesterol drugs resulting from authoritative medical journals containing scientific articles (as quoted above) calls into question the widespread prescription of statins. Popular interpretations in the UK are said to have driven some 200,000 people to stop using statins over a six-month period until mid-2016, according to study authors funded by the British Heart Foundation. They conclude there may be up to 2,000 additional heart attacks or strokes for 10 years as a consequence, but admit that it is impossible to be sure.
The UK National Institute for Health and Nursing Excellence asserts that statins can prevent up to 28,000 heart attacks and 16,000 strokes each year in the UK. The guide, which is based on evidence from a group led by Prof. Rory Collins in a clinical trial service unit at Oxford University, was questioned by the British Medical Journal, which campaigned against the use of drugs and excessive medical care.
The undesirable effects of academic statin controversy are the spread of alternative therapies that can be scientifically questionable. Cardiologist Steven Nissen at the Cleveland Clinic commented "We lost the battle for the heart and mind of our patients to the website..." promoting unproven medical therapy.
References
External links
- Statin pages in Bandolier , evidence-based medical journals (small content after 2004)
- Choice of NHS: High Cholesterol Prevention (diet), etc.
Source of the article : Wikipedia
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