|Biological target||HMG-CoA reductase|
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications. Statins have been found to reduce cardiovascular disease and mortality in those who are at high risk of cardiovascular disease. The evidence is strong that statins are effective for treating cardiovascular disease in the early stages of the disease (secondary prevention) and in those at elevated risk but without cardiovascular disease (primary prevention).
Side effects of statins include muscle pain, increased risk of diabetes mellitus, and abnormalities in liver enzyme tests. Additionally, they have rare but severe adverse effects, particularly muscle damage. They inhibit the enzyme HMG-CoA reductase which plays a central role in the production of cholesterol. High cholesterol levels have been associated with cardiovascular disease.
As of 2010, a number of statins are on the market: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Several combination preparations of a statin and another agent, 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 pharmaceutical in history. The manufacturer Pfizer reported sales of US$12.4 billion in 2008. Due to patent expirations, several statins became available in 2016 as less expensive generics.
Clinical practice guidelines generally recommend people try "lifestyle modification", including a cholesterol-lowering diet and physical exercise, before statin use. Statins or other pharmacologic agents may be recommended for those who do not meet their lipid-lowering goals through diet and lifestyle changes. Statins appear to work equally well in males and females.
In 2016 the United States Preventive Services Task Force recommended statins for those who have at least one risk factor for coronary heart disease, are between 40 and 75 years old, and have at least a 10% 10-year risk of heart disease. The risk factors for coronary heart disease included abnormal lipid levels in the blood, diabetes mellitus, high blood pressure, and smoking. The risk of heart disease is estimated using the ACC/AHA Pooled Cohort equation. They recommended selective use of low-to-moderate doses statins in the same adults who have a calculated 10-year cardiovascular disease event risk of 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. A 2013 Cochrane review found a decrease in risk of death and other poor outcomes without any evidence of harm. For every 138 people treated for 5 years one fewer dies and for every 49 treated one fewer has an episode of heart disease. A 2011 review reached similar conclusions. And a 2012 review found benefits in both women and men. A 2010 review concluded that treating people with no history of cardiovascular disease reduces cardiovascular events in men but not women, and provides no mortality benefit in either sex. Two other meta-analyses published that year, one of which used data obtained exclusively 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 that is 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 developing heart attack or stroke of 7.5% or more. In this latter group, statin assignment was not automatic, but was recommended to occur only after a clinician-patient risk discussion with shared decision making where other risk factors and lifestyle are addressed, the potential for benefit from a statin is weighed against the potential for adverse effects or drug interactions and informed patient preference is elicited. Moreover, if a risk decision was uncertain, factors such as family history, coronary calcium score, ankle-brachial index, and an inflammation test (hs-CRP ≥ 2.0 mg/L) were suggested to inform the risk decision. Additional factors that could be used were an LDL-C ≥ 160 or a very high lifetime risk. However, critics such as Steven E. Nissen say that the AHA/ACC guidelines were not properly validated, overestimate the risk by at least 50%, and recommend statins for patients who will not benefit, based on populations whose observed risk is lower than predicted by the guidelines. The European Society of Cardiology and the European Atherosclerosis Society recommend the use of statins for primary prevention, depending on baseline estimated cardiovascular score and LDL thresholds.
Statins are effective in decreasing mortality in people with pre-existing cardiovascular disease. They are also advocated for use in people at high risk of developing coronary heart disease. On average, statins can lower LDL cholesterol by 1.8 mmol/l (70 mg/dl), which translates into an estimated 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduced risk of stroke after long-term treatment. A greater benefit is observed with high-intensity statin therapy. They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").
While no direct comparison exists, all statins appear effective regardless of potency or degree of cholesterol reduction. There do appear to be some differences between them, with simvastatin and pravastatin appearing superior in terms of side-effects.
A comparison of simvastatin, pravastatin, and atorvastatin, based on their effectiveness against placebos, found, at commonly prescribed doses, no differences among the statins in reducing cardiovascular morbidity and mortality, and lipids.
In children statins are effective at reducing cholesterol levels in those with familial hypercholesterolemia. Their long term safety is, however, unclear. Some recommend that if lifestyle changes are not enough statins should be started at 8 years old.
Statins may be less effective in reducing LDL cholesterol in people with familial hypercholesterolemia, especially those with homozygous deficiencies. These people have defects usually in either the LDL receptor or apolipoprotein B genes, both of which are responsible for LDL clearance from the blood. Statins remain a first-line treatment in familial hypercholesterolemia, although other cholesterol-reducing measures may be required. In people with homozygous deficiencies, statins may still prove helpful, albeit at high doses and in combination with other cholesterol-reducing medications.
Contrast induced nephropathy
A 2014 meta-analysis found that statins could reduce the risk of contrast-induced nephropathy by 53% in people undergoing coronary angiography/percutaneous interventions. The effect was found to be stronger among those with preexisting kidney dysfunction or diabetes mellitus.
|Choosing a statin for people with special considerations|
|Condition||Commonly recommended statins||Explanation|
|Kidney transplantation recipients taking ciclosporin||Pravastatin or Fluvastatin||Drug interactions are possible, but studies have not shown that these statins increase exposure to ciclosporin.|
|HIV-positive people taking protease inhibitors||Atorvastatin, Pravastatin or Fluvastatin||Negative interactions are more likely with other choices|
|Persons taking gemfibrozil, a non-statin cholesterol-lowering drug||Atorvastatin||Combining gemfibrozil and a statin increases risk of rhabdomyolysis and subsequently kidney failure|
|Persons taking the anticoagulant warfarin||Any statin||The statin use may require that the warfarin dose be changed, as some statins increase the effect of warfarin.|
The most important adverse side effects are muscle problems, an increased risk of diabetes mellitus, and increased liver enzymes in the blood due to liver damage. Over 5 years of treatment statins result in 75 cases of diabetes, 7.5 cases of bleeding stroke, and 5 cases of muscle damage per 10,000 people treated. This could be because, as statins inhibit the enzyme (HMG-CoA reductase) that makes cholesterol, statins also inhibit the other processes of this enzyme, such as CoQ10 production, and CoQ10 production is important for muscle cells and in blood sugar regulation.
Other possible adverse effects include neuropathy, pancreatic and liver dysfunction, and sexual dysfunction. The rate at which such events occur has been widely debated, in part because the risk/benefit ratio of statins in low-risk populations is highly dependent on the rate of adverse events. A Cochrane meta-analysis of statin clinical trials in primary prevention found no evidence of excess adverse events among those treated with statins compared to placebo. Another meta-analysis found a 39% increase in adverse events in statin treated people relative to those receiving placebo, but no increase in serious adverse events. The author of one study argued that adverse events are more common in clinical practice than in randomized clinical trials. A systematic review concluded that while clinical trial meta-analyses underestimate the rate of muscle pain associated with statin use, the rates of rhabdomyolysis are still "reassuringly low" and similar to those 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 fraction of side effects reported by people on statins are actually attributable to the statin.
There are reports of cognitive decline with statins. In 2012, in recognition of an increase in reports and increasing concerns over the relationship between statins and memory loss (including reports of transient global amnesia), forgetfulness and confusion, the Food and Drug Administration (FDA) added to its required labeling on statin medications a warning about possible cognitive impacts. The effects are described as rare, non-serious, and reversible upon cessation of treatment.
In observational studies 10–15% of people who take statins experience muscle problems; in most cases these consist of muscle pain. These rates, which are much higher than those seen in randomized clinical trials have been the topic of extensive debate and discussion.
Rare reactions include myopathies such as myositis (inflammation of the muscles) or even rhabdomyolysis (destruction of muscle cells), which can in turn result in life-threatening kidney injury. The risk of statin-induced rhabdomyolysis increases with older age, use of interacting medications such as fibrates, and hypothyroidism. Coenzyme Q10 (ubiquinone) levels are decreased in statin use; CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking as of 2007. The gene SLCO1B1 (Solute carrier organic anion transporter family member 1B1) codes for an organic anion-transporting polypeptide that is involved in the regulation of the absorption of statins. A common variation in this gene was found in 2008 to significantly increase the risk of myopathy.
Records exist of over 250,000 people 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 10-fold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) were combined with a fibrate (fenofibrate or gemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001.
Some researchers have suggested hydrophilic statins, such as fluvastatin, rosuvastatin, and pravastatin, are less toxic than lipophilic statins, such as atorvastatin, lovastatin, and simvastatin, but other studies have not found a connection. Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage. Tendon rupture does not appear to occur.
The relationship between statin use and risk of developing diabetes remains unclear and the results of systematic reviews and meta-analyses are mixed. Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes. Use in postmenopausal women is associated with an increased risk for diabetes. The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear. Statins are thought to decrease cells' uptake of glucose from the bloodstream in response to the hormone insulin. One way this is thought to occur is by interfering with cholesterol synthesis which is necessary for the production of certain proteins responsible for glucose uptake into cells such as GLUT1.
Statins may reduce the risk of esophageal cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, 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.
Combining any statin with a fibrate or niacin (other categories of lipid-lowering drugs) increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. Monitoring liver enzymes and creatine kinase is especially 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 kidney function.
Consumption of grapefruit or grapefruit juice inhibits the metabolism of certain statins. Bitter oranges may have a similar effect. Furanocoumarins in grapefruit juice (i.e. bergamottin and dihydroxybergamottin) inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however, it is a major inhibitor of only lovastatin, simvastatin, and to a lesser degree, atorvastatin) and some other medications (flavonoids (i.e. naringin) were thought to be responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). The absolute prohibition of grapefruit juice consumption for users of some statins is controversial.
The FDA notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may increase the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.
Mechanism of action
Statins act by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Because statins are similar in structure to HMG-CoA on a molecular level, they will fit into the enzyme's active site and compete with the native substrate (HMG-CoA). This competition reduces the rate by which HMG-CoA reductase is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol. A variety of natural statins are produced by Penicillium and Aspergillus fungi as secondary metabolites. These natural statins probably function to inhibit HMG-CoA reductase enzymes in bacteria and fungi that compete with the producer.
Inhibiting cholesterol synthesis
By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night, so statins with short half-lives are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-acting simvastatin taken at night rather than the morning, but have shown no difference in the long-acting atorvastatin.
Increasing LDL uptake
In rabbits, 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 proteases that cleave membrane-bound sterol regulatory element binding proteins, which then migrate to the nucleus and bind to the sterol response elements. The sterol response elements then facilitate increased transcription of various other proteins, most notably, LDL receptor. The LDL receptor is transported to the liver cell membrane and binds to passing LDL and VLDL particles (colloquially, "bad cholesterol"), mediating their uptake into the liver, where the cholesterol is reprocessed into bile salts and other byproducts. This results in a net effect of less LDL circulating in blood.
Decreasing of specific protein prenylation
Statins, by inhibiting the HMG CoA reductase pathway, simultaneously inhibit the production of both cholesterol and specific prenylated proteins (see diagram).This inhibitory effect on protein prenylation may be involved, at least partially, in the improvement of endothelial function, modulation of immune function, and other pleiotropic cardiovascular benefits of statins, as well as in the fact that a number of other drugs that lower LDL have not shown the same cardiovascular risk benefits in studies as statins, and may also account for certain of the 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 elevated blood sugar (diabetes).
As noted above, 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 blood clot formation
In 2008, the JUPITER study showed benefit in those who had no history of high cholesterol or heart disease, but only elevated C-reactive protein levels. The conclusions of this study are, however, controversial.
|Cerivastatin||Lipobay, Baycol (withdrawn from the market in August, 2001 due to risk of serious rhabdomyolysis)||Synthetic||various CYP3A isoforms|
|Fluvastatin||Lescol, Lescol XL||Synthetic||CYP2C9|
|Lovastatin||Mevacor, Altocor, Altoprev||Naturally occurring, fermentation-derived compound. It is found in oyster mushrooms and red yeast rice||CYP3A4|
|Mevastatin||Compactin||Naturally occurring compound found in red yeast rice||CYP3A4|
|Pitavastatin||Livalo, Livazo, Pitava||Synthetic||CYP2C9 and CYP2C8 (minimally)|
|Pravastatin||Pravachol, Selektine, Lipostat||Fermentation-derived (a fermentation product of bacterium Nocardia autotrophica)||Non-CYP|
|Rosuvastatin||Crestor||Synthetic||CYP2C9 and CYP2C19|
|Simvastatin||Zocor, Lipex||Fermentation-derived (simvastatin is a synthetic derivate of a fermentation product of Aspergillus terreus)||CYP3A4|
|Simvastatin + ezetimibe||Vytorin, Inegy||Combination therapy: statin + cholesterol absorption inhibitor|
|Lovastatin + niacin extended-release||Advicor, Mevacor||Combination therapy|
|Atorvastatin + amlodipine||Caduet, Envacar||Combination therapy: statin + calcium antagonist|
|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 have found these foodstuffs to reduce circulating cholesterol, but the quality of the trials has been judged to be low. Due to patent expiration, most of the block-buster branded statins have been generic since 2012, including atorvastatin, the largest-selling branded drug.
|Statin equivalent dosages|
|% LDL reduction (approx.)||Atorvastatin||Fluvastatin||Lovastatin||Pravastatin||Rosuvastatin||Simvastatin|
|10–20%||–||20 mg||10 mg||10 mg||–||5 mg|
|20–30%||–||40 mg||20 mg||20 mg||–||10 mg|
|30–40%||10 mg||80 mg||40 mg||40 mg||5 mg||20 mg|
|40–45%||20 mg||–||80 mg||80 mg||5–10 mg||40 mg|
|46–50%||40 mg||–||–||–||10–20 mg||80 mg*|
|50–55%||80 mg||–||–||–||20 mg||–|
|* 80-mg dose no longer recommended due to increased risk of rhabdomyolysis|
|Starting dose||10–20 mg||20 mg||10–20 mg||40 mg||10 mg; 5 mg if hypothyroid, >65 yo, Asian||20 mg|
|If higher LDL reduction goal||40 mg if >45%||40 mg if >25%||20 mg if >20%||--||20 mg if LDL >190 mg/dL (4.87 mmol/L)||40 mg if >45%|
|Optimal timing||Anytime||Evening||With evening meals||Anytime||Anytime||Evening|
In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, began the search for a cholesterol-lowering drug. Research had already shown cholesterol is mostly manufactured by the body in the liver, using the enzyme HMG-CoA reductase. Endo and his team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as mevalonate is a precursor of many substances required by organisms for the maintenance of their cell walls (ergosterol) or cytoskeleton (isoprenoids). The first agent they identified was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum.
A British group isolated the same compound from Penicillium brevicompactum, named it compactin, and published their report in 1976. The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition.
Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs. P. Roy Vagelos, chief scientist and later CEO of Merck & Co, was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the fungus Aspergillus terreus, first marketed in 1987 as Mevacor.
A link between cholesterol and cardiovascular disease, known as the lipid hypothesis, had already been suggested. Cholesterol is the main constituent of atheroma, the fatty lumps in the wall of arteries that occur in atherosclerosis and, when ruptured, cause the vast majority of heart attacks. Treatment consisted mainly of dietary measures, such as a low-fat diet, and poorly tolerated medicines, such as clofibrate, cholestyramine, and nicotinic acid. Cholesterol researcher Daniel Steinberg writes that while the Coronary Primary Prevention Trial of 1984 demonstrated cholesterol lowering could significantly reduce the risk of heart attacks and angina, physicians, including cardiologists, remained largely unconvinced.
Society and culture
To market statins effectively, Merck had to convince the public of the dangers of high cholesterol, and doctors that statins were safe and would extend lives. As a result of public campaigns, people in the United States became familiar with their cholesterol numbers and the difference between "good" and "bad" cholesterol, and rival pharmaceutical companies began producing their own statins, such as pravastatin (Pravachol), manufactured by Sankyo and Bristol-Myers Squibb. In April 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study, were announced. Researchers tested simvastatin, later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008. For his "pioneering research into a new class of molecules" for "lowering cholesterol," Endo was inducted into the National Inventors Hall of Fame in Alexandria, Virginia in 2012. Michael C. Brown and Joseph Goldstein, who won the Nobel Prize for related work on cholesterol, said of Endo: "The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo."
In 2014 The Federal Drug Administration (FDA) issued a report of the side effects of statin usage, which found that some patients reported cognitive problems, including issues with forgetfulness, memory loss, and confusion. Other patients, who run a risk of raised blood sugar levels that statins can lead to Type-2 Diabetic Mellitus were also of concern. There was a further report released in March 2015, which states Finnish researchers had determined that patients using statins have a significant risk of developing Type 2 diabetes mellitus.
The publication of a report entitled "Cholesterol confusion and statin controversy" by Robert DuBroff (a research cardiologist, University Of New Mexico) and Michel de Lorgeril (a medical researcher at the French Centre 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 merely suggested that an association with cholesterol levels does not necessarily indicate a cause of Coronary Heart Disease, but may be also simply a coincidence or an incidental consequence.
The public controversy over cholesterol medication use resulted from authoritative medical journals which ran scientific articles (such as the one quoted above) questioning the widespread prescriptions of statins. Popular interpretation in Britain is said to have prompted an estimated 200,000 people to stop using statins over a six-month period to mid 2016, according to the authors of a study funded by the British Heart Foundation. They conclude there could be up to 2,000 extra heart attacks or strokes over the following 10 years as a consequence, but admit that it is impossible to be certain.
The UK National Institute for Health and Care Excellence asserts that statins could prevent up to 28,000 heart attacks and 16,000 strokes each year in Britain. That guidance, which was based on evidence from the group led by Prof Rory Collins at the clinical trials service unit at Oxford University, was questioned by the British Medical Journal, which is campaigning against the over-use of medicines and medical treatment
An unintended effect of the academic statin controversy is the spread of scientifically questionable alternative therapies. Cardiologist Steven Nissen at Cleveland Clinic commented "We are losing the battle for the hearts and minds of our patients to Web sites..." promoting unproven medical therapies.
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