Clinical practice guidelines generally recommend people to 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.
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 less dies and for every 49 treated one less 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 20%. In 2014, NICE issued draft guidance lowering the threshold to a 10 year risk of 10% or more. 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. 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 CVD. They are also currently advocated for use in patients at high risk of developing 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. They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").
Statins have been studied for improving operative outcomes in cardiac and vascular surgery. Mortality and adverse cardiovascular events were reduced in statin groups.
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 atorvastatin, pravastatin and simvastatin, based on their effectiveness against placebos, found, at commonly prescribed doses, no statistically significant differences among agents in reducing cardiovascular morbidity and mortality.
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.
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 increased concentrations of liver enzymes, muscle problems, and an increased risk of diabetes. Other possible adverse effects include cognitive loss, neuropathy, pancreatic and hepatic 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 group 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 by the Canadian Working Group Consensus Conference that considered published meta analyses of clinical trials, spontaneous adverse event reports to the FDA, and published cohort studies 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 patient years). A systematic review co-authored by Ben Goldacre concluded that only a small fraction of side effects reported by patients on statins are actually attributable to the statin.
There are anecdotal reports of significant cognitive decline with statins. There is no strong evidence to support or exclude this effect. Two randomized clinical trials found cognitive issues, while two did not.[Dead link] A systematic review by the Canadian Working Group Consensus Conference concluded that the available evidence "is not strongly supportive of a major adverse effect of statins". A meta-analysis reported in Annals of Internal Medicine concluded that there is moderate quality evidence of no increase in dementia, mild cognitive impairment or cognitive performance scores, although the strength of the evidence is limited, particularly for high doses. In 2012, in recognition of an increase in anecdotal reports and increasing concerns over the relationship between statins and memory loss (including reports of transient global amnesia), forgetfulness and confusion, the FDA added to its required labeling on statin drugs 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. 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[update]. 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.
Graham et al. (2004) reviewed records of over 250,000 patients treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The incidence of rhabdomyolyis was 0.44 per 10,000 patients treated with statins other than cerivastatin. However, the risk was over 10-fold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, or 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, but the newer statins, characterized by longer pharmacological half-lives and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates. Some researchers have suggested 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; the risk of myopathy was suggested to be lowest with pravastatin and fluvastatin, probably because they are more hydrophilic 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.
Statins are associated with a slightly increased risk of diabetes (2-17% in one review). Higher doses have a greater effect. However, the benefits in cardiovascular disease outweighed the risks of diabetes.
Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a reduced risk.
Combining any statin with a fibrate or niacin, another category of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in 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
Atorvastatin bound to HMG-CoA reductase: PDB entry 1hwk
The HMG-CoA reductase pathway, which is blocked by statins via inhibiting the rate limiting enzyme HMG-CoA reductase.
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 protease enzymes that cleave a protein called "membrane-bound sterol regulatory element binding protein", which migrates to the nucleus and causes increased production of various other proteins and enzymes, including the LDL receptor. The LDL receptor then relocates to the liver cell membrane and binds to passing LDL and VLDL particles (the "bad cholesterol" linked to disease). LDL and VLDL are drawn out of circulation into the liver, where the cholesterol is reprocessed into bile salts. These are excreted, and subsequently recycled mostly by an internal bile salt circulation.
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). A 2012 study found that statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation. The study concluded, "These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan [animal] species, and may explain the pleiotropic (non-cholesterol related) health effects of statins." This inhibitory effect on protein prenylation may be involved, at least partially, in the improvement of endothelial function and other pleiotropic cardiovascular benefits of statins, and may also account for certain of the benefits seen in cancer reduction with statins.
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.)
* 80-mg dose no longer recommended due to increased risk of rhabdomyolysis
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.
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."
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