Statins (orHMG-CoA reductase inhibitors) are aclass of medications that lowercholesterol. They are prescribed typically to people who are at high risk ofcardiovascular disease.[1]
Side effects of statins includemuscle pain, increased risk ofdiabetes, and abnormal blood levels of certainliver enzymes.[5] Additionally, they have rare but severe adverse effects, particularly muscle damage, and very rarelyrhabdomyolysis.[6][7]
They act by inhibiting the enzymeHMG-CoA reductase, which plays a central role in the production of cholesterol. High cholesterol levels have been associated with cardiovascular disease.[8]
Statins are usually used to lower blood cholesterol levels and reduce risk for illnesses related to atherosclerosis, with a varying degree of effect depending on underlyingrisk factors and history of cardiovascular disease.[16] A 2022 systematic review found theabsolute risk reductions for three hard outcomes – all-cause mortality, myocardial infarction, and stroke – to be 0.8%, 1.3%, and 0.4%, respectively (relative risk: 9%, 29%, 14%). The association between effect size and LDL cholesterol reduction was unclear, and there was significant clinical and statisticalheterogeneity between trials.[17]Clinical practice guidelines generally recommend that people at low risk start with lifestyle modification through a cholesterol-lowering diet andphysical exercise; for those unable to meet their lipid-lowering goals through such methods, statins can be helpful.[18][19] The medication appears to work equally well regardless of sex,[20] although some sex-related differences in treatment response were described.[21]
If there is an underlying history of cardiovascular disease, it has a significant impact on the effects of statin. This can be used to divide medication usage into broad categories ofprimary andsecondary prevention.[22]
For the primary prevention of cardiovascular disease, theUnited States Preventive Services Task Force (USPSTF) 2016 guidelines recommend statins for those who have at least one risk factor forcoronary heart disease, are between 40 and 75 years old, and have at least a 10% 10-year risk of heart disease, as calculated by the 2013 ACC/AHA Pooled Cohort algorithm.[22][23][24] Risk factors for coronary heart disease includedabnormal lipid levels in the blood,diabetes mellitus,high blood pressure, andsmoking.[23] 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.[23] In people over the age of 70, statins decrease the risk of cardiovascular disease but only in those with a history of heavy cholesterol blockage in their arteries.[25]
Most evidence suggests that statins are also effective in preventing heart disease in those withhigh cholesterol but no history of heart disease. A 2013Cochrane review found a decrease in risk of death and other poor outcomes without any evidence of harm.[4] For every 138 people treated for 5 years, one fewer dies; for every 49 treated, one fewer has an episode of heart disease.[11] A 2011 review reached similar conclusions,[26] and a 2012 review found benefits in both women and men.[27] A 2010 review concluded that treatment without history of cardiovascular disease reduces cardiovascular events in men but not women, and provides no mortality benefit in either sex.[28] Two other meta-analyses published that year, one of which used data obtained exclusively from women, found no mortality benefit in primary prevention.[29][30]
TheNational 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%.[31] Guidelines by theAmerican College of Cardiology and theAmerican Heart Association recommend statin treatment for primary prevention of cardiovascular disease in adults with LDL cholesterol ≥ 190 mg/dL (4.9 mmol/L) or those with diabetes, age 40–75 with LDL-C 70–190 mg/dL (1.8–4.9 mmol/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 mg/dL (4.14 mmol/L) or a very high lifetime risk.[32] 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 people who will not benefit, based on populations whose observed risk is lower than predicted by the guidelines.[33] TheEuropean 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.[34]
Statins are effective in decreasing mortality in people with pre-existingcardiovascular disease.[35] Pre-existing disease can have many manifestations. Defining illnesses include a prior heart attack, stroke, stable or unstableangina,aortic aneurysm, or other arterialischemic disease, in the presence of atherosclerosis.[22] They are also advocated for use in people at high risk of developing coronary heart disease.[36] On average, statins can lowerLDL 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 ofstroke after long-term treatment.[37] A greater benefit is observed with high-intensity statin therapy.[38] They have less effect than thefibrates orniacin in reducingtriglycerides and raisingHDL-cholesterol ("good cholesterol").[39][40]
No studies have examined the effect of statins on cognition in patients with prior stroke. However, two large studies (HPS and PROSPER) that included people with vascular diseases reported that simvastatin and pravastatin did not impact cognition.[41]
Statins have been studied for improving operative outcomes in cardiac and vascular surgery.[42] Mortality and adverse cardiovascular events were reduced in statin groups.[43]
Older adults who receive statin therapy at time of discharge from the hospital after aninpatient stay have been studied. People with cardiac ischemia not previously on statins at the time of admission have a lower risk of major cardiac adverse events and hospital readmission two years post-hospitalization.[44][45]
All statins appear effective regardless of potency or degree of cholesterol reduction.[26][46][47] Simvastatin and pravastatin appear to have a reduced incidence of side-effects.[5][48][49]
According to the 2015 Cochrane systematic review, atorvastatin showed greater cholesterol-lowering effect in women than in men compared to rosuvastatin.[50]
In children, statins are effective at reducing cholesterol levels in those withfamilial hypercholesterolemia.[51] Their long term safety is, however, unclear.[51][52] Some recommend that if lifestyle changes are not enough statins should be started at 8 years old.[53]
Statins may be less effective in reducing LDL cholesterol in people with familial hypercholesterolemia, especially those withhomozygous deficiencies.[54] These people have defects usually in either theLDL receptor orapolipoprotein B genes, both of which are responsible for LDL clearance from the blood.[55] Statins remain a first-line treatment in familial hypercholesterolemia,[54] although other cholesterol-reducing measures may be required.[56] In people with homozygous deficiencies, statins may still prove helpful, albeit at high doses and in combination with other cholesterol-reducing medications.[57]
A 2014meta-analysis found that statins could reduce the risk ofcontrast-induced nephropathy by 53% in people undergoingcoronary angiography/percutaneous interventions. The effect was found to be stronger among those with preexisting kidney dysfunction or diabetes mellitus.[58]
The risk of cardiovascular disease is similar in people with chronic kidney disease and coronary artery disease and statins are often suggested.[16] There is some evidence that appropriate use of statin medications in people with chronic kidney disease who do not require dialysis may reduce mortality and the incidence of major cardiac events by up to 20% and are not that likely to increase the risk of stroke or kidney failure.[16]
Asthma
Statins have been identified as having a possible adjunct role in the treatment of asthma through anti-inflammatory pathways.[59] There is low quality evidence for the use of statins in treating asthma, however further research is required to determine the effectiveness and safety of this therapy in those with asthma.[59]
The statin use may require that the warfarin dose be changed, as some statins increase the effect of warfarin.[65]
The most important adverse side effects are muscle problems, an increased risk ofdiabetes mellitus, andincreased liver enzymes in the blood due toliver damage.[5][66] Over 5 years of treatment statins result in 75 cases of diabetes, 7.5 cases ofbleeding stroke, and 5 cases of muscle damage per 10,000 people treated.[35] This could be due to the statins inhibiting the enzyme (HMG-CoA reductase), which is necessary to make cholesterol, but also for other processes, such asCoQ10 production, which is important for muscle function and sugar regulation.[67]
Other possible adverse effects includeneuropathy,[68][69]pancreatic andliver dysfunction, andsexual dysfunction.[70] 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.[71][72][73] ACochrane meta-analysis of statin clinical trials in primary prevention found no evidence of excess adverse events among those treated with statins compared to placebo.[4] 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.[74] The author of one study argued that adverse events are more common in clinical practice than inrandomized clinical trials.[70] A systematic review concluded that while clinical trial meta-analyses underestimate the rate of muscle pain associated with statin use, the rates ofrhabdomyolysis are still "reassuringly low" and similar to those seen in clinical trials (about 1–2 per 10,000 person years).[75] Another systematic review from the International Centre for Circulatory Health of theNational Heart and Lung Institute inLondon concluded that only a small fraction of side effects reported by people on statins are actually attributable to the statin.[76]
Multiple systematic reviews and meta-analyses have concluded that the available evidence does not support an association between statin use and cognitive decline.[77][78][79][80][81] A 2010 meta-review of medical trials involving over 65,000 people concluded that Statins decreased the risk of dementia, Alzheimer's disease, and even improved cognitive impairment in some cases.[82][needs update] Additionally, both the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study[83] and the Health Protection Study (HPS) demonstrated that simvastatin and pravastatin did not affect cognition for patients with risk factors for, or a history of, vascular diseases.[84]
There are reports of reversible cognitive impairment with statins.[85] The U.S.Food and Drug Administration (FDA) package insert on statins includes a warning about the potential for non-serious and reversible cognitive side effects with the medication (memory loss, confusion).[86]
In observational studies 10–15% of people who take statins experiencemuscle problems; in most cases these consist ofmuscle pain.[6] These rates, which are much higher than those seen in randomized clinical trials[75] have been the topic of extensive debate and discussion.[35][87]
Muscle pain and other symptoms often cause patients to stop taking a statin.[88] This is known as statin intolerance. A 2021 double-blindmultiple crossoverrandomized controlled trial (RCT) in statin-intolerant patients found that adverse effects, including muscle pain, were similar between atorvastatin and placebo.[89] A smaller double-blind RCT obtained similar results.[90] The results of these studies help explain why statin symptom rates in observational studies are so much higher than in double-blind RCTs and support the notion that the difference results from thenocebo effect; that the symptoms are caused by expectations of harm.[91]
Media reporting on statins is often negative, and patient leaflets inform patients that rare but potentially serious muscle problems can occur during statin treatment. These create expectations of harm. Nocebo symptoms are real and bothersome and are a major barrier to treatment. Because of this, many people stop taking statins,[92] which have been proven in numerous large-scale RCTs to reduce heart attacks, stroke, and deaths[93] – as long as people continue to take them.
Serious muscle problems such asrhabdomyolysis (destruction of muscle cells) andstatin-associated autoimmune myopathy occur in less than 0.1% of treated people.[94] Rhabdomyolysis can in turn result in life-threateningkidney injury. The risk of statin-induced rhabdomyolysis increases with older age, use of interacting medications such asfibrates, andhypothyroidism.[95][96]Coenzyme Q10 (ubiquinone) levels are decreased in statin use;[97] CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking as of 2017[update].[98] The geneSLCO1B1 (Solute carrier organic anion transporter family member 1B1) codes for anorganic 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.[99]
Records exist of over 250,000 people treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.[100] The incidence of rhabdomyolysis 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 afibrate (fenofibrate orgemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001.[101]
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.[102]Lovastatin induces the expression of geneatrogin-1, which is believed to be responsible in promoting muscle fiber damage.[102] Tendon rupture does not appear to occur.[103]
The relationship between statin use and risk of developingdiabetes remains unclear and the results of reviews are mixed.[104][105][106][107] Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes.[108] Use in postmenopausal women is associated with an increased risk for diabetes.[109] The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear.[106] However, recent findings have indicated the inhibition ofHMGCoAR as a key mechanism.[110] Statins are thought to decrease cells' uptake of glucose from the bloodstream in response to thehormoneinsulin.[106] 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 asGLUT1.[106]
Combining any statin with afibrate orniacin (other categories of lipid-lowering drugs) increases the risks forrhabdomyolysis to almost 6.0 per 10,000 person-years.[100] 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 inkidney function.[128]
Consumption ofgrapefruit orgrapefruit juiceinhibits the metabolism of certain statins, andbitter oranges may have a similar effect.[129] Furanocoumarins in grapefruit juice (i.e.bergamottin anddihydroxybergamottin) inhibit thecytochrome P450 enzymeCYP3A4, 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[130] (flavonoids (i.e.naringin) were thought to be responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (includingmyopathy/rhabdomyolysis). The absolute prohibition of grapefruit juice consumption for users of some statins is controversial.[131]
The U.S.Food and Drug Administration (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.[132]
Studies have found that the use of statins may protect against getting osteoporosis and fractures or may induce osteoporosis and fractures.[133][134][135][136] A cross-sectional retrospective analysis of the entire Austrian population found that the risk of getting osteoporosis is dependent on the dose used.[137]
Atorvastatin bound to HMG-CoA reductase:PDB entry1hwk[138]The HMG-CoA reductase pathway, which is blocked by statins via inhibiting the rate limiting enzymeHMG-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,[140] so statins with shorthalf-lives are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-actingsimvastatin taken at night rather than the morning,[141][142] but have shown no difference in the long-actingatorvastatin.[143]
In rabbits,liver cells sense the reduced levels of liver cholesterol and seek to compensate by synthesizingLDL receptors to draw cholesterol out of the circulation.[144] This is accomplished viaproteases that cleave membrane-boundsterol regulatory element binding proteins, which then migrate to thenucleus 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 livercell membrane and binds to passingLDL andVLDL particles, 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.[citation needed]
Statins, by inhibiting the HMG CoA reductase pathway, inhibit downstream synthesis of isoprenoids, such asfarnesyl pyrophosphate andgeranylgeranyl pyrophosphate. Inhibition of proteinprenylation for proteins such asRhoA (and subsequent inhibition ofRho-associated protein kinase) may be involved, at least partially, in the improvement of endothelial function, modulation of immune function, and otherpleiotropic cardiovascular benefits of statins,[145][146][147][148][149][150] 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,[151] and may also account for some of the benefits seen in cancer reduction with statins.[152] 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)[153] and elevated blood sugar (diabetes).[154]
As noted above, statins exhibit action beyond lipid-lowering activity in the prevention ofatherosclerosis through so-called "pleiotropic effects of statins".[148] The pleiotropic effects of statins remain controversial.[155] The ASTEROID trial showed directultrasound evidence ofatheroma regression during statin therapy.[156] Researchers hypothesize that statins preventcardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):[155]
In 2008, theJUPITER trial showed statins provided benefit in those who had no history ofhigh cholesterol or heart disease, but only in those with elevated high-sensitivityC-reactive protein (hsCRP) levels, an indicator for inflammation.[157] The study has been criticized due to perceived flaws in the study design,[158][159][160] althoughPaul M. Ridker, lead investigator of the JUPITER trial, has responded to these criticisms at length.[161]
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
As the target of statins, the HMG-CoA reductase, is highly similar betweeneukaryota andarchaea, statins also act as antibiotics against archaea by inhibiting archaeal mevalonate biosynthesis. This has been shown in vivo and in vitro.[162] Since patients with a constipation phenotype present with higher abundance of methanogenic archaea in the gut, the use of statins for management ofirritable bowel syndrome has been proposed and may actually be one of the hidden benefits of statin use.[163][164]
The statins are divided into two groups:fermentation-derived andsynthetic. Some specific types are listed in the table below. Note that the associated brand names may vary between countries.
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.[175] The relative potency of pitavastatin has not yet been fully established, but preliminary studies indicate a potency similar to rosuvastatin.[176]
Theoyster mushroom, a culinary mushroom, naturally contains lovastatin.
Some types of statins are naturally occurring, and can be found in such foods asoyster mushrooms andred 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.[177]Due to patent expiration, most of the block-buster branded statins have been generic since 2012, including atorvastatin, the largest-selling[178] branded drug.[179][180][181][182][183][184][185]
The role of cholesterol in the development of cardiovascular disease was elucidated in the second half of the 20th century.[186] Thislipid hypothesis prompted attempts to reduce cardiovascular disease burden by lowering cholesterol. Treatment consisted mainly ofdietary measures, such as alow-fat diet, and poorly tolerated medicines, such asclofibrate,cholestyramine, andnicotinic 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.[187] Scientists in academic settings and the pharmaceutical industry began trying to develop a drug to reduce cholesterol more effectively. There were several potential targets, with 30 steps in the synthesis of cholesterol from acetyl-coenzyme A.[188]
In 1971,Akira Endo, a Japanese biochemist working for the pharmaceutical companySankyo, began to investigate this problem. Research had already shown cholesterol is mostly manufactured by the body in the liver with the enzyme HMG-CoA reductase.[12] Endo and his team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, asmevalonate is a precursor of many substances required by organisms for the maintenance of their cell walls orcytoskeleton (isoprenoids).[139] The first agent they identified wasmevastatin (ML-236B), a molecule produced by the fungusPenicillium citrinum.[citation needed]
A British group isolated the same compound fromPenicillium brevicompactum, named itcompactin, and published their report in 1976.[189] The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition.[190][191] 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 ofMerck & Co, was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolatedlovastatin (mevinolin, MK803) from the fungusAspergillus terreus, first marketed in 1987 as Mevacor.[12]
In the 1990s, as a result of public campaigns, people in the United States became familiar with their cholesterol numbers and the difference between HDL and LDL cholesterol, and various pharmaceutical companies began producing their own statins, such as pravastatin (Pravachol), manufactured by Sankyo andBristol-Myers Squibb. In April 1994, the results of a Merck-sponsored study, theScandinavian Simvastatin Survival Study, were announced. Researchers testedsimvastatin, 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%.[12][192] In 1995, Zocor and Mevacor both made Merck overUS$1 billion.[12]
As of 2016[update] misleading claims exaggerating the adverse effects of statins had received widespread media coverage, with a consequent negative impact to public health.[35] Controversy over the effectiveness of statins in the medical literature was amplified in popular media in the early 2010s, leading an estimated 200,000 people in the UK 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 estimated that there could be up to 2,000 extra heart attacks or strokes over the following 10 years as a consequence.[195] An unintended effect of the academic statin controversy has been the spread of scientifically questionablealternative therapies. CardiologistSteven Nissen atCleveland Clinic commented "We are losing the battle for the hearts and minds of our patients to Web sites..."[196] promoting unproven medical therapies.Harriet Hall sees a spectrum of "statin denialism" ranging frompseudoscientific claims to the understatement of benefits and overstatement of side effects, all of which is contrary to the scientific evidence.[197]
Several statins have been approved asgeneric drugs in the United States:
A modelling study in the UK found that people aged 70 and older who take statins live longer in good health than those who do not, regardless of whether they have cardiovascular disease.[225][226]
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