Statin

For the primary prevention of cardiovascular disease, the United States Preventive Services Task Force (USPSTF) 2016 guidelines recommend 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, as calculated by the 2013 ACC/AHA Pooled Cohort algorithm.[18][19][20] Risk factors for coronary heart disease included abnormal lipid levels in the blood, diabetes mellitus, high blood pressure, and smoking.[19] 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.[19] 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.[21]

Most evidence suggests that statins are also 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.[4] For every 138 people treated for 5 years, one fewer dies; for every 49 treated, one fewer has an episode of heart disease.[10] A 2011 review reached similar conclusions,[22] and a 2012 review found benefits in both women and men.[23] 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.[24] Two other meta-analyses published that year, one of which used data obtained exclusively from women, found no mortality benefit in primary prevention.[25][26]

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%.[27] 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.[28] 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.[29] 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.[30]

Statins are effective in decreasing mortality in people with pre-existing cardiovascular disease.[31] Pre-existing disease can have many manifestations. Defining illnesses include a prior heart attack, stroke, stable or unstable angina, aortic aneurysm, or other arterial ischemic disease, in the presence of atherosclerosis.[18] They are also advocated for use in people at high risk of developing coronary heart disease.[32] 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.[33] A greater benefit is observed with high-intensity statin therapy.[34] They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").[35][36]

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.[37]

Statins have been studied for improving operative outcomes in cardiac and vascular surgery.[38] Mortality and adverse cardiovascular events were reduced in statin groups.[39]

Older adults who receive statin therapy at time of discharge from the hospital after an inpatient 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.[40][41]

While no direct comparison exists, all statins appear effective regardless of potency or degree of cholesterol reduction.[22] Simvastatin and pravastatin appear to have a reduced incidence of side-effects.[5]

A comparison of simvastatin, pravastatin, and atorvastatin, based on their effectiveness against placebos, found no differences in reduction of cardiovascular disease or lipid levels in the blood.[42] A 2015 Cochrane systematic review update reported that rosuvastatin is more than three-fold more potent than atorvastatin.[43]

According to the 2015 Cochrane systematic review, atorvastatin showed greater cholesterol-lowering effect in women than in men compared to rosuvastatin.[43]

In children statins are effective at reducing cholesterol levels in those with familial hypercholesterolemia.[44] Their long term safety is, however, unclear.[44][45] Some recommend that if lifestyle changes are not enough statins should be started at 8 years old.[46]

Statins may be less effective in reducing LDL cholesterol in people with familial hypercholesterolemia, especially those with homozygous deficiencies.[47] 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.[48] Statins remain a first-line treatment in familial hypercholesterolemia,[47] although other cholesterol-reducing measures may be required.[49] In people with homozygous deficiencies, statins may still prove helpful, albeit at high doses and in combination with other cholesterol-reducing medications.[50]

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.[51]

Multiple systematic reviews and meta-analyses have concluded that the available evidence does not support an association between statin use and cognitive decline.[68][69][70][71][72] Statins have been shown to decrease the risk of dementia, Alzheimer's disease, and improve cognitive impairment in some cases in 2010.[73] Additionally, both the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study[74] 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.[75]

There are reports of reversible cognitive impairment with statins.[76] 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).[77]

In observational studies 10–15% of people who take statins experience muscle problems; in most cases these consist of muscle pain.[6] These rates, which are much higher than those seen in randomized clinical trials[66] have been the topic of extensive debate and discussion.[31][78]

Muscle and other symptoms often cause patients to stop taking a statin.[79] This is known as statin intolerance.  A recent randomized controlled trial (RCT)[80] gave statin-intolerant patients a statin or a placebo inside capsules that looked the same, making the study double-blind – participants did not know which they were taking in any period, statin or placebo.  This was repeated 3 times, so there were 6 periods in random order. Patients were queried about their symptoms, which were similar on the statin and on the placebo, showing that statin intolerance depends on people knowing they're taking a statin.  A smaller double-blind RCT obtained similar results.[81]  After being shown their symptom scores, the majority of participants in these 2 studies intended to restart statin treatment. The results of these studies help explain why statin symptom rates in observational studies are so much higher than in double-blind RCTs. The difference results from the nocebo effect, which is the opposite of the placebo effect: the symptoms are caused by expectations of harm.[82]

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,[83] which have been proven in numerous large-scale RCTs to reduce heart attacks, stroke, and deaths[84] – as long as people continue to take them.

Serious muscle problems such as rhabdomyolysis (destruction of muscle cells) and statin-associated autoimmune myopathy occur in less than 0.1% of treated people.[85] Rhabdomyolysis 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.[86][87] Coenzyme Q10 (ubiquinone) levels are decreased in statin use;[88] CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking as of 2017.[89] 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.[90]

Records exist of over 250,000 people treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.[91] 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 a fibrate (fenofibrate or gemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001.[92]

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.[93] Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.[93] Tendon rupture does not appear to occur.[94]

The relationship between statin use and risk of developing diabetes remains unclear and the results of reviews are mixed.[95][96][97][98] Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes.[99] Use in postmenopausal women is associated with an increased risk for diabetes.[100] The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear.[97] However, recent findings have indicated the inhibition of HMGCoAR as a key mechanism.[101] Statins are thought to decrease cells' uptake of glucose from the bloodstream in response to the hormone insulin.[97] 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.[97]

Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a reduced risk.[102][103][104][105][106] Specifically, statins may reduce the risk of esophageal cancer,[107] colorectal cancer,[108] gastric cancer,[109][110] hepatocellular carcinoma,[111] and possibly prostate cancer.[112][113] They appear to have no effect on the risk of lung cancer,[114] kidney cancer,[115] breast cancer,[116] pancreatic cancer,[117] or bladder cancer.[118]

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.[91] 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, and bitter oranges may have a similar effect.[119] 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[120] (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.[121]

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.[122]

Studies have found that the use of statins may protect against getting osteoporosis and fractures or may induce osteoporosis and fractures.[123][124][125][126] A cross-sectional retrospective analysis of the entire Austrian population found that the risk of getting osteoporosis is dependent on the dose used.[127]

Statin consumption has been connected with increased prevalence of neuropathy.[128][129]

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,[132] 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,[133][134] but have shown no difference in the long-acting atorvastatin.[135]

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.[136] 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, 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.

Statins, by inhibiting the HMG CoA reductase pathway, inhibit downstream synthesis of isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inhibition of protein prenylation for proteins such as RhoA (and subsequent inhibition of Rho-associated protein kinase) may be involved, at least partially, in the improvement of endothelial function, modulation of immune function, and other pleiotropic cardiovascular benefits of statins,[137][138][139][140][141][142] 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,[143] and may also account for some of the benefits seen in cancer reduction with statins.[144] 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)[145] and elevated blood sugar (diabetes).[146]

As noted above, statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis through so-called "pleiotropic effects of statins."[140] The pleiotropic effects of statins remain controversial.[147] The ASTEROID trial showed direct ultrasound evidence of atheroma regression during statin therapy.[148] Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):[147]

1. Improve endothelial function
2. Modulate inflammatory responses
3. Maintain plaque stability
4. Prevent blood clot formation

In 2008, the JUPITER trial showed statins provided benefit in those who had no history of high cholesterol or heart disease, but only in those with elevated high-sensitivity C-reactive protein (hsCRP) levels, an indicator for inflammation.[149] The study has been criticized due to perceived flaws in the study design,[150][151][152] although Paul M. Ridker, lead investigator of the JUPITER trial, has responded to these criticisms at length.[153]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|alt=Statin Pathway edit]]

Statin Pathway edit

1. The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

As the target of statins, the HMG-CoA reductase, is highly similar between eukaryota and archaea, statins also act as antibiotics against archaea by inhibiting archaeal mevalonate biosynthesis. This has been shown in vivo and in vitro.[154] Since patients with a constipation phenotype present with higher abundance of methanogenic archaea in the gut, the use of statins for management of irritable bowel syndrome has been proposed and may actually be one of the hidden benefits of statin use.[155][156]