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86-937: Statins (or HMG-CoA reductase inhibitors ) are a class of medications that lower cholesterol . They are prescribed typically to people who are at high risk of cardiovascular disease . Low-density lipoprotein (LDL) carriers of cholesterol play a key role in the development of atherosclerosis and coronary heart disease via the mechanisms described by the lipid hypothesis . As lipid-lowering medications , statins are effective in lowering LDL cholesterol; they are widely used for primary prevention in people at high risk of cardiovascular disease, as well as in secondary prevention for those who have developed cardiovascular disease. Side effects of statins include muscle pain , increased risk of diabetes , and abnormal blood levels of certain liver enzymes . Additionally, they have rare but severe adverse effects, particularly muscle damage, and very rarely rhabdomyolysis . They act by inhibiting

172-426: A 10% 10-year risk of heart disease, as calculated by the 2013 ACC/AHA Pooled Cohort algorithm. Risk factors for coronary heart disease included abnormal lipid levels in the blood , diabetes mellitus , high blood pressure , and smoking . 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. In people over

258-744: 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"). 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. Statins have been studied for improving operative outcomes in cardiac and vascular surgery. Mortality and adverse cardiovascular events were reduced in statin groups. Older adults who receive statin therapy at time of discharge from

344-565: A 2012 review found benefits in both women and men. 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. 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

430-486: A common molecular mechanism of action modulate the activity of a specific biological target . The definition of a mechanism of action also includes the type of activity at that biological target. For receptors, these activities include agonist , antagonist , inverse agonist , or modulator . Enzyme target mechanisms include activator or inhibitor . Ion channel modulators include opener or blocker . The following are specific examples of drug classes whose definition

516-459: 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 reviews are mixed. Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes. Use in postmenopausal women

602-475: A hierarchy. For example, fibrates are a chemical class of drugs (amphipathic carboxylic acids) that share the same mechanism of action ( PPAR agonist ), the same mode of action (reducing blood triglyceride levels), and are used to prevent and treat the same disease ( atherosclerosis ). However, not all PPAR agonists are fibrates, not all triglyceride-lowering agents are PPAR agonists, and not all drugs used to treat atherosclerosis lower triglycerides. A drug class

688-672: A kilogram of weight loss can reduce LDL cholesterol by 0.8 mg/dl. Eating a diet with a high proportion of vegetables, fruit, dietary fibre, and low in fats results in a modest decrease in total cholesterol. Eating dietary cholesterol causes a small rise in serum cholesterol, the magnitude of which can be predicted using the Keys and Hegsted equations. Dietary limits for cholesterol were proposed in United States, but not in Canada, United Kingdom, and Australia. However, in 2015

774-671: A modest positive, dose-related relationship between cholesterol intake and LDL cholesterol. A number of other conditions can also increase cholesterol levels including diabetes mellitus type 2 , obesity , alcohol use, monoclonal gammopathy , dialysis therapy, nephrotic syndrome , hypothyroidism , Cushing's syndrome and anorexia nervosa . Several medications and classes of medications may interfere with lipid metabolism: thiazide diuretics , ciclosporin , glucocorticoids , beta blockers , retinoic acid , antipsychotics , certain anticonvulsants and medications for HIV as well as interferons . Genetic contributions typically arise from

860-584: 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, as well as in

946-630: A potency similar to rosuvastatin. Drug class A drug class is a group of medications and other compounds that share similar chemical structures , act through the same mechanism of action (i.e., binding to the same biological target ), have similar modes of action , and/or are used to treat similar diseases. The FDA has long worked to classify and license new medications. Its Drug Evaluation and Research Center categorizes these medications based on both their chemical and therapeutic classes. In several major drug classification systems, these four types of classifications are organized into

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1032-994: A potential risk factor for cholesterol-related cardiovascular disease, and avoiding them in an adult diet is recommended. The National Lipid Association recommends that people with familial hypercholesterolemia restrict intakes of total fat to 25–35% of energy intake, saturated fat to less than 7% of energy intake, and cholesterol to less than 200 mg per day. Changes in total fat intake in low calorie diets do not appear to affect blood cholesterol. Increasing soluble fiber consumption has been shown to reduce levels of LDL cholesterol, with each additional gram of soluble fiber reducing LDL by an average of 2.2 mg/dL (0.057 mmol/L). Increasing consumption of whole grains also reduces LDL cholesterol, with whole grain oats being particularly effective. Inclusion of 2 g per day of phytosterols and phytostanols and 10 to 20 g per day of soluble fiber decreases dietary cholesterol absorption. A diet high in fructose can raise LDL cholesterol levels in

1118-451: A prior heart attack, stroke, stable or unstable angina , aortic aneurysm , or other arterial ischemic disease, in the presence of atherosclerosis. 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

1204-661: Is 4 mmol/L, and 2 mmol/L for LDL. In the United States, the National Heart, Lung, and Blood Institute within the National Institutes of Health classifies total cholesterol of less than 200 mg/dL as "desirable", 200 to 239 mg/dL as "borderline high", and 240 mg/dL or more as "high". There is no absolute cutoff between normal and abnormal cholesterol levels, and values must be considered in relation to other health conditions and risk factors. Higher levels of total cholesterol increase

1290-512: 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 U.S. Food and Drug Administration (FDA) notified healthcare professionals of updates to

1376-455: Is also a risk factor. Diet has an effect on blood cholesterol, but the size of this effect varies between individuals. A diet high in sugar or saturated fats increases total cholesterol and LDL. Trans fats have been shown to reduce levels of high-density lipoprotein while increasing levels of LDL. A 2016 review found tentative evidence that dietary cholesterol is associated with higher blood cholesterol. As of 2018 there appears to be

1462-590: 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 of primary and secondary prevention. 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

1548-413: 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. However, recent findings have indicated the inhibition of HMGCoAR as a key mechanism. 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

1634-410: Is based on a specific mechanism of action: This type of categorisation of drugs is from a biological perspective and categorises them by the anatomical or functional change they induce. Drug classes that are defined by common modes of action (i.e. the functional or anatomical change they induce) include: This type of categorisation of drugs is from a medical perspective and categorises them by

1720-473: Is by interfering with cholesterol synthesis which is necessary for the production of certain proteins responsible for glucose uptake into cells such as GLUT1 . Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a reduced risk. Specifically, 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

1806-462: Is composed of VLDL), while LDL was usually estimated by the Friedewald formula: LDL ≈ {\displaystyle \approx } total cholesterol – HDL – (0.2 x fasting triglycerides). However, this equation is not valid on nonfasting blood samples or if fasting triglycerides are elevated (>4.5 mmol/L or >~400 mg/dL). Recent guidelines have, therefore, advocated

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1892-477: Is diagnosed with familial hypercholesterolemia, clinicians, family, or both, contact first- and second-degree relatives to come forward for testing and treatment. Research suggests that clinician-only contact results in more people coming forward for testing. Treatment recommendations have been based on four risk levels for heart disease. For each risk level, LDL cholesterol levels representing goals and thresholds for treatment and other action are made. The higher

1978-469: Is found. The U.S. Preventive Services Task Force in 2008 strongly recommends routine screening for men 35 years and older and women 45 years and older for lipid disorders and the treatment of abnormal lipids in people who are at increased risk of coronary heart disease. They also recommend routinely screening men aged 20 to 35 years and women aged 20 to 45 years if they have other risk factors for coronary heart disease . In 2016 they concluded that testing

2064-608: 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 (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

2150-523: Is lacking as of 2017. 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 rhabdomyolysis

2236-570: Is observed with the use of high-intensity statin therapy. Statins may improve quality of life when used in people without existing cardiovascular disease (i.e. for primary prevention). Statins decrease cholesterol in children with hypercholesterolemia, but no studies as of 2010 show improved outcomes and diet is the mainstay of therapy in childhood. Other agents that may be used include fibrates , nicotinic acid , and cholestyramine . These, however, are only recommended if statins are not tolerated or in pregnant women. Injectable antibodies against

2322-511: Is often not sufficient to achieve the desired lowering of LDL, and lipid-lowering medications are usually required. If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed. About 34 million adults in the United States have high blood cholesterol. Although hypercholesterolemia itself is asymptomatic , longstanding elevation of serum cholesterol can lead to atherosclerosis (build-up of fatty plaques in

2408-501: Is on the World Health Organization's List of Essential Medicines with simvastatin being the listed medicine. 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. Patient compliance with statin usage

2494-589: Is one of three major classes of lipids produced and used by all animal cells to form membranes. Plant cells manufacture phytosterols (similar to cholesterol), but in rather small quantities. Cholesterol is the precursor of the steroid hormones and bile acids . Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles ( lipoproteins ). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). All

2580-685: Is problematic despite robust evidence of the benefits. 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 underlying risk factors and history of cardiovascular disease. Clinical practice guidelines generally recommend people start with lifestyle modification through a cholesterol-lowering diet and physical exercise . For those unable to meet their lipid-lowering goals through such methods, statins can be helpful. The medication appears to work equally well regardless of sex, although some sex-related differences in treatment response were described. If there

2666-734: Is relatively short, hypercholesterolemia is not a risk factor for death by any cause including coronary heart disease. Among people older than 70, hypercholesterolemia is not a risk factor for being hospitalized with myocardial infarction or angina . There are also increased risks in people older than 85 in the use of statin drugs. Because of this, medications which lower lipid levels should not be routinely used among people with limited life expectancy. The American College of Physicians recommends for hypercholesterolemia in people with diabetes : A 2002 survey found that 1.1% of U.S. adults who used alternative medicine did so to treat high cholesterol. Consistent with previous surveys, this one found

Statin - Misplaced Pages Continue

2752-527: Is thus composed by one element ("anti-inflammatory") that designates the mechanism of action, and one element ("nonsteroidal") that separates it from other drugs with that same mechanism of action. Similarly, one might argue that the class of disease-modifying anti-rheumatic drugs (DMARD) is composed by one element ("disease-modifying") that albeit vaguely designates a mechanism of action, and one element ("anti-rheumatic drug") that indicates its therapeutic use. Other systems of drug classification exist, for example

2838-493: Is typically defined by a prototype drug , the most important, and typically the first developed drug within the class, used as a reference for comparison. This type of categorisation of drugs is from a chemical perspective and categorises them by their chemical structure. Examples of drug classes that are based on chemical structures include: This type of categorisation is from a pharmacological perspective and categorises them by their biological target. Drug classes that share

2924-559: The Biopharmaceutics Classification System which determines a drugs' attributes by solubility and intestinal permeability. Hypercholesterolemia Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet , obesity , inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia ), or the presence of other diseases such as type 2 diabetes and an underactive thyroid . Cholesterol

3010-512: The Dietary Guidelines Advisory Committee in the United States removed its recommendation of limiting cholesterol intake. A 2020 Cochrane review found replacing saturated fat with polyunsaturated fat resulted in a small decrease in cardiovascular disease by decreasing blood cholesterol. Other reviews have not found an effect from saturated fats on cardiovascular disease. Trans fats are recognized as

3096-621: 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. The study has been criticized due to perceived flaws in the study design, although Paul M. Ridker , lead investigator of the JUPITER trial, has responded to these criticisms at length. Click on genes, proteins and metabolites below to link to respective articles. As

3182-508: 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. A 2014 meta-analysis found that statins could reduce

3268-433: The LDL receptor gene . Familial hypercholesterolemia affects about one in 250 individuals. The Lithuanian Jewish population may exhibit a genetic founder effect . One variation, G197del LDLR which is implicated in familial hypercholesterolemia, has been dated to the 14th century. The utility of these variations has been the subject of debate. Cholesterol is measured in milligrams per deciliter (mg/dL) of blood in

3354-421: 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

3440-596: The 2015 Cochrane systematic review, atorvastatin showed greater cholesterol-lowering effect in women than in men compared to rosuvastatin. 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

3526-565: The Food and Drug Administration approved the labeling of foods containing specified amounts of phytosterol esters or phytostanol esters as cholesterol-lowering; in 2003, an FDA Interim Health Claim Rule extended that label claim to foods or dietary supplements delivering more than 0.8 g/day of phytosterols or phytostanols. Some researchers, however, are concerned about diet supplementation with plant sterol esters and draw attention to lack of long-term safety data. Rates of high total cholesterol in

Statin - Misplaced Pages Continue

3612-491: 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. There are reports of reversible cognitive impairment with statins. 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

3698-577: The United States and some other countries. In the United Kingdom, most European countries and Canada, millimoles per liter of blood (mmol/L) is the measure. For healthy adults, the UK National Health Service recommends upper limits of total cholesterol of 5 mmol/L, and low-density lipoprotein cholesterol (LDL) of 3 mmol/L. For people at high risk of cardiovascular disease, the recommended limit for total cholesterol

3784-582: 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. 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. For every 138 people treated for 5 years, one fewer dies; for every 49 treated, one fewer has an episode of heart disease. A 2011 review reached similar conclusions, and

3870-438: The arteries, so-called 'hardening of the arteries'). Over a period of decades, elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive narrowing of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow. A sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying

3956-622: 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 due to the statins inhibiting the enzyme (HMG-CoA reductase), which is necessary to make cholesterol, but also for other processes, such as CoQ 10 production, which is important for muscle function and 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

4042-494: The blood. Statins are the typically used medications, in addition to healthy lifestyle interventions. Statins can reduce total cholesterol by about 50% in the majority of people, and are effective in reducing the risk of cardiovascular disease in both people with and without pre-existing cardiovascular disease. In people without cardiovascular disease, statins have been shown to reduce all-cause mortality, fatal and non-fatal coronary heart disease, and strokes. Greater benefit

4128-537: The body. Insufficient blood supply to the heart may cause chest pain , and ischemia of the eye may manifest as transient visual loss in one eye . Insufficient blood supply to the legs may manifest as calf pain when walking , while in the intestines it may present as abdominal pain after eating a meal . Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath

4214-552: The brain can cause a stroke. If the development of the stenosis or occlusion is gradual, blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point tissue ischemia (restriction in blood supply) may manifest as specific symptoms . For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack ) may manifest as temporary loss of vision, dizziness and impairment of balance , difficulty speaking , weakness or numbness or tingling , usually on one side of

4300-409: 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. 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

4386-517: The combined effects of multiple genes, known as "polygenic," although in certain cases, they may stem from a single gene defect, as seen in familial hypercholesterolemia . In familial hypercholesterolemia, mutations may be present in the APOB gene ( autosomal dominant ), the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia ( HCHOLA3 ) variant of the PCSK9 gene, or

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4472-420: The entire Austrian population found that the risk of getting osteoporosis is dependent on the dose used. 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

4558-458: The enzyme HMG-CoA reductase , which plays a central role in the production of cholesterol. High cholesterol levels have been associated with cardiovascular disease. There are various forms of statins, some of which include atorvastatin , fluvastatin , lovastatin , pitavastatin , pravastatin , rosuvastatin , and simvastatin . Combination preparations of a statin and another agent, such as ezetimibe/simvastatin , are also available. The class

4644-499: 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 some 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

4730-459: The general population under the age of 40 without symptoms is of unclear benefit. In Canada, screening is recommended for men 40 and older and women 50 and older. In those with normal cholesterol levels, screening is recommended once every five years. Once people are on a statin further testing provides little benefit except possibly to determine compliance with treatment. In the UK , after someone

4816-487: 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 . Pre-existing disease can have many manifestations. Defining illnesses include

4902-680: The hidden benefits of statin use. The statins are divided into two groups: fermentation -derived and synthetic . 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. The relative potency of pitavastatin has not yet been fully established, but preliminary studies indicate

4988-428: 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. All statins appear effective regardless of potency or degree of cholesterol reduction. Simvastatin and pravastatin appear to have a reduced incidence of side-effects. According to

5074-594: The incidence of major cardiac events by up to 20% and are not that likely to increase the risk of stroke or kidney failure. Asthma Statins have been identified as having a possible adjunct role in the treatment of asthma through anti-inflammatory pathways. 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. The most important adverse side effects are muscle problems, an increased risk of diabetes mellitus , and increased liver enzymes in

5160-570: The lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol, are associated with an increased risk of atherosclerosis and coronary heart disease . In contrast, higher levels of HDL cholesterol are protective. Avoiding trans fats and replacing saturated fats in adult diets with polyunsaturated fats are recommended dietary measures to reduce total blood cholesterol and LDL in adults. In people with very high cholesterol (e.g., familial hypercholesterolemia), diet

5246-425: The majority of individuals (55%) used it in conjunction with conventional medicine . A systematic review of the effectiveness of herbal medicines used in traditional Chinese medicine had inconclusive results due to the poor methodological quality of the included studies. A review of trials of phytosterols and/or phytostanols, average dose 2.15 g/day, reported an average of 9% lowering of LDL-cholesterol. In 2000,

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5332-837: The medication (memory loss, confusion). 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. Muscle and other symptoms often cause patients to stop taking a statin. This is known as statin intolerance. A 2021 double-blind multiple crossover randomized controlled trial (RCT) in statin-intolerant patients found that adverse effects, including muscle pain, were similar between atorvastatin and placebo. A smaller double-blind RCT obtained similar results. 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

5418-1157: The notion that the difference results from the nocebo effect ; that the symptoms are caused by expectations of harm. 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, which have been proven in numerous large-scale RCTs to reduce heart attacks, stroke, and deaths – 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. 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 . Coenzyme Q10 (ubiquinone) levels are decreased in statin use; CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy

5504-487: The pathology they are used to treat. Drug classes that are defined by their therapeutic use (the pathology they are intended to treat) include: Some drug classes have been amalgamated from these three principles to meet practical needs. The class of nonsteroidal anti-inflammatory drugs (NSAIDs) is one such example. Strictly speaking, and also historically, the wider class of anti-inflammatory drugs also comprises steroidal anti-inflammatory drugs . These drugs were in fact

5590-472: 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

5676-400: The predominant anti-inflammatories during the decade leading up to the introduction of the term "nonsteroidal anti-inflammatory drugs." Because of the disastrous reputation that the corticosteroids had got in the 1950s, the new term, which offered to signal that an anti-inflammatory drug was not a steroid, rapidly gained currency. The drug class of "nonsteroidal anti-inflammatory drugs" (NSAIDs)

5762-553: 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. Studies have found that the use of statins may protect against getting osteoporosis and fractures or may induce osteoporosis and fractures. A cross-sectional retrospective analysis of

5848-412: The prevention of atherosclerosis through so-called "pleiotropic effects of statins". The pleiotropic effects of statins remain controversial. 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): In 2008,

5934-716: The protein PCSK9 ( evolocumab , bococizumab , alirocumab ) can reduce LDL cholesterol and have been shown to reduce mortality. In the US, guidelines exist from the National Cholesterol Education Program (2004) and a joint body of professional societies led by the American Heart Association . In the UK, the National Institute for Health and Clinical Excellence has made recommendations for

6020-438: 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. By inhibiting HMG-CoA reductase, statins block

6106-625: 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). Another systematic review from the International Centre for Circulatory Health of the National Heart and Lung Institute in London concluded that only a small fraction of side effects reported by people on statins are actually attributable to

6192-455: The risk category, the lower the cholesterol thresholds. For those at high risk, a combination of lifestyle modification and statins has been shown to decrease mortality. Lifestyle changes recommended for those with high cholesterol include: smoking cessation, limiting alcohol consumption, increasing physical activity, and maintaining a healthy weight. Overweight or obese individuals can lower blood cholesterol by losing weight – on average

6278-456: 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. 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

6364-531: 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. The risk of cardiovascular disease is similar in people with chronic kidney disease and coronary artery disease and statins are often suggested. 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

6450-435: 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

6536-540: The risk of cardiovascular disease, particularly coronary heart disease. Levels of LDL or non-HDL cholesterol both predict future coronary heart disease; which is the better predictor is disputed. High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction. In the past, LDL and VLDL levels were rarely measured directly due to cost. Levels of fasting triglycerides were taken as an indicator of VLDL levels (generally about 45% of fasting triglycerides

6622-656: 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

6708-439: The short-acting simvastatin taken at night rather than the morning, but have shown no difference in the long-acting atorvastatin . 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

6794-482: The skin around the eyelids), arcus senilis (white or gray discoloration of the peripheral cornea ), and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons , especially of the fingers. Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows. Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include weight, diet , and stress . Loneliness

6880-584: The statin. Multiple systematic reviews and meta-analyses have concluded that the available evidence does not support an association between statin use and cognitive decline. 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. Additionally, both the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study and

6966-511: 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. 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

7052-474: The treatment of elevated cholesterol levels, published in 2008, and a new guideline appeared in 2014 that covers the prevention of cardiovascular disease in general. The Task Force for the management of dyslipidaemias of the European Society of Cardiology and the European Atherosclerosis Society published guidelines for the management of dyslipidaemias in 2011. Among people whose life expectancy

7138-402: The use of direct methods for measurement of LDL wherever possible. It may be useful to measure all lipoprotein subfractions ( VLDL , IDL , LDL , and HDL) when assessing hypercholesterolemia and measurement of apolipoproteins and lipoprotein (a) can also be of value. Genetic screening is now advised if a form of familial hypercholesterolemia is suspected. Classically, hypercholesterolemia

7224-601: 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

7310-480: Was categorized by lipoprotein electrophoresis and the Fredrickson classification . Newer methods, such as "lipoprotein subclass analysis", have offered significant improvements in understanding the connection with atherosclerosis progression and clinical consequences. If the hypercholesterolemia is hereditary (familial hypercholesterolemia), more often a family history of premature, earlier onset atherosclerosis

7396-536: 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

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