Inhibit the enzyme hydroxymethylglutaryl coenzyme A reductase (HMG Co A reductase) which catalyzes the formation of mevalonate, a key step in cholesterol synthesis.
Inhibit production of mevalonate and other and other cholesterol intermediates in the isoprenoid pathway.
The Inhibition of the conversion of HMG-COA to me alonic acid, which is the precursor in the de novo cholesterol biosynthetic pathway, results in decreased cholesterol production and reduces intracellular storage.
The above process increases ilow density lipoprotein receptors at the cellular surface to bind to free LDL, triggering endocytosis and lysosomal degradation that culminates in the reduction in reduction in circulating LDL blood levels.
Most cholesterol is derived from intracellular synthesis, rather than from diet and statins produce intracellular cholesterol depletion.
what is a compensatory response cholesterol depleted cells that regulate LDL receptors on the cell surface to internalize more cholesterol for cellular needs.
In the liver, this increases removal of cholesterol, rich LDL particles from the circulation, explaining the LDL cholesterol lowering effect of statins.
Statins reduce the hepatic production of cholesterol by inhibiting HMG-co-A reductase, but this activity alone does not lower the circulating concentration of cholesterol.
LDL-C is lowered by increasing the hepatic number of surface LDL-C receptors.
Reducing the quantity of cholesterol in the liver results in an increase in hepatic LDL receptors, and it is this downstream activity of statins that results in reduction of circulating LDL-C.
Potent drugs of this class can lower the LDL cholesterol level in the blood by 30 to 50% and have profound benefits in both primary and secondary prevention of cardiovascular disease.
Most patients with atherosclerotic cardiovascular disease treated with statins do not achieve target LDL cholesterol levels: in this situation daily ezetimbe or twice monthly PCSk9 Inhibitors are indicated.
Lower lipids based on inhibition of cholesterol synthesis in the liver.
Most commonly used drug in the world: roughly 45 million people in the US take statins.
Patient adherence to statin therapy is less than 50% within one year of the prescription.
In the United States, an estimated 19 million men receive the class of lipid-lowering medications known as statins.
More tha 25% of Medicare patients receive statins.
Benefits accrue in primary prevention after 2 years.
Approximately 50% of asymptomatic elderly patients starting statins take this medication after six months.
The magnitude of the long-term clinical benefit and risk reduction with statin therapy is directly proportional to the absolute reductions in LDL-C levels.
High intensity statins such as atorvastatin 80mg and rosuvastatin 40 mg are expected to reduce LDL-C cholesterol by approximately 50% regardless of baseline levels.
Ezetimibe when added to statins typically reduces LDL-C level by an additional 20-25%.
Patients with clinical atherosclerotic cardiovascular disease should receive maximal tolerated statin therapy to lower their low density lipoprotein cholesterol levels by at least 50%
In older adults with moderate hyperlipidemia and hypertension who were randomized to initiate statin therapy for primary prevention, instead of receiving usual care, experienced no benefit.
Randomized controlled studies and metaanalyses report a 20-44% reduction in cardiac events after initiation of statin therapy with comparable cardioprotective benefits for men and women alike.
Statins induce atherosclerotic plaque regression when LDL-C levels are lowered to less than one hundred milligrams per deciliter.
A meta-analysis of more than 90,000 patients indicates that for every 39 mg/dL that statins lower the LDL cholesterol level, the risk of major adverse cardiovascular events, is reduced by approximately 25% and 20% relative decreased coronary heart disease mortality. (Baigent C et al).
High intensity statin treatment yield to reduction in the LDL cholesterol level of approximately 50%.
Statins reduce acute coronary event after acute coronary symptoms, including chest pain, diaphoresis, and radiation of pain to the arm and jaw.
Statins do not reduce coronary calcium, but do not slow its accumulation.
The average LDL cholesterol-lowering effect of the highest doses of approved statins are 63% for rosuvastatin (40 mg), 57% for atorvastatin (80 mg), 46% for simvastatin (80 mg), 41% for pitavastatin (4 mg), 40% for lovastatin (80 mg), 34% for pravastatin (80 mg), and 31% for fluvastatin (80 mg) (Smith MEb et al).
Most low-density lipoprotein cholesterol lowering is obtained with the first 5 to 10 mg of statin.
Its effects are due to mevolanate dependant and mevalonate independent mechanisms.
Statins improve vasorelaxant responses, suppresses vascular inflammation, increases stability of atherosclerotic plaque, has anti-thrombotic effects, and anti-oxidant actions.
Statins anti-inflammatory effects occur rapidly, stabilizing unstable plaques and reducing inflammation.
Any use of statins was associated with a lower risk of development of primary open angle glaucoma.
Among adults aged 40 years and older, higher serum cholesterol levels were associated with higher risk of POAG, while 5 or more years of statin use compared with never use of statins was associated with a lower risk of POAG.
Coronary atherosclerosis is an inflammatory disease as noted by an elevated C reactive proteins, which statins effectively reduce.
Studies suggest that statins may slow the damage to white matter in the brain in individuals with mild cognitive impairment.
There is no effect of statins on brain structure.
Lowers risk of breast cancer, and for women with breast cancer, it increases survival.
Lipid-lowering medications are associated with a decrease in cancer-specific mortality ( British Journal of Clinical Pharmacology).
Adherence to lipid lowering medicines is inversely associated with cancer-specific mortality.
Statin use reduces the risk of venous thromboembolism recurrence by approximately 25% (Stewart L).
Individuals taking statins have a lower volume of white matter hyperintensities, suggesting less cerebrovascular pathology, and they also show a higher white matter fractional anisotropy, signaling better integrity of the white mat
SEARCH trial was a 6.7 year randomized double-blind trial comparing the efficacy and safety of 80 mg of simvastatin compared to 20 mg of simvastatin, with or without B12 and folate in survivors of acute myocardial infarction, stroke, or arterial revascularization: cardiovascular events occurred in 25.7% of the 20 mg group, 24.5% in the 80 mg group, a 6% reduction in a relative risk of major adverse cardiovascular events consistent with the 13 milligrams per deciliter difference in LDL cholesterol levels.
Approximately 20,000,000 patients are treated with statins, but an estimated 10 to 20% are unable to tolerate such agents or the higher doses necessary to achieve LDL-C goals, primarily because of muscle related side effects.
Myopathy with serum creatine kinase more than 10 times the upper limits of normal, with unexplained muscle weakness or pain developed in 0.9% of patients in the above study in the 80 mg group, but only in .02% of patients in the 20 mg group (SEARCH trial).
Some patients with statin associated muscle symptoms experience marked elevation in serum creatinine kinase, most however do not.
((Rhabdomyolysis)) rare at 0.0005% events.
In a multicenter, randomized, placebo-controlled showed no overall effects of atorvastatin 20 mg once a day on muscle symptoms compared with placebo in individuals who previously reported severe muscle symptoms when taking statins.
It is evidence busting the myth of the need to stop statin therapy because of vague non-severe muscle symptoms, which as the BMJ study shows, are common in both placebo and statin-treated patients.
Statins are generally well tolerated with a good safety profile.
Severe statin-associated adverse effects on muscle such as myopathy: 1 in 10,000 people treated annually and rhabdomyolysis: 0.2 in 10,000 people treated annually are rare.
The causal relationship between statins and less severe muscle symptoms is unclear.
No significant difference in symptoms between participants given placebo and those given 20 mg of atorvastatin once a day.
Results showed 90% of the symptoms attributable to the nocebo effect.
In the GAUSS-3 trial, during re-challenge with a statin, 26.5% in the placebo group, but not statin group, reported muscle symptoms, suggesting that symptoms are not always related to statin use.
Cessation of the drug in patients with toxic syndrome is associated with recovery, but it is not necessarily the case with autoimmune autoimmune muscle injury.
Lower serum cholesterol and incidence of cardiovascular events.
May modulate innate, and adaptive immune system and anti-inflammatory effects and counteract deleterious effects of sepsis on the coagulation system by inhibiting tissue factor expression and reducing prothrombin fragment levels and by increasing the expression of thrombomodulin.
Long-term use not associated with adverse events.
Adverse events occur in 3-15% of patients.
The primary adverse effect limiting use is myopathy ranging from benign myalgia to potentially fatal rhabdomyolysis.
The incidence of myalgias in statin users is 1:1000.
surveillance is highly recommended.[26]
Statin intolerance refers to a clinical syndrome characterized by the inability to use statins long term because of symptoms or biomarker abnormalities attributed to such drugs.
A recent meta-analysis places the overall rate of statin intolerance at approximately 9%, with older age, obesity, diabetes, chronic liver disease, and chronic kidney disease increasing the risk.
Unintended consequences of statins include muscle pain, cramps, and fatigue, which may reduce physical activity and or aerobic exercise.
Associated with a higher incidence of diabetes, elevation serum CPK, liver dysfunction, inflammation, and myopathy and attenuated training induced increases in cardiorespiratory fitness levels.
A small excess in new cases of diabetes at one excess case of incident diabetes per hundred individuals treated with moderate intensity statin based on a 0.1% rate of incident diabetes per year, or approximately one percent in 10 years.
A British study reported a 363% increase risk of diabetes after 15-20 years of statin treatment (Macedo AF).
Its major documented side effects include: myalgias, glucose intolerance, and hemorrhagic strokes, the latter which her only in patients with poorly controlled hypertension.
Can increase hemoglobin A1 C levels, and pre-diabetics progressed to diabetes in the majority of individuals on statins.
Cardiorespiratory fitness improves and attenuates the risk for developing type two diabetes with statins exposure.
Its diabetogenic effect appears to be dose related.
Statin intolerance is classified as either complete, intolerance to any statin at any dose, or partial, with tolerance to some statins at some doses.
In patients without cognitive dysfunction short-term data reveals no adverse effects on cognition, and long-term data suggesting a prevention of dementia (Swiger KJ et al).
Significantly reduces mortality in patients who have survived myocardial infarction or unstable angina.
Patients with myocardial injury but no signs of type 1 myocardial infarction have high mortality rates when treated with low intensity statin therapy and should be treated with high intensity statin therapy.
Reduces the risk of stroke among patients with a history of coronary artery disease.
Long-term uses associated with decreased risk of strokes.
Reverse progression of carotid artery stenosis over time.
The increase in LDL-c lowering efficacy is increased by 7% only for each doubling of the dose of a statin.
Statins increase PCSK9 each dosage increase and PCSK9 increases the degradation of hepatic LDL receptors, preventing additional LDL-C reduction.
Reduce recurrent ischemic events in the first 16 weeks in patients with acute coronary syndromes.
Reduce cardiovascular disease and may reduce the risk of osteoporotic fractures.
Given to patients with acute coronary syndromes, coronary artery disease, diabetes, high risk hypertension and diabetes reduces the risk of cardiovascular disease events.
HOPE trial Heart Outcomes Prevention Evaluation trial Evaluated the effects of statins in participants without known atherosclerotic cardiovascular disease, but with at least one risk factor in the lower risk primary prevention group.
Taking statins may be necessary:
In the presence of ASCVD statin therapy is the most effective and safest way to lower cholesterol and the chances of having a heart attack or stroke.
Very high LDL cholesterol , 190 mg/dL or higher.
For Type 2 diabetics between 40 and 75 years of age.
For individuals with likelihood of having a heart attack or stroke in the next 10 years of 7.5% or higher. and are between 40 and 75 years of age.
For patients whose 10 year risk of ASCVD is 20% or more should try to reduce LDL-C levels by at least 50%, the same goal as for people with clinical ASCVD.
For patients with a family history of premature heart attack or stroke.
The use of statins is associated with a relative risk reduction for ASCVD events regardless of baseline risk, but the absolute risk reduction is small in those at low risk and considerably greater in those at higher risk, especially in individuals with higher baseline low density lipoprotein cholesterol levels.
LDL-cholesterol > 160 md/dL
hs-CRP >2.
Results from other special testing such as CAC scoring, ABI.
People who have had a heart attack, stroke or other types of ASCVD tend to benefit the most from taking the highest dose of statin therapy.
Because not all patients will be able to take the optimum dose of statin, non-statin drugs may be recommended:
In the HOPE trial 13,000 patients were randomized to 10 mg of rosuvastatin or placebo and followed for a median 5.6 years: demonstrated a relative risk reduction
of 22.9% in the statin arm of cardiovascular events death, myocardial infarction or stroke.
Statins have been found to have activity against staph aureus infections.
Found to have antimicrobial effect against methicillin susceptible S Aureus and to a lesser extent against MRSA.
Use increases an individual’s risk for developing insomnia.
Use associated with decreased risk of bacteremia, including community-acquired staph aureus bacteremia.
Long term use of statins over 12 years was associated with reduced risk for community-acquired staph aureus bacteremia of approximately 30% (Smit).
Community-acquired staph aureus bacteremia risk reduction was associated with increasing dosage of statins.
Has antibacterial effect in multidrug-resistant organisms including Vancomycin resistant enterococci, enterobacter aerogenes, and Acinetobacter baumanni.
Reported to inhibit host cell Invasion, inhibits adhesion and biofilm formation, and reduces in cell viability and extracellular polysaccharide production.
Statins have been found to have activity against staph aureus infections.
Found to have antimicrobial effect against methicillin susceptible S Aureus and to a lesser extent against MRSA.
Has antibacterial effect in multidrug-resistant organisms including Vancomycin resistant enterococci, enterobacter aerogenes, and Acinetobacter baumanni.
Reported to inhibit host cell Invasion, inhibits adhesion and biofilm formation, and reduces in cell viability and extracellular polysaccharide production.
West of Scotland Coronary Prevention Study (WOSCOPS) found a 31% reduction in coronary events with pravastatin compared with placebo in men and included a small population of patients with symptomatic atherosclerosis disease: 6595 men aged 45-64, no pevious history of myocardial infartion and mean cholesterol of 272 mg/dL
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS) recruited men and women found a 37% reduction in first coronary events with lovastatin: randomized 6605 asymptomatic adults with mean L
JUPITER trial enrolled 17,802 healthy men and women with a LDL-C less than 130 mg/dL and an elevated high sensitivity C-reactive protein greater than 2.0 mg/L: aggressive lowering of LDL-C in those randomized to receive rosuvastin 20 mg, reduce the risk of myocardial infarction, stroke and revascularization by about 44% and total mortality by 20%.
In a retrospective study of 229,918 adults who initiated statin treatment from 1998 to 2006 conferred at least a 45% reduction in the risk of death (Shalev).
Meta-analysis of 14 clinical trials with statins indicated that such drugs can reduce the five-year incidence of major coronary events, coronary revascularization and stroke by each 20% for each millimole per liter (about 39 mg per deciliter) reduction in LDL-C (Baigent C et al).
In an analysis of eight randomized trials statins did not reduce overall mortality, and it was suggested that statins should not be prescribed for true primary prevention in women of any age and men older than 69 years (Abramson).
In a sex-based meta-analysis involving 43,193 patients statin therapy reduced risk of cardiovascular events in all outcomes for women and men (Gutierrez j et al).
Statins did not reduce all cause mortality in women versus men or stroke in the above study.
Statin therapy is effective intervention in the secondary prevention of cardiovascular events in both sexes, but there is no benefit on stroke and all cause mortality in women.
Some studies suggest that modest reduction of 12% in all cause mortality (Kearney).
An international multicenter registry study observed a substantial reduction in 30-day and 90-day stroke risk after a TIA presentation in patients on statins, if they had evidence of carotid stenosis, but not otherwise (Merwick A et al.).
Statins reduce stroke risk when initiated months after transient ischemic attack (TIA)/stroke.
Statins reduce early vascular events in acute coronary syndromes.
In acute symptomatic carotid stenosis, statin pretreatment was associated with reduced stroke risk supporting the hypothesis that statins started acutely after TIA symptom onset may also be beneficial to prevent early stroke.
The addition of bile acid sequestrants, niacin, or ezetimibe to statins adds an additional 10-20% reduction in LDL cholesterol.
SLCO2B1 is an organic anionic transporter whose expression increases on progression from hormone sensitive to castrate resistant disease.
ACC/AHA cholesterol guidelines, which identify four groups of patients that would likely benefit from moderate to high intensity statin therapy: 1) those with established clinical arteriosclerosis vascular disease, 2) those age 40-75 years who have diabetes, 3) those with low density lipoprotein cholesterol levels of 190 mg/dL or higher and, 4) those age 40-75 years who have low density lipoprotein cholesterol levels of 72-189 mg/dL and am estimated risk of 7.5% or greater.
Statins compete with dehydrepiandrosterone for influx by SLCO2 B1 which may decrease prostate cancer tumor’s available androgen pool.
Use of statins associated with the median ten-month prolongation in time to progression with androgen deprivation therapy and 17% reduction in hazard of progression during ADT therapy.
There is a beneficial role of statin use after diagnosis across the continuum of prostate cancer.
In a meta-analysis of six studies, the use of statins was associated with a 24% lower risk of cancer mortality among patients with prostate cancer.
In studies of men with advanced prostate cancer, those who were taking a statin at the time of the initiation of androgen-deprivation therapy had a longer time to progression compared with nonusers of statins.
Larsen et al study included 31,790 men with prostate cancer, of whom 7,365 died of the disease, and reported a hazard ratio. for postdiagnostic statin use and prostate cancer mortality of 0.83.
A biologic mechanisms that underlie this association have been postulated as cholesterol being a precursor of androgens, and can act by reducing androgen bioavailability, thereby limiting tumor growth.
Cholesterol-independent pathways that mediate statin action in prostate cancer may also be operative.
Statins use transporters that interfere with androgen precursor cellular uptake by blocking solute carrier organic anionic transporters.
Significantly reduce C-Reactive proteins.
High sensitivity C-Reactive Protein (CRP) levels is an inflammatory biomarker.
In healthy patients with high sensitivity C-reactive protein (hsCRP) without elevated low density lipoproteins levels, using a statin reduced the levels of the LDL-C and significantly reduced risk of myocardial infarction, stroke and death.
Decreases platelet aggregation, improves endothelial function and inhibits inflammation.
May induce angiogenesis by recruiting bone marrow stem cells.
Improvement in endothelial function results in improvements in myocardial perfusion.
All agents are associated with myopathy, ranging from asymptomatic increases in creatinine kinase to muscle aches, weakness, or even fatal rhabdomyolysis.
Risk of myopathy is increased with escalating doses.
Have antioxidant activity.
Can be found in the lens.
Use associated with lowered risk of nuclear cataracts.
If myopathy is not recognized and drug therapy continues, rhabdomyolysis and acute renal failure may occur.
Myopathy more likely to occur when a statin is used in combination with fibrates, niacin, or inhibitors of the cytochrome P-450 system.
Patients with underlying renal dysfunction or infection are at increased risk of myopathy.
Routine periodic monitoring of liver enzymes is not effective, and liver disease caused by statins is very rare.
When liver disease is suspected, serum bilirubin is the preferred laboratory test for screening.
Decrease LDL-C (low-density lipoprotein-cholesterol)-levels in the order of 25-35%.
Reduces relative risk for coronary events 24-37%.
Despite statins annual cardiovascular events range from 1.7-2.5% in primary prevention trials and 6.4-7.8% in secondary prevention trials.
Reduce the risk of coronary heart disease events for women with cardiovascular disease.
For women without cardiovascular disease lipid lowering does not appear to have a beneficial effect over a 6 year study.
An observational study involving 153,840 postmenopausal women in the women’s health initiative accessed patients for statin use at baseline and then for three years: 7% were taking statins at baseline and their use was associated with a 48% greater risk of developing diabetes compared with women not taking such medications (:Culver AL et al).
Associated with increased risk for developing type two diabetes and the risk is found to be dose related.
The US preventive Services Task Force recommended with moderate grade evidence, that in adults aged 40 – 75 years who had an estimated 10 year ascvd risk of 10% or higher and at least one major risk factor should be offered to a low to moderate intensity Statin with a weaker endorsement for the use of low-to-moderate intensity statins for those with risk between 7 1/2 and 10%.
USPSTF finds insufficient evidence to make specific recommendations for the use of statins for adults older than 75 years.
Among US veterans 75 years and older and free of ASCVD at baseline, new statin use was significantly associated with a lower risk of all cause mortality and cardiovascular mortality (Orkaby AR).
PROSPER trial of statins for patients with the mean age or older to 75 years, in the primary prevention there is no significant benefit on coronary deaths, non fatal myocardial infarction, and fatal of a non-fatal stroke.
The ACC/ AHA guidelines shows no mortality benefit of statin treatments for individuals older than 75 years, where is other reports suggest harm, including the possibility of increasing mortality with statin use in this age group.
Reduces exercise-induced myocardial ischemia in hypercholesterolemic patients with mild or severe epicardial coronary stenosis.
Induce vascular remodeling with reduced atherosclerotic burden without changes in the lumen size.
Reduce death and myocardial infarction with only a minor improvement in coronary artery stenosis.
Does not reduce the risk of osteoporotic fracture.
Reduces the risk of coronary artery disease in elderly individuals.
In elderly does not reduce risk of stroke.
Patients without modifiable cardiovascular risk factors derive no benefit from initiating statins after the 75 years of age.
Statin treatment is associated with less acute coronary syndrome or all-cause death in elderly patients treated for secondary prevention or primary prevention with identified modifiable risk factors.
Statins decrease major vascular events like stroke and heart attack regardless of age.
The evidence is less robust for people over age 75, but evidence suggests this age group may also benefit.
In the Cholesterol Treatment Trialists’ Collaboration analysis 28 large research clinical trials of statin therapy compared to placebo or usual care.
The analysis included over 185,000 patients,of which 8 percent were over age 75.
Participants took statins for about five years, on average.
For each 1.0 mmol/L (38.6 mg/dL) decrease in LDL that resulted from statin use, the risk of major vascular events decreased by 21 percent overall.
All age groups showed a significant decrease in major vascular events associated with statin use.
There was a significant trend towards smaller risk reduction with increasing age for major coronary events like heart attacks.
Results showed less evidence of benefits for statins in people over age 75 who do not already have vascular disease.
The absolute benefit of decreasing LDL with statins may be substantial in older individuals, because the absolute risk of major vascular events increases exponentially with age in untreated individuals.
Intensive lipid-lowering therapy with intensive atorvastatin is more effective than moderate doses of pravastatin in reducing progression of coronary atheroslerosis in with coronary artery disease.
Reduce CRP in patients with mixed hyperlipidemia and
Hypoparathyroidism is associated with statin myopathy possibly because with hypocalcemia it produces a myopathy with elevated CK levels.
Interferes with the production of coenzyme Q10.
All treated patients should have liver functions.
Most common adverse liver effects is asymptomatic and usually transient elevation of serum aminotransferase (transaminitis).
Most often liver function test abnormalities occur in the first 12 weeks of treatment.
Most commonly elevated aminotransferase levels are not accompanied by histological changes.
Liver changes may be related to alterations in lipid components in hepatocyte membrane with increased permeability of liver enzymes.
Alanine aminotransferase (ALT) elevations are more reliable than aspartate aminotransferase (AST) levels in monitoring liver functions.
Clinically significant hepatotoxicity from statins are rare events.
Statin induced liver disease defined as ALT level 2-3 times normal and a conjugated bilirubin level 2 times normal, but a 10 times ALT level should be the level to distinguish hepatotoxicity from transaminitis (FDA).
Patients with persistent elevations in ALT greater than 10 times normal often associated with co-morbid conditions, and concomitant use of hepatotoxic medications that can interact with statins or can induce hepatotoxicity.
Medication history, chemistry tests and liver imaging are necessary to exclude other processes that may account for elevated liver function tests.
Most statins are metabolized by the cytochrome system and therefore hepatotoxicity may be a result of drug interactions.
In true statin related liver toxicity no diagnostic biochemical or histological pattern of injury exists.
A retrospective study suggest that patients who discontinue statin therapy because of myopathies and do not have rhabdomyolysis, can be successfully rechallenged with the same or a lower dose of the same statin or with a different statin.
In the above study many patients are able to tolerate an alternate-day regimen (Zhang et al).
Statin-related myalgias and hepatotoxicity are dose-related.
Reducing systemic drug concentration may lower the incidence of statin associated adverse reactions.
Every-other-day dosing, especially of the newer statins with longer half-lives such as rosuvastatin and atorvastatin, preserves lipid-lowering effects, with a degree shown to be similar to that seen in patients receiving daily statin therapy.
The higher potency statins may be taken it anytime during the day or night.
The elimination half life of rosuvastatin is 19 hours and that of atorvastatin is 13 hours.
Muscle symptoms related to statin therapy have a spectrum ranging from benign myalgias with pain or soreness with no creatine kinase [CK] elevation to myopathy with symptoms of myalgia with a CK level higher than 10 times the upper limit of normal to life-threatening rhabdomyolysis
Incidence of myopathy ranges from about 1.5% to 5%.
The major sites of myopathy pain involve thighs, calves, or both.
Although the average time to onset of symptoms varies, the median time to the onset of symptoms is 1 month, with a range up to 12 months.
Risk factors for muscle-related adverse symptoms include advanced age, female gender, small body frame, and comorbid medical conditions, drug interactions, and high doses of statins.
Fibrates, amiodarone, cyclosporine, macrolide antibiotics, protease inhibitors, and verapamil increase the likelihood of a muscle-related adverse affects.
Atorvasatin, simvastatin and lovastatin are metabolized by CYP3A4 and increase risk of drug interactions.
Pravastatin is renally eliminated and not metabolized by the CYP system.
Fluvastatin and rosuvastatin are primarily metabolized by CYP2C9.
In most patients muscle symptoms resolve quickly on cessation of therapy.
At first presentation of symptoms, CK levels should be done and compared with baseline values.
If the CK level is more than 10 times normal or higher than 10,000 IU/L, statin therapy should be discontinued, and for patients with CK levels less than 10 times normal the CK level and symptoms may be monitored and, if tolerable, the patient may continue on therapy at the same or a reduced dosage.
In patients with muscle symptoms the statin should be discontinued until the patient is asymptomatic and then the patient may be rechallenged with the same or a different statin at the same or a reduced dosage.
Among patients who were rechallenged with a statin after a statin-related event, 90% ultimately could tolerate the statin and continued to take the statin 12 months after the initial event.
Rechallenging with the same or a lower dose of the same or a different statin can help identify patients who are experiencing a true ADR as well as maintain the treatment�s lipid-lowering and maximum cardiovascular benefit.
Some patients may benefit from a switch to a more potent statin, such as rosuvastatin, but at a lower dosage to achieve the same reduction of LDL.
If a drug interaction is the cause of muscle pain, a switch to a statin not metabolized by CYP3A4 or eliminated via the renal system is an option.
If symptoms develop on rechallenge, therapy, the statin may be discontinued altogether and treatment may be switched to a nonstatin lipid-lowering medication.
Hepatocellular, cholestatic and mixed patterns of abnormalities have been described, as well as autoimmune hepatitis.
Acute liver failure to statins reportedly very rare, as lovastatin associated liver failure reportedly 1 in 130,000 patient years (Dujovne CA, Onofrei MD).
Of 51,741 liver transplants for acute liver failure fro 1990-2002 only 3 cases were associated with statins (Russo MW).
Myopathy is accompanying muscle weakness occurs in 1 in 1000 patients.
In cases of persistent elevations of liver functions the dosage of the drug should be reduced or treatment discontinued.
25% reduction in the incidence of coronary events is associated with a reduction of 40 mg per deciliter in the LDL cholesterol level.
Patients with LDL cholesterol in the normal range-below 100 mg per deciliter- receive as much benefit as patients with high LDL levels suggesting benefits related to more than the cholesterol lowering effect.
West Scotland coronary Prevention Study (WOSCOPS) randomized, double blind placebo controlled trial of pravastatin (Pravachol) in middle aged men with hypercholesterolemia without a history of myocardial infarction: after 5 years the combined outcome of death from coronary heart disease or definite myocardial infarction was reduced from 7.9% in the placebo group to 5.5% in the statin group, and the risk of death from definite or suspected coronary artery disease was reduced from 1.9% to 1.3%.
West Scotland coronary Prevention Study (WOSCOPS) as above was extended for 10 years after its completion and revealed that there was a persistent reduction in coronary artery events in the pravastatin group.
Atorvastatin (Lipitor) reduces the risk of stroke and myocardial infarction in patients with type 2 diabetes who demonstrate risk factors of heart disease.
Combination with a fibrate prevents the lowering of HDL cholesterol that may be seen with the use of a statin alone.
The Heart Protection Study randomized 20,000 patients to daily simvastatin or placebo for up to 5 years and no difference in cancer incidence was noted to be present among the groups (7.9% vs. 7.8%).
Strong association of myopathy with the rs4363657 single nucleotide polymorphism located within SLCO1B1 on chromosome 12.
SLCOO1B1 encodes the organic anion transporting polypeptide OATP1B1, which has been shown to regulate hepatic uptake of statins.
rs4149056 C allele in the population is 15% and these patients have a high risk of myopathy.
Fasting lipid levels should be done at the initiation of statin therapy and 4-12 weeks following treatment to assess effectiveness.
Thereafter fasting lipid levels should be performed every 3-12 months if clinically indicated.
Routine assessment of creatinine kinase and liver function testing is not recommended.
Use in patients with prostate cancer reduces all cause and prostate cancer specific mortality.
Newly diagnosed patients with nonmetastatic prostate cancer had a 24% reduction in risk for prostate cancer death and 14% reduction in all-cause mortality if they were treated with statins (Yu et al).
As a consequence different half-lives, atorvastatin can be taken at any time during the day with consistent efficacy, but simvastatin should be taken at night.
Cytochrome P450 is the major enzyme involved in the metabolic degradation of many statins.
In patients with muscle related intolerance who refuse to take statins management may include very low or intermittent administration of statins, or use of Ezetimibe , but the strategy seldom achieve greater than 50% reduction recommended my current guidelines.
Data from almost 5,000 U.S. veterans, indicate statins may improve survival for multiple myeloma patients: patients who used a statin had a 21% reduced risk of death from any cause and a 24% reduced risk of death from myeloma, and overall survival of statin users was 39.5 months compared to 27 months among nonusers.
High-intensity statin therapy was associated with markedly reduced rates of knee and hip replacement surgery for osteoarthritis or rheumatoid arthritis in a longitudinal cohort study comparing nearly 180,000 statin users with an equal number of propensity-matched nonusers, Jie Wei, PhD,
Statin treatment is generally associated with reduced likelihood of hypoglycemia, however in patients with low serum albumin, the use of high-intensity statins is associated with an increased risk, regardless of diabetes status.
A retrospective analysis suggests that older individuals taking statins had a 25% decreased risk for death than those not taking statins.
The study included data on patients aged 75 years or older from the Veterans Health Administration who were free of atherosclerotic cardiovascular disease, and who had a clinical visit between 2002 and 2012.
Mean follow-up was 6.8 years.
More than 57,000 patients were newly initiated statin users during the study period.
There were 53,296 reported cardiovascular deaths, with 22.6 and 25.7 cardiovascular deaths per 1,000 person-years, respectively, among users vs. non-users.
For atherosclerotic cardiovascular disease outcome, there were 66.3 and 70.4 events per 1,000 person-years, respectively, for users versus non-users.
The hazard ratio was 0.75 for all-cause mortality, 0.80 for cardiovascular mortality, and 0.92 for the composite atherosclerotic cardiovascular disease events in statin users versus non-users.
Results of the study found the benefit of statins held true regardless of whether a person was older or younger or had a condition such as dementia.