Everything about The Statin totally explained
The
statins (or
HMG-CoA reductase inhibitors) form a class of
hypolipidemic drugs used to lower
cholesterol levels in people with or at risk of
cardiovascular disease. They lower cholesterol by inhibiting the enzyme
HMG-CoA reductase, which is the
rate-limiting enzyme of the mevalonate pathway of
cholesterol synthesis. Inhibition of this enzyme in the
liver stimulates
LDL receptors, resulting in an increased
clearance of
low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks.
History
Akira Endo and Masao Kuroda of
Tokyo,
Japan commenced research into inhibitors of HMG-CoA reductase in
1971 (Endo 1992). This team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as
mevalonate is a precursor of many substances required by organisms for the maintenance of their cell wall (
ergosterol) or
cytoskeleton (
isoprenoids).
The first agent isolated was
mevastatin (ML-236B), a molecule produced by
Penicillium citrinum. The
pharmaceutical company Merck & Co. showed an interest in the Japanese research in
1976, and isolated
lovastatin (mevinolin, MK803), the first commercially marketed statin, from the mold
Aspergillus terreus. Dr Endo was awarded the 2006
Japan Prize for his work on the development of statins.
Indications and uses
Statins, the most potent cholesterol-lowering agents available, lower
LDL cholesterol (so-called "bad cholesterol") by 30–50%. However, they've less effect than the
fibrates or
niacin in reducing
triglycerides and raising
HDL-cholesterol ("good cholesterol"). Professional guidelines generally require that the patient has tried a cholesterol-lowering diet before statin use is considered; statins or other pharmacologic agents may then be recommended for patients who don't meet their lipid-lowering goals through diet and lifestyle approaches.
The indications for the prescription of statins have broadened over the years. Initial studies, such as the
Scandinavian Simvastatin Survival Study (4S), supported the use of statins in
secondary prevention for cardiovascular disease, or as primary prevention only when the risk for cardiovascular disease was significantly raised (as indicated by the
Framingham risk score). Indications were broadened considerably by studies such as the
Heart Protection Study (HPS), which showed preventative effects of statin use in specific risk groups, such as
diabetics. The
ASTEROID trial, published in 2006, using only a statin at high dose, achieved lower than usual target calculated LDL values and showed disease regression within the
coronary arteries using
intravascular ultrasonography.
Based on clinical trials, the
National Cholesterol Education Program guidelines, and the increasing focus on aggressively lowering LDL-cholesterol, the statins continue to play an important role in both the primary and secondary prevention of
coronary heart disease,
myocardial infarction,
stroke and
peripheral artery disease.
Research continues into other areas where statins also appear to have a favorable effect:
inflammation,
dementia,
cancer,
nuclear cataracts, and
hypertension.
Members
The statins are divided into two groups:
fermentation-derived and
synthetic.
The statins include, in alphabetical order (brand names vary in different countries):
LDL-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potency of pitavastatin hasn't yet been fully established.
Comparative effectiveness
No large scale comparison exists that examines the effectiveness of the various statins against one another.
An independent analysis has been done to compare atorvastatin, pravastatin and simvastatin, based on their effectiveness against
placebos. It found that, at commonly prescribed doses, there are no
statistically significant differences in reducing cardiovascular morbidity and mortality.
Safety
Adverse effects
While some patients on statin therapy report
myalgias,
muscle cramps, or far less-frequent gastrointestinal or other symptoms, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose.
Liver enzyme derangements may also occur, typically in about 0.5%, are also seen at similar rates with placebo use and repeated enzyme testing, and generally return to normal either without discontinuance over time or after briefly discontinuing the drug. Multiple other side-effects occur rarely; typically also at similar rates with only placebo in the large statin safety/efficacy trials.
A clearer major safety concern,
myositis,
myopathy, rarely with
rhabdomyolysis (the pathological breakdown of
skeletal muscle) may lead to
acute renal failure when muscle breakdown products damage the kidney.
Coenzyme Q10 (ubiquinone) levels are decreased in statin use; Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking.
One
2004 study found that of 10,000 patients treated for one year, 0.44 will develop rhabdomyolysis.
Cerivastatin, which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x). All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological
half-lives and more cellular specificity, have had a better ratio of
efficacy to lower adverse effect rates. The risk of myopathy is lowest with
pravastatin and
fluvastatin probably because they're more hydrophillic and as a result have less muscle penetration.
Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.
Despite initial concerns that statins might increase the risk of
cancer, various studies concluded later that statins have no influence on cancer risk (including the
heart protection study and a 2006
meta-analysis). Indeed, a 2005 trial showed that patients taking statins for over 5 years
reduced their risk of
colorectal cancer by 50%; this effect wasn't exhibited by
fibrates. The trialists warn that the
number needed to treat would approximate 5000, making statins unlikely tools for primary prevention. However, in a recent meta-analysis of 23 statin treatment arms with 309,506 person-years of follow-up, there was an inverse relationship between achieved LDL-cholesterol levels and rates of newly diagnosed cancer that the authors claim requires further investigation.
Drug interactions
Combining any statin with a
fibrate, another category of lipid-lowering drugs, increases the risks for
rhabdomyolysis to almost 6.0 per 10,000 person-years. (it had been thought that
flavonoids were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice isn't recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins. This isn't recommended as a result of the increased risk and potential for statin toxicity.
Pharmacogenomics
A 2004 study showed that patients with one of two common
single nucleotide polymorphisms (small genetic variations) in the
HMG-CoA reductase gene were less responsive to statins.
Mode of action
Cholesterol lowering
steroid biosynthesis through the
HMG-CoA reductase pathway. Cholesterol, both from dietary intake and secreted into the
duodenum as
bile from the liver, is typically absorbed at a rate of 50% by the
small intestines. The typical diet in the United States and many other Western countries is estimated as adding about 200–300 mg/day to intestinal intake, an amount much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor.
Cholesterol isn't water-soluble, and is therefore carried in the blood in the form of
lipoproteins, the type being determined by the
apoprotein, a protein coating that acts as an
emulsifier. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, and
insulin resistance.
Low density lipoprotein (LDL) and
very low density lipoprotein (VLDL) carry cholesterol toward tissues, and elevated levels of these lipoproteins are associated with
atheroma formation (fat-containing deposits in the arterial wall) and
cardiovascular disease.
High density lipoprotein, in contrast, carries cholesterol back to the liver and is associated with protection against cardiovascular disease.
Statins act by
competitively inhibiting HMG-CoA reductase, the first committed
enzyme of the
HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, they cause
liver cells to make more
LDL receptors, leading to increased clearance of low-density lipoprotein from the bloodstream.
Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the
ASTEROID trial, which demonstrated regression of
atheroma employing
intravascular ultrasound.
- Improving endothelial function
- Modulate inflammatory responses
- Maintain plaque stability
- Prevent thrombus formation
Controversy
Some scientists take a skeptical view of the need for many people to require statin treatment. Given the wide indications for which statins are prescribed, and the declining benefit in groups at lower baseline risk of cardiovascular events, the evidence base for expanded statin use has been questioned by some researchers. A much smaller minority, exemplified by
The International Network of Cholesterol Skeptics, question the "
lipid hypothesis" itself and argue that elevated cholesterol hasn't been adequately linked to heart disease. These groups claim that statins are not as beneficial or safe as suggested.
Further Information
Get more info on 'Statin'.
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