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The role of statins in reducing cholesterol levels and coronary heart disease. | ||
What Are Statins?The statins (or HMG-CoA reductase inhibitors) are used to lower cholesterol levels in people with or at risk of cardiovascular disease. The first results can be seen after one week of use and the effect is maximal after four to six weeks. CholesterolCholesterol is critical to the normal function of every cell in the body. However, it also contributes to the development of atherosclerosis, a condition in which cholesterol-containing plaques form within arteries. These plaques block the arteries and reduce the flow of blood to the tissues. When plaques rupture, a blood clot forms on the plaque, thereby further blocking the artery and reducing the flow of blood. When blood flow is reduced sufficiently in the arteries that supply blood to the heart, the result is angina (chest pain on exertion) or a heart attack. If the clot occurs on plaques in the brain, the result is a stroke. If the clots occur on plaques in the leg, they cause intermittent claudication (pain in the legs when walking). By reducing the production of cholesterol, statins are able to slow the formation of new plaques and occasionally can reduce the size of plaques that already exist. In addition, through mechanisms that are not well understood, statins may also stabilize plaques and make them less prone to rupturing and promoting the development of clots. HistoryResearch into inhibitors of HMG-CoA reductase began in Japan in 1971. It was believed that some microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, by defending their cell wall. The first statin isolated was mevastatin produced by Penicillium citrinum. Merck & Co. isolated lovastatin the first commercially marketed statin, from the mold Aspergillus terreus. Mechanism of actionStatins inhibit the enzyme HMG-CoA reductase, the enzyme controlling the first step of sterol (cholesterol) synthesis, in the liver. Because statins are similar to HMG-CoA on a molecular level they take the place of HMG-CoA in the enzyme and reduce the rate by which it is able to produce mevalonate, the next molecule in the pathway to cholesterol. IndicationsStatins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (bad cholesterol). This results in a 60% decrease in the number of cardiac events (heart attack, sudden cardiac death), and a 17% reduced risk of stroke. Clinical guidelines require that the patient has tried a cholesterol-lowering diet before statin use is commenced; statins are recommended for patients who do not meet lipid-lowering goals through diet and lifestyle approaches alone. The indications for the prescription of statins have broadened over the years. Initial studies, such as the Scandinavian Simvastatin Survival Study , supported the use of statins in secondary prevention for cardiovascular disease (secondary prevention activities are aimed at early disease detection increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms), or as primary prevention (primary prevention avoids the development of a disease) only when the risk for cardiovascular disease was significantly raised (as indicated by the Framingham risk score).9801Indications 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.0601 The statins have increasingly played an important role in both the primary and secondary prevention of coronary heart disease, myocardial infarction, stroke and peripheral artery disease. Crestor, Rosuvastatin, could reduce by 44 percent the risk of heart problems among patients who have normal cholesterol but with with elevated High-sensitivity C-Reactive Protein - hsCRP. CRP is a protein produced by the liver that plays an important role in inflammatory processes and serves as a biological marker to measure the risk of artery blockage. The study of 17,802 men and women aged 50 or more demonstrated that 20 milligrams of Crestor taken daily significantly reduced the combined risk of myocardial infarction, stroke, hospitalization for unstable angina, or death from cardiovascular causes by 44 percent compared to placebo among men and women with elevated hsCRP but low to normal cholesterol levels. The combined risk of heart attack, stroke or death from heart disease was reduced by 47 percent, the risk of heart attack was cut by more than half, the risk of stroke by nearly half and total mortality was reduced by 20 percent.0802 Research continues into other areas where statins also appear to have a beneficial effect including:-
Fermentation-derived and synthetic StatinsThe statins are divided into two groups: fermentation-derived and synthetic. The statins include, in alphabetical order:
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.0301 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.0602 The CURVES study, which compared the efficacy of different doses of atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin for reducing LDL and total cholesterol in patients with hypercholesterolemia, found that atorvastatin was more effective without increasing adverse events.9802 The statins also differ in how strongly they interact with other drugs. Specifically, pravastatin (Pravachol) and rosuvastatin (Crestor) levels in the body are less likely to be elevated by other drugs that may be taken at the same time as the statins because the enzymes in the liver that eliminate pravastatin and rosuvastatin are not blocked by many of the drugs that block the enzymes that eliminate other statins. This prevents the levels of pravastatin and rosuvastatin from rising and leading to increased toxicity.
Safety of StatinsStatins are generally well-tolerated. 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 trials and usually resolve, either on their own or by temporarily reducing or stopping the dose. There are two major side effects that occur relatively rarely: raised liver enzymes and skeletal muscle damage. Liver enzyme changes may 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 discontinuation over time or after briefly discontinuing the drug. A major safety concern, myositis, myopathy, rarely with rhabdomyolysis (the pathological breakdown of skeletal muscle) may lead to acute renal failure when muscle breakdown products damages the kidneys. There is a genetic predispositon due to a common variation in the SLCO1B1 gene, which participates in the absorption of statins, and has also been shown to significantly increase the risk of myopathy. All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological half-lives 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 are more hydrophillic and as a result have less muscle penetration. Several studies have concluded that statins have no influence on cancer risk0501,0603. Combining any statin with a fibrate, another group of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in renal function. Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins. This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not 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. Mode of action of statinsMost circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, 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 developed countries is about 200–300 mg/day, an amount much smaller than that secreted into the intestine in the bile. Thus it is internal production is an important factor. Cholesterol is not water-soluble, and is therefore carried in the blood in the form of lipoproteins. 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. Conversely, high density lipoprotein (HDL), carries cholesterol back to the liver and is associated with protection against cardiovascular disease. Statins act by competitively inhibiting HMG-CoA reductase. 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. Evidence of the action of statin-based cholesterol lowering on atherosclerosis was provided by the ASTEROID trial, which has demonstrated regression of atheroma employing intravascular ultrasound.0601 Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Currently it is believed that statins prevent cardiovascular diseaseeby four mechanisms (all subjects of a large body of biomedical research):
A much smaller minority, exemplified by The International Network of Cholesterol Skeptics, question the "lipid hypothesis" itself and argue that elevated cholesterol has not been adequately linked to heart disease. These groups claim that statins are not as beneficial or safe as suggested.
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