Statin



Associate Editor-in-Chief:: Elliot B. Tapper, MD. Department of Medicine, Beth Israel Deaconess Medical Centre

Overview
The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceutical agents 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.

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 has not yet been fully established.

Cholesterol lowering
Most circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, via carbohydrate metabolism 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 is not 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.

Non-cholesterol related actions
Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):
 * 1) Improving endothelial function
 * 2) Modulate inflammatory responses
 * 3) Maintain plaque stability
 * 4) Prevent thrombus formation

Indications and uses
Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (so-called "bad cholesterol") by 30–50%. However, they have 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 do not 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 pulmonary hypertension.

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.

Safety
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.

Hepatic Injury
While clinically important hepatotoxicity is exceedingly rare, statin hepatopathy is more common and ranges from mild liver enzyme derangements to, rarely, liver failure. The first response to liver enzyme elevation in the setting of statin use ought to be to rule out other causes. .

Any drug-induced hepatopathy is defined as an elevation in the alanine aminotransferase (ALT) levels of greater than 3-times the upper limit of normal or elvation of indirect bilirubin levels of greater than 2 times the upper limit of normal. With respect to statins, the liver injury is purely hepatocellular - a 'transaminitis' - and present as a dose-dependent, class-effect in 1-3% of patients taking statins, as observed in clinical trials (though often not significantly different from transaminase elevations in the placebo groups). Generally - in more than 70% of instances - these elevations return to normal over time. Rarely, this injury becomes chronic. If patients are to experience a clinically significant liver injury from statin use, it typically manifests itself within 9-11 weeks. Liver failure is the rarest side-effect; 3 patients have required liver transplantation (though 2 were taking the long-discontinued cerivistatin).

Myopathy
Statin induced muscle pain is common while serious muscle damage is rare. Many patients complain of muscle pain without laboratory evidence of muscle damage. The chief concern, however, is frank muscle breakdown or rhabdomyolysis which can leaded to renal failure, though it is very rare. 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. In a review of the randomized-controlled trials for statin therapy, 7 patients experienced rhabdomyolysis while receiving statins at the same time as 5 patients who were receiving placebo. Between 1990 and 2002, the Food and Drug Administration received 3339 reports of patients with rhabdomyolysis while taking a statin, 10.4% of which were life-threatening. However, 52% of these patients were taking other medications associated with rhabdomyolisis.

The pathophysiology of statin-myopathy is fairly well understood. On one hand, Co-Enzyme Q-10 (ubiquinone) levels are decreased in statin use; Ubiquinoine is a product of the steroid synthesis pathways and as such its production is reduced in statin use. It is also a key component of the electron transport chain of mitochondria. Accordingly, with less ubiquinone, the cell is less likely to meet its energy needs and may die. Coenzyme Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking. Additionally, statins - and not their metabolites - are directly toxic to liver cells. They have been shown to increase cell-death by causing both an increase in intracellular calcium concentration and the translocation into the mitochondria of bax, a pro-apoptotic protein.

The risk of myopathy may be lowest with pravastatin and fluvastatin probably because they are less lipophillic and as a result have less muscle penetration.

Neuromuscular Disorders and Mitochrondrial Myopathies
There is also a small, but growing literature of statin use 'unmasking' latent neurmuscular disorders and mitochondrial myopathies such as McArdle's Disease, Kennedy's Disease, MELAS, and Myasthenia Gravis.

Cancer Concerns
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 was not exhibited by fibrates. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.

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. 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&mdash;furanocoumarins in grapefruit juice inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however it is a major inhibitor of only atorvastatin, lovastatin and simvastatin) and some other medications (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 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. This is not recommended as a result of the increased risk and potential for statin toxicity.

Controversy
Some scientists take a skeptical view of the need for many people to require statin treatment. The International Network of Cholesterol Skeptics is a group that has questioned the "lipid hypothesis" that supports cholesterol lowering as a preventive measure for heart disease, and has argued that statins - especially at higher doses - may not be as beneficial or safe as suggested. Similarly, some authors argue that recommendations for the expanded use of statins to stave off cardiovascular disease are not supported by evidence.