Statin

The statins, also known as HMG-CoA reductase inhibitors, belong to a class of hypolipidemic agents widely used as pharmaceuticals to lower cholesterol levels in individuals at risk for cardiovascular disease due to hypercholesterolemia. These medications work by inhibiting the enzyme HMG-CoA reductase, which plays a crucial role in determining the speed of cholesterol synthesis. By inhibiting this enzyme in the liver, statins stimulate the LDL receptors, leading to increased clearance of LDL from the bloodstream and ultimately resulting in decreased blood cholesterol levels. The initial effects of statin therapy can usually be observed after just one week of use, with maximum efficacy achieved within four to six weeks.

Statin mechanism

Members

The statins encompass several members, listed below in alphabetical order (please note that brand names may vary across different countries):

• Atorvastatin (Lipitor, Torvast)
• Blorivastatin (Lipex)
• Cerivastatin (Lipobay, Baycol) – withdrawn from the market in 2001 due to the risk of serious adverse effects.
• Fluvastatin (Lescol)
• Lovastatin (Mevacor, Altocor)
• Mevastatin – a naturally occurring compound found in red yeast rice (Monascus purpureus)
• Pitavastatin (Livalo, Pitava)
• Pravastatin (Pravachol, Selektine, Lipostat)
• Rosuvastatin (Crestor)
• Simvastatin (Zocor, Lipex)

It's worth noting that the LDL-lowering potency may vary among these agents. Cerivastatin was considered the most potent, followed by rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potency of pitavastatin has not yet been fully established.

The statins can be classified into two groups based on their origin:

Fermentation-derived statins: These include lovastatin, simvastatin, and pravastatin. Synthetic statins: This group comprises fluvastatin, atorvastatin, cerivastatin, and rosuvastatin. Fermentation-derived statins are generally considered more effective in reducing LDL levels, although the underlying reasons for this phenomenon have not been fully elucidated.

Mode of Action

Cholesterol Lowering

Most cholesterol circulating in the body is synthesized internally through the HMG-CoA reductase pathway, which is responsible for producing approximately 1000 mg of cholesterol within a 24-hour period. In addition to internal production, cholesterol is absorbed from dietary sources and secreted into the duodenum as bile from the liver. The small intestines typically absorb about 50% of the cholesterol, while the diet in the United States and other Western countries contributes an estimated 200-300 mg/day to the intestinal intake, which is much smaller compared to the amount secreted into the intestine through bile. Hence, internal production plays a significant role in cholesterol levels.

Since cholesterol is not water-soluble, it is transported in the bloodstream in the form of lipoproteins. The specific type of lipoprotein is determined by the apoprotein, which acts as an emulsifier. The balance between different lipoproteins is influenced by various factors, including genetics, diet, and insulin resistance. Low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) transport cholesterol to tissues and elevated levels of these lipoproteins are associated with the development of atheroma (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 exert their effects by competitively inhibiting HMG-CoA reductase, the initial and crucial enzyme in the HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, statins induce an upregulation of LDL receptors in liver cells, leading to increased clearance of LDL from the bloodstream. This mechanism ultimately results in decreased LDL cholesterol levels.

The efficacy of statins in reducing atherosclerosis, a major contributor to cardiovascular disease, has been supported by direct evidence. Studies such as the ASTEROID trial have demonstrated the regression of atheroma using intravascular ultrasound imaging following treatment with statins. This trial provided significant evidence of the beneficial impact of statins on atherosclerosis.

Non-Cholesterol Related Actions

Statins have been found to exhibit actions beyond their lipid-lowering effects in the prevention of atherosclerosis. Researchers have proposed four mechanisms through which statins may contribute to the prevention of cardiovascular disease, all of which are subjects of extensive biomedical research:

Improving Endothelial Function: Endothelial cells line the inner surface of blood vessels and play a vital role in maintaining vascular health. Statins have been shown to enhance endothelial function by promoting the production of nitric oxide, a molecule that helps relax and dilate blood vessels, improving blood flow.

Modulating Inflammatory Responses: Chronic inflammation is a key contributor to the development and progression of atherosclerosis. Statins have been found to possess anti-inflammatory properties, reducing the production of pro-inflammatory molecules and inhibiting immune cell activation within the arterial wall.

Maintaining Plaque Stability: Atherosclerotic plaques can become unstable and prone to rupture, leading to the formation of blood clots that can block arteries and cause heart attacks or strokes. Statins have been shown to promote plaque stability by decreasing inflammation within the plaque, inhibiting the breakdown of the fibrous cap that covers the plaque, and reducing the accumulation of inflammatory cells.

Preventing Thrombus Formation: Statins have antithrombotic effects, meaning they help prevent the formation of blood clots. They do so by inhibiting platelet aggregation and reducing the production of clot-promoting substances, thus decreasing the risk of cardiovascular events related to clot formation.

The non-cholesterol related actions of statins contribute to their overall cardiovascular benefits beyond cholesterol reduction. These additional effects make statins valuable therapeutic agents in the prevention and treatment of cardiovascular disease.

Proper Use of This Medicine Use this medicine only as directed by your doctor. Do not use more or less of it, and do not use it more often or for a longer time than your doctor ordered. Remember that this medicine will not cure your condition but it does help control it. Therefore, you must continue to take it as directed if you expect to keep your cholesterol levels down. Follow carefully the special diet your doctor gave you. This is the most important part of controlling your condition, and is necessary if the medicine is to work properly. For patients taking atorvastatin and simvastatin:

• Do not take these medicines with large amounts of grapefruit juice

For patients taking lovastatin:

• For extended-release tablets: This medicine works better when it is taken at bedtime. The extended-release tablets should be swallowed whole. They should not be chewed, crushed, or cut.
• For tablets: This medicine works better when it is taken with food. If you are taking this medicine once a day, take it with the evening meal. If you are taking more than one dose a day, take each dose with a meal or snack.

Dosing— The dose of these medicines will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so. The number of capsules or tablets that you take depends on the strength of the medicine. For atorvastatin

• For oral dosage form (tablets):
• For high cholesterol:
• Adults—10 to 80 milligrams (mg) once a day.
• Children 10 to 17 years of age—10 to 20 milligrams (mg) once a day.
• Childrenyounger than 10 years of age—Use and dose must be determined by your doctor.

For cerivastatin

• For oral dosage form:

Note: Removed from the market by Bayer in August 2001 For fluvastatin

• For oral dosage form (capsules):
• For high cholesterol:
• Adults—20 to 40 milligrams (mg) once a day in the evening.
• Children—Use and dose must be determined by your doctor.

For lovastatin

• For oral dosage form (extended-release tablets):
• For high cholesterol:
• Adults—10 to 60 milligrams (mg) once a day at bedtime.
• Children—Use and dose must be determined by your doctor.
• For oral dosage form (tablets):
• For high cholesterol:
• Adults— 20 to 80 milligrams (mg) a day taken as a single dose or divided into smaller doses. Take with evening meals.
• Children—Use and dose must be determined by your doctor.

For pravastatin

• For oral dosage form (tablets):
• For high cholesterol:
• Adults—10 to 40 mg once a day at bedtime.
• Children—Use and dose must be determined by your doctor.

For simvastatin

• For oral dosage form (tablets):
• For high cholesterol:
• Adults—5 to 80 mg a day.
• Children—Use and dose must be determined by your doctor.

Missed dose— If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses. Storage— To store this medicine:

• Keep out of the reach of children.
• Store away from heat and direct light.
• Do not store in the bathroom, near the kitchen sink, or in other damp places. Heat or moisture may cause the medicine to break down.
• Keep the medicine from freezing. Do not refrigerate.
• Do not keep outdated medicine or medicine no longer needed. Be sure that any discarded medicine is out of the reach of children.

Precautions While Using This Medicine It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly to lower your cholesterol levels and that it does not cause unwanted effects. Check with your doctor immediately if you think that you may be pregnant. HMG-CoA reductase inhibitors may cause birth defects or other problems in the baby if taken during pregnancy. Your doctor may recommend an appropriate method of birth control to prevent adolescent girls and women of child bearing potential from getting pregnant. Do not stop taking this medicine without first checking with your doctor. When you stop taking this medicine, your blood cholesterol levels may increase again. Your doctor may want you to follow a special diet to help prevent this from happening. Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine. Check with your doctor immediately if you have unexplained muscle pain, tenderness, or weakness.

Side Effects of This Medicine

• Side Effects of This Medicine

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. Check with your doctor as soon as possible if any of the following side effects occur:

• Less common or rare
• Fever; muscle aches or cramps; severe stomach pain; unusual tiredness or weakness

Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. However, check with your doctor if any of the following side effects continue or are bothersome:

• More common
• Constipation; diarrhea; dizziness; gas; headache; heartburn; nausea ; skin rash; stomach pain

• Rare
• Decreased sexual ability; trouble in sleeping

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor.

Brand Names Some commonly used brand names are: In the U.S.—

• Altoprev
• Lescol
• Lipitor
• Mevacor
• Pravachol
• Zocor

In Canada—

• Lescol
• Mevacor
• Pravachol
• Zocor

Statin Resources
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