Atorvastatin

Atorvastatin is the active ingredient in the most popular prescription medicine in the world and a member of the statin family of drugs. By lowering cholesterol production in the body, atorvastatin lowers the risk of death from cardiovascular disease, and has several additional benefits. It has been studied in more than 400 ongoing and completed clinical studies involving over 80,000 patients. The U.S. Food and Drug Administration originally approved atorvastatin in December, 1996. Annual sales of atorvastatin exceed $12 billion.

Other Names

Lipitor is Pfizer's brand name for atorvastatin throughout most of the English-speaking world. Caduet is Pfizer's brand name for a combination of amlodipine (a drug to lower blood pressure) and atorvastatin. Worldwide, over 30 different names are used for atorvastatin (alone or in combination with amlodipine) including the following:

• Atorva (India)
• Cardyl (Spain)
• Tahor (France)

Uses

As part of a program that includes dietary and lifestyle changes, atorvastatin has many uses in lowering lipid (fats) levels and preventing heart disease.

Atorvastatin is used to treat dyslipidemias, which are disorders characterized by abnormal levels of lipids in the blood. Specifically, atorvastatin is used along with dietary therapy to decrease elevated serum total cholesterol and low-density lipoprotein cholesterol (LDL-C; so-called “bad” cholesterol), apolipoprotein B (apo B), and triglyceride concentrations. It is also used to increase concentrations of high-density lipoprotein cholesterol (HDL-C; the so-called “good” cholesterol).

Familial hypercholesterolemia is an inherited condition characterized by high cholesterol levels. Atorvastatin is used to lower cholesterol in individuals as young as ten years who have familial hypercholesterolemia (LDL-C levels >than 190 mg/dl (or >than 160 mg/dl) and who have a family history of coronary heart disease (CHD).

The lipid-lowering effect of atorvastatin reduces the risk of CHD. Therefore, atorvastatin is used as primary prevention of heart attack, stroke, or angina in people who have multiple risk factors for CHD: age, smoking, high blood pressure, low HDL-C, or a family history of early CHD. Primary prevention refers to interventions that prevent the first occurrence of a disease or condition. Primary prevention of CHD is done for people who have no clinical evidence of cardiovascular disease but who at risk. Atorvastatin is also used in primary prevention of cardiovascular events (e.g., heart attack, stroke)in people with type 2 diabetes.

Atorvastatin is also used as secondary prevention. Secondary prevention refers to interventions that protect against recurrence of a disease or condition. Secondary prevention with atorvastatin is done in people who have CHD. In these people, atorvastatin is used to reduce the risk of heart attack, stroke, or hospitalization for congestive heart failure (CHF). Atorvastatin has also been shown to slow the progression of coronary atherosclerosis in patients with CHD.

How Atorvastatin is taken

Atorvastatin is taken as tablets by mouth once a day, with or without food. Tablets containing 10 mg, 20 mg, 40 mg, or 80 mg are available. Low doses may be given initially, with gradual escalation depending on changes in blood lipid concentrations and the presence or absence of side effects.

How It Works

Like other statins, atorvastatin inhibits a key enzyme (HMG CoA reductase) that the body uses to make cholesterol. Lower cholesterol concentrations in the liver (the primary site of cholesterol synthesis) lead to a compensatory increase in the number of LDL receptors on the surface of liver cells. These receptors bind to, and eventually degrade, LDL-C.

Benefits

Atorvastatin can lower the risk of cardiac events (heart attacks, sudden cardiac death) by 60% and can lower the risk of stroke by 17%. ^[1]

Side Effects

• Mild stomach pain, gas, bloating, stomach upset, heartburn
• Nausea, stomach pain or upset stomach
• Constipation, bloating, gas
• Stuffy nose
• Itching, skin rash

Risks and Precautions

• The major risk associated with atorvastatin use is muscle damage. Symptoms of this damage include muscle pain, tenderness, or weakness with fever or flu symptoms and dark colored urine. This damage could lead to kidney failure.

• Atorvastatin can cause birth defects.

• People with diabetes, underactive thyroid glands, kidney disease, or muscle disease sometimes need additional tests before or during atorvastatin therapy since dosage adjustments may be required.

Drug Interactions

Atorvastatin is metabolized in the liver by an enzyme called CYP3A4. It is also removed from the blood by proteins that pump it into the intestines for excretion. Many drugs inhibit the activity of CYP3A4 and the intestinal proteins. Accordingly, atorvastatin has the potential to interact with numerous drugs, and several interactions have already been documented. When CYP3A4 and the intestinal proteins are inhibited by drugs, atorvastatin levels in the body increase. Examples of drugs that interact with atorvastatin in this way are listed below:

• Antifungal agents: itraconazole (Sporanox), fluconazole (Diflucan), or ketoconazole (Nizoral)
• antibiotics: erythromycin
• Antiretrovirals; ritonavir (Norvir), indinavir (Crixivan), or saquinavir (Fortovase)
• drugs that modulate the immune system such as cyclosporine (Neoral), sirolimus (Rapamune), or tacrolimus (Prograf)

Atorvastatin has been shown to prevent the excretion of digoxin, a drug used to improve heart function.

Niacin, a medication also used for lipid control, can increase the concentration of atorvastatin in the blood.

History

In the early 1950s, aware of the importance of cholesterol in cardiovascular disease, scientists at Merck began researching how cholesterol was made in the body. By 1956, they demonstrated that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) was converted to mevalonic acid, a precursor of cholesterol, by a particular enzyme named HMG-CoA reductase. This enzyme is especially important in cholesterol synthesis, since it serves as the slowest (i.e., the rate-limiting) step in the multistep process of making cholesterol from much simpler precursors. By the 1970s, with knowledge of the importance of HMG CoA reductase, scientists had begun screening compounds to find ones with the ability to inhibit the enzyme. Lovastatin, a compound isolated from the fungus Aspergillus terreus, was the result of their search; commercial development resulted in lovastatin's appearance on the market as Mevacor. Mevacor was approved for use in patients with severe hypercholesterolemia in 1982 and for patients with elevated cholesterol levels five years later.

Over the next decade, statins were developed to reduce the gastrointestinal side effects of lovastatin. Atorvastatin was discovered at Yamanouchi, a Japanese company, in collaboration with Pfizer.

Controversy

In June 2008, Pfizer settled a patent dispute with the Indian firm Ranbaxy over marketing generic versions of atorvastatin, delaying the release of generic versions in the US until November 2011.

In February 2008, Pfizer discontinued Lipitor commercials featuring Dr. Robert Jarvik, who became famous for inventing an artificial heart. When it became evident that Dr. Jarvik is not a cardiologist (and has never been licensed to practice medicine), Pfizer faced criticism from some members of Congress.

Alternatives

There is no approved generic form of atorvastatin; it is only available as Lipitor or (in combination with amlodipine as Caduet. However, several other statin drugs are available and data are available that compare these to atorvastatin:

• Compared to simvastatin (the active ingredient in Zocor), atorvastatin lowered bad cholesterol to a greater extent in clinical studies.

The safety profile of atorvastatin is consistent with that of most other statins.^[2]

Clinical Trials

Several ongoing clinical trials are investigating the safety and utility of atorvastatin. Some of these trials are detailed below:

• "Differences in Atorvastatin Metabolite Ratios as a Diagnostic Tool in Detecting Atorvastatin Induced Myotoxicity," which is attempting to improve detection of who may be at increased risk for an important adverse event sometimes associated with atorvastatin.^[3]

• "Phase II Study of Atorvastatin Safety and Antitumor Effects in Non-Hodgkin's Lymphoma," which aims to study the drug's potential utility in this type of cancer.^[4]

• "Atorvastatin in New Onset Type 1 Diabetes Mellitus." This study will treat newly-diagnosed people with type 1 diabetes with atorvastatin and measure serum concentrations of C-peptide, a marker of the body's own level of insulin production. Investigators hope to find evidence that atorvastatin can delay or reverse the destruction of beta cells in these patients.^[5] Previous work in mice has shown that although atorvastatin inhibits certain cells of the immune system that are responsible for the development of type 1 diabetes, it does not prevent the disease from developing.^[6]

References

1. ↑ Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003 Jun 28;326(7404):1423. Abstract | Full Text | PDF
2. ↑ Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (lipitor), a new HMG-CoA reductase inhibitor. Arch Intern Med. 1998 Mar 23;158(6):577-84. Abstract | Full Text | PDF
3. ↑ Myotoxicity study NCT00199745, from clinicaltrials.gov Details
4. ↑ NHL study NCT00185731, from clinicaltrials.gov Details
5. ↑ Atorvastatin in type 1 diabetes study NCT00529191, from clinicaltrials.gov Details
6. ↑ Lozanoska-Ochser B, Barone F, Pitzalis C, Peakman M. Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells. Diabetes. 2006 Apr;55(4):1004-10. Abstract | Full Text | PDF