Statins

• Introduction to statins
• Cholesterol
  • What is cholesterol?
  • What are triglycerides?
  • What is a ‘normal’ cholesterol level?
• Statins
  • What are statins?
  • How do statins work?
  • Why use statins?
  • How effective are statins?
  • Are statins safe?
• Statins and combination therapies

Introduction to statins

Statins are a type of lipid-lowering drug in common use in Australia. Statins may be prescribed to help lower levels of LDL-cholesterol in the blood, for example in the treatment of hypercholesterolaemia. This in turn can reduce the risk of diseases such as coronary heart disease. The uses and side-effects of statins are outlined below.

Cholesterol

What is cholesterol?
Cholesterol is a waxy, fat-like substance that is naturally found in the walls of the body’s cells. The level of cholesterol in the body is determined by two things: the amount of cholesterol that we absorb in our intestines, and the amount that we produce in our liver.
Having some cholesterol in the body is normal and healthy – we need it to produce certain hormones, vitamin D, and bile acids that help to digest fat. But if we have too much cholesterol, it can build up in arteries and lead to coronary heart disease and many other serious conditions.
There are two major types of cholesterol found in the blood: low-density lipoprotein (LDL) cholesterol, sometimes referred to as ‘bad’ cholesterol, and high-density lipoprotein (HDL) cholesterol, or ‘good’ cholesterol.

• Low density lipoprotein (LDL) cholesterol is called ‘bad’ because it is a major contributor to the development of atherosclerosis – the sticky plaques that can form inside blood vessels and contribute to problems like stroke.
• High density lipoprotein (HDL) is ‘good’ because it helps remove cholesterol from these developing plaques, taking it back to the liver to be excreted from the body in bile. Levels of HDL in the body can be raised by things like exercise, and lowered by smoking.

What are triglycerides?
Triglycerides (TG) are another form of fat found in the body. They are chains of high-energy fatty acids, and are responsible for providing our cells much of the energy they need to function. Triglycerides come from the fat we eat in food. The fat is processed in the liver to make triglycerides, and these in turn are then packaged with other substances to form ‘chylomicrons‘, which travel in the blood to supply energy to cells. Some triglycerides are also bound up in the liver with cholesterols to form lipoproteins (see above).
High levels of triglyceride in the blood are bad because they put people at risk of diseases such as coronary heart disease. In most cases, if the triglyceride level is raised, cholesterol levels will also be abnormal.

What is a ‘normal’ cholesterol level?
There is no simple answer to this question – we still don’t know exactly how much of each type of cholesterol is ‘good’ for us. The National Heart Foundation and The Cardiac Society of Australia and New Zealand give the following target levels:

• Total cholesterol < 4.0 mmol/L
• LDL-cholesterol < 2.5 mmol/L
• HDL-cholesterol > 1.0 mmol/L

These numbers indicate a level to aim for in patients with other risk factors for coronary heart disease, such as a family history of the disease, or diabetes mellitus. In people with no other risk factors, safe levels may be slightly higher. In general, though, it is healthier to have low levels of LDL-cholesterol and high levels of HDL-cholesterol.

Statins

What are statins?
Statins are a type of lipid-lowering drug that are used to lower LDL- and total cholesterol levels in the blood. The four statins currently available in Australia are atorvastatin, fluvastatin, pravastatin and simvastatin.

How do statins work?
Statins work by blocking the action of an enzyme called HMG-CoA reductase, which is the enzyme that controls the rate of cholesterol production in the body. By doing this, the availability of cholesterol is reduced. Statins also increase production of the receptor for ‘bad’ LDL-cholesterol, which helps clear LDL-cholesterol from the circulation; and help liver cells take up more LDL cholesterol from the blood as it passes through. The resulting effect is a reduction of total cholesterol, LDL cholesterol and triglyceride fats. A small increase in high-density lipoprotein cholesterol (HDL-C), the ‘good’ cholesterol, is also produced.

Why use statins?
High levels of LDL cholesterol and total cholesterol in the blood put people at risk of diseases such as coronary heart disease. Often, lifestyle modifications such as increasing exercise, quitting smoking and eating a diet low in saturated fat can have a small positive effect on cholesterol levels, but these measures may not be enough in themselves. In these cases, people may be prescribed lipid-lowering drugs such as statins to help reach their target lipid levels.

How effective are statins?
Statins can reduce the level of LDL-cholesterol in the blood by 30 to 63 per cent. Atorvastatin in particular has a strong effect on LDL-cholesterol. In terms of the action on high-density lipoprotein (HDL) cholesterol, simvastatin has been reported to be effective in increasing the level. Atorvastatinis also effective for the reduction of triglyceride levels. The strength of this effect increases with the dose of the drugs taken. Many studies have confirmed the safety and efficacy of statin therapy in reducing overall mortality from cardiovascular disease. There are guidelines currently recommending their use in virtually all patients at high risk of coronary heart disease.

Are statins safe?
Statins are considered one of the safest classes of lipid-lowering drugs. They are well tolerated in the short term. Common side-effects include headache, nausea and vomiting, constipation, diarrhoea, or rash. Muscle pain and break down of muscle tissue may also occur, but this is uncommon with statin therapy alone. Patients at increased risk of developing muscle problem associated with statin therapy are those with kidney failure, thyroid problems and liver disease. Patients started on statins should report muscle ache or weakness that have recently developed.
Liver function abnormality may also occur. Liver problems are dependent on the dose used and mainly occur in the first three months of treatment. A recent study involving 1014 patients found no cases of significant liver problem due to the use of statin. In a review, it was also reported that statin-related liver inflammation occurred infrequently.

Statins and combination therapies
Even with more effective statins now becoming available, considerations of cost, safety, and other concerns often make it impossible for patients to reach the desired level of LDL cholesterol by taking just a single statin. This is because doubling the dose of a statin only further reduces the level of LDL cholesterol by 6%, but increases the toxic effect and costs significantly. (One exception to this is a type of drug called fluvastatin in the extended-release formulation at the 80 mg dose.)
The solution to this problem may be the use of “Combination Therapy”, where a statin is combined with another class of lipid lowering-drug. Not only does this mean that the dose of statin can be kept relatively low, with lower cost and side-effects, but the other drug will have a different sort of action and may therefore provide extra benefit. For example, statins are effective at LDL cholesterol lowering, but are less effective than some other classes of lipid-lowering drugs (for example, fibrates) in the action on triglyceride fats. Combining two drugs therefore provide the benefits of two different classes of therapy. Combination therapy is also much better at reducing heart disease.
Currently available combination therapies in the United States are lovastatin plus extended-release niacin (Advicor) and simvastatin plus ezetimibe (Vytorin). Not every patient needs more than a drug, but it now looks like combination therapy may be a better way to increase treatment benefit than increasing the dose of a single statin therapy.

References

1. Bakker-Arkema, RG, Davidson, MH, Goldstein, RJ, et al. Efficacy and safety of a new HMG CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996; 276:128.
2. Charles, EC, Olson, KL, Sandhoff, BG, et al. Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization. Am J Med 2005; 118:618.
3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high risk individuals: a randomised placebo controlled trial. Lancet 2002; 360: 7-22.
4. Istvan, ES, Deisenhofer, J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292:1160.
5. Jones, PH, Davidson, MH, Stein, EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003; 92:152.
6. Kastelein, JJ, Isaacsohn, JL, Ose, L, et al. Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels. Am J Cardiol 2000; 86:221.
7. Larsen, ML, Illingworth, DR. Drug treatment of dyslipoproteinemia. Med Clin North Am 1994; 78:225.
8. Medscape: Statin Therapy: Risks vs Benefit: An Expert Interview With Eliot A. Brinton, MD [online]. 2004 [cited 2005 December 15th]. Available from: [URL Link]
9. National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Lipid Management Guidelines – 2001. Med J Aust 2001; 175, Suppl 5 Nov: S57-S88.
10. Rosenson, RS. Rosuvastatin: a new inhibitor of HMG-coA reductase for the treatment of dyslipidemia. Expert Rev Cardiovasc Ther 2003; 1:495.
11. Smith, CC, Bernstein, LI, Davis, RB, et al. Screening for statin-related toxicity: the yield of transaminase and creatine kinase measurements in a primary care setting. Arch Intern Med 2003; 163:688.
12. Staels, B, Dallongeville, J, Auwerx, J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98:2088.

Drugs used in this treatment:

• Lipitor (Atorvastatin calcium)
• Pravachol (Pravastatin sodium)
• Vytorin (Ezetimibe/ Simvastatin)
• Zocor (Simvastatin)