Fibrates

• What are lipids?
  • Cholesterol
  • Triglycerides
  • What is a ‘normal’ lipid profile?
• What are fibrates?
  • How do they work?
• Who should take fibrates?
• Are fibrates safe?
  • Side effects of fibrates may include
  • Potential drug interactions associated with fibrates may include

Fibrates are types of fat or lipid lowering medication. Lipids in the blood are mainly made up of cholesterol and triglycerides, and elevated levels of these have been associated with cardiovascular problems such as atherosclerosis (hardening of arteries), heart attack and stroke. Fibrates are derivatives of fibric acid which are particularly suited to reducing the triglyceride levels of lipid in the blood. They also have the effect of increasing HDL cholesterol (‘good cholesterol’) in the blood. Common examples of fibrates include gemfibrozil, fenofibrate and clofibrate.

What are lipids?

‘Lipids’ is a term that we use to refer to the fats that circulate in our blood. This includes both cholesterol and triglycerides.

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) cholesterol 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.

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. When looking at lipid levels in the blood, doctors can assess triglyceride levels separately from cholesterol levels. This is important because a patient may have a raised triglyceride level but normal cholesterol levels. In most cases, however, if the triglyceride level is raised, cholesterol levels will also be abnormal. This situation describes the disease we call hypercholesterolaemia. People with diseases such as diabetes mellitus may be at particularly high risk of developing hypercholesterolaemia.

What is a ‘normal’ lipid profile?
There is no simple answer to this question – we still don’t know exactly what level of lipids in the blood 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 triglycerides, and high levels of HDL-cholesterol.

What are fibrates?

Fibrates are a type of lipid-lowering drug that are particularly good at decreasing triglyceride levels in the blood. Two different fibrate drugs are commonly prescribed in Australia: gemfibrozil and fenofibrate.

How do they work?
Fibrates lower triglyceride levels by two methods:

• by reducing production of triglycerides in the liver; and
• by increasing the rate at which triglycerides are removed from the bloodstream.

Fibrates have been shown to reduce triglyceride levels by 35-50 percent in patients with high lipid levels. Additionally, fibrates (and in particular the drug gemfibrozil) have been shown to increase good HDL cholesterol levels by up to 15-25 percent. The effect of fibrates on LDL-cholesterol levels is not always the same in every patient. In most people, fibrates will lower LDL-C levels slightly. In some people, though, and particularly in people with a type of hypercholesterolaemia called ‘type I hyperlipoproteinaemia’, fibrates may actually raise LDL-C levels slightly.

Who should take fibrates?

Fibrates are particularly suited to patients who have high levels of triglycerides in their blood, or patients with low levels of HDL-cholesterol. This is common in patients who have type 2 diabetes mellitus. Fibrates may also be prescribed to someone with high blood lipid levels who has not responded to other treatments, such as a statin.

Are fibrates safe?

Fibrates are generally safe, with most patients experiencing only mild side effects.

Side effects of fibrates may include:

• gastrointestinal symptoms: dyspepsia (indigestion), abdominal pain or diarrhoea
• allergic reactions
• fever or chills
• generalised body aches and pains

One serious but rare side effect of fibrate therapy is called rhabdomyolysis, where breakdown of muscle cells occurs, resulting in muscle pain, weakness, and even death. The risk of this occurring is greater when kidney function is impaired or when fibrates are combined with statins.

Potential drug interactions associated with fibrates may include:

• Interactions with other lipid lowering drugs such as statins.
• Interactions with the blood thinning drug warfarin.

Overall, the evidence so far suggests that fibrates are effective at reducing the incidence of coronary heart disease, but have no significant effect on mortality. See the review on using fibrates for more information or talk to your doctor. (Kindly contributed by Dr Jocelyne Benatar)

References

1. Braunwald, Fauci, Kasper, Hauser, Longo, Jameson. Harrison’s Principles of Internal Medicine. 16th edition. Sydney, McGraw-Hill, 2005, pp. 2286-2297.
2. Desouza, C. ‘Drugs affecting homocysteine metabolism – impact on cardiovascular risk,’ Drugs. 2002, 62(4) 605-616
3. Despres, JP. ‘Role of fibric acid derivatives in the management of risk factors for coronary heart disease,’ Drugs. 2004, 64(19), 2177-2198
4. Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Manttari M, Manninen V. Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease: an ancillary study in the Helsinki Heart Study frame population. Ann Med 1993; 25: 41-45
5. MIMS Australia Pty Ltd [online]. Jezil (Gemfibrozil). MediMedia Publishing; NSW: 2005
6. MIMS Australia Pty Ltd [online]. Lipidil (Fenofibrate). MediMedia Publishing; NSW: 2005
7. Rosenson RS. Lipid lowering with fibric acid derivatives. UptoDate.com. 2006. Available at URL: uptodate.com (last accessed 20/02/2006)
8. Rubins HB, Robins SJ, Collins D. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002; 162: 2597-2604.
9. Tenenbaum, A; Motro, M; Fisman E.Z., Tanne,D; Boyko, V; Behar S, Bezafibrate for the Secondary Prevention of Myocardial Infarction in Patients With Metabolic Syndrome, Arch Intern Med. 2005;165:1154-1160.