Is it time to stop using Fibrates?

What do high cholesterol levels in our bodies mean?
What medications are used to treat high cholesterol levels?
Some of the major studies involving Cholesterol lowering drugs & their benefits
The Helsinki Heart study
The Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)
Bezafibrate Infarct Prevention (BIP) trial
The FIELD trial

What do high cholesterol levels in our bodies mean?

Cholesterol is a waxy, fat like substance naturally found in our cell walls. It is an important substance that the body needs, to produce hormones, Vitamin D and bile acids that help to digest fat. However, if we have excessive amounts of cholesterol, it can build up in arteries and lead to conditions such as heart disease.

What medications are used to treat high cholesterol levels?

The most commonly used group of drugs used to treat high cholesterol levels are statins. Statins are a type of lipid-lowering drug used to lower LDL and total cholesterol levels in the blood. The statins currently available in Australia include Atorvastatin, fluvastatin, pravastatin and simvastatin.

Another class of drugs acting to lower LDL levels are the bile acid sequestrants - cholestyramine, colesevelam, colestipol and nicotinic acid.

Fibrates increase our HDL cholesterol levels and lower triglyceride (TG) levels. These include: Clofibrate, Gemfibrozil and Fenofibrate. This would lead to the assumption that fibrates will reduce the risk of heart and major vessel disease and mortality. This has been demonstrated in another class of drugs used to treat high cholesterol levels, known as statins. Statins such as Simvastatin and Atorvastatin have been shown to have a major benefit on clinical outcomes in the overall mortality level in conditions such as stroke and coronary heart disease. Their use has now been recommended in patients with heart disease, diabetes and also those at higher risk of cardiovascular disease. These include: people with high blood pressure, a family history of heart disease, those who smoke and drink excessive amounts of alcohol.

Clinical studies performed in patients have shown that reducing LDL cholesterol levels by 1mg/dL appears to reduce the risk of heart disease by 1%. However, it seems that raising HDL cholesterol levels by a similar amount has a greater effect on overall risk of heart disease, reducing the risk by as much as 2-3%. This would infer that modifying our HDL cholesterol levels using drugs such as fibrates would be at least as effective, if not more effective, than modifying LDL cholesterol levels.

In a study involving 266 cases and 308 control patients (ie those patients who served as a baseline, in whom no interventional events were carried out in), the levels of triglyceride in the serum were shown to be a strong and independent predictor of outcome over seven years of follow-up. This was regardless of the levels of HDL cholesterol present.

Further evidence can be found in another study incorporating data from eight studies in over 28000 patients (about 80% male). These studies took into account the effects of HDL cholesterol. The studies showed that for every 1mmol/L increase in serum triglyceride concentration, the relative risk of heart disease increased by 14% in men and 37% in women. However, at this point in time, there is no evidence to specifically support the idea that targeting triglyceride levels alone reduce the incidence of heart and major vessel disease.

Drugs used to help prevent the development of heart disease often have to be given for many years and have to fulfil a number of criteria to justify their use. These include:

-they need to make you live longer or feel better,

-the numbers of people which need to be treated, to prevent events have to be low enough to outweigh the negative effects of taking the medications for many years.

Results of the Fenofibrate Intervention and Event Lowering in Diabetes study have been published. These results can help us review current evidence on fibrates.

Some of the major studies involving Cholesterol lowering drugs & their benefits

A number of trials have investigated fibrates in regards to primary and secondary prevention of heart and major vessel disease. These include:

-The primary prevention trial

-The Helsinki Heart study

-The secondary prevention trials

-The Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)

-Bezafibrate Infarct Prevention (BIP) trial

-The FIELD trial (focusing on patients with diabetes and high cholesterol levels).

The Helsinki Heart study

The Helsinki Heart study was a 5 year, randomised trial that tested the efficacy of a fibrate called Gemfibrozil in 4081 middle aged men, who had low HDL cholesterol levels. Results of the study showed a 34% reduction in heart disease, but no difference in mortality compared to placebo.

The Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)

The VA-HIT study was a randomised 5 year study that tested the effect of gemfibrozil compared to placebo on 2531 men with heart disease and low HDL cholesterol levels. This study once again showed a reduction in heart and blood vessel disease related events, but no difference in mortality.

Bezafibrate Infarct Prevention (BIP) trial

The BIP study investigated the effects of bezafibrate compared to placebo in 1470 men with heart attack, and whilst coronary heart disease events were reduced, mortality was the same in both groups.

The FIELD trial

Analysis of these major studies showed that whilst there were no mortality benefits, there was a trend to benefit in the group of patients with diabetes. FIELD was designed to look more closely at this subgroup of patients with diabetes. This study investigated the effects of fenofibrate in patients with diabetes and undesirable levels of cholesterol (low HDL cholesterol, raised TG) who were not on statins to assess clinical outcomes. The study population importantly included 22% of patients with known coronary heart disease. Patients were randomised to receive either fenofibrate 200mg daily or placebo for an average of 5 years. Clinical outcomes were assessed by a committee who did not known who received the medication vs placebo.

During the FIELD trial, two other large statin trials, the Heart Protection Study (HPS) and Collaborative Atorvostatin Diabetes Study (CARDS) were published which resulted in a large percentage of patients being prescribed statins (17% in the placebo group and 8% in the fenofibrate group) by the end of the study.

Whilst there was a significant 24% reduction in non fatal heart attacks, there was a non significant (19%) increase in coronary disease death, mostly in patients with known coronary heart disease. Total mortality was slightly increased in the fenofibrate group but this was not statistically significant. The one benefit of note was a decrease in small vessel disease.

A study published in April 2005, further supported the fact that fibrates may reduce non fatal cardiovascular events but do not reduce mortality. Unlike FIELD, there was a non significant trend to reduction in cardiac mortality, but a significant increase in non cardiac mortality. The increase in non cardiac mortality has not been shown to be due to any specific cause and FIELD has failed to add to this puzzling data.

In conclusion, studies have failed to demonstrate that fibrates do not fulfil the criteria for drugs used long term, to reduce the risk of events even in patients with low HDL cholesterol levels and high triglyceride levels. Ironically, this is the patient group most commonly prescribed fibrates. Fibrate medications have not yet been shown to make you live longer or feel better. These is a concerning trend towards increasing non-cardiac mortality. This suggests that there may be an unexplained toxic effect of these drugs taken in the long term.

Compared to other secondary prevention strategies which have been proven to be effective - eg low dose aspirin, statins and ACE inhibitors / angiotensin receptor blockers (ARBs) aggressive management of blood pressure, fibrates compare unfavourably. This is especially in regards to the numbers needed to treat, to prevent adverse events. Only 19 people need to be given statins to prevent a major event (such as death, stroke or heart attacks) whereas results of the FIELD study show that 100 people need to be given fibrates to prevent a non fatal heart attack (with no mortality benefit).

There are currently efficacious, safe and proven medications available to be used in prevention of cardiovascular disease. It is difficult to justify the use of fibrates in the light of current evidence. They do have a place in certain situations such as in patients with very high triglyceride levels who are at risk of pancreatitis. There are further studies in progress, which investigate the efficacy and safety of fibrates in combination with other medications such as statins. The ACCORD trial which explores this combination is due to be released in 2010.

However, in the end, blood results indicating high cholesterol levels are only surrogate endpoints, and it may be more important to focus on your clinical outcomes rather than trying to change your blood test results. It is recommended that medications with proven major clinical benefits are prescribed, based on results of studies with major clinical outcomes.