Why treat hypercholesterolaemia?

Over the last 20 years, the benefits of treating hypercholesterolaemia have been demonstrated clearly. Before that, many clinical trials showed inconclusive results because:

• Early treatments were not particularly effective in reducing blood cholesterol levels
• Studies included too few patients to obtain clear results – it is more difficult to get a clear answer from a trial if there have been relatively few clinical events
• Patients who were recruited to studies had a low risk of suffering from cardiovascular disease (CVD).
• Since the 1980s, clinical trials have clearly shown the benefits of lowering blood cholesterol levels, particularly if the risk of CVD is high.

Cholesterol lowering reduces heart attacks

A 1981 study in Norway showed that changing diet to reduce blood lipids and stopping smoking reduced the number of coronary events (mainly heart attacks) by 45 per cent. However, it was difficult in this study to separate the effects of stopping smoking (achieved by 45 per cent of subjects) from those of cholesterol reduction (13 per cent).

Three years later, doctors in America showed that lowering blood cholesterol with the drug cholestyramine reduced the number of heart attacks by 1 per cent in 4,000 middle-aged men, even though the fall in cholesterol was relatively modest at 8.5 per cent. Similar results were found in Helsinki in 1987 using gemfibrozil, a different type of cholesterol-lowering drug. The blood total cholesterol levels fell 10 per cent whereas the number of coronary events (fatal and non­fatal heart attacks, onset of angina, coronary artery bypass grafts) fell 37 per cent.

These studies suggest that lowering cholesterol reduces coronary events but they did not show a change in death rate. This is important because effective treatment would reduce deaths from CVD. We need to be sure that treatment doesn’t increase the rate of other diseases, such as cancer. There are several possible reasons why a change in death rate was not found, the most important being that a relatively small number of individuals were studied for a short period of time using drugs that had a modest cholesterol-lowering effect.

Cholesterol lowering slows arterial disease

Doctors then studied the effect of cholesterol-lowering treatment on what was happening within arteries. Seven studies published between 1987 and 1994, using different treatments, showed similar results.

Before giving treatment, arterial narrowing caused by plaques was assessed from X-rays. Follow-up X-rays showed considerably less progression of arterial disease in patients who had received active cholesterol-lowering treatment rather than placebo (dummy tablets). In a small number of patients the size of the abnormalities in the arterial walls actually shrank. Even when the abnormalities did not shrink, it is thought that treatment stabilised the plaques, reducing the risk of thrombosis and complete blockage of the artery.

Cholesterol lowering improves survival

The first evidence that patients with high total cholesterol levels live longer if cholesterol is reduced came from pooling the results of several clinical trials. This technique is called meta-analysis, and has greater statistical power than individual clinical trials.

Meta-analysis showed that lowering blood cholesterol by 10 per cent in patients with an average cholesterol level of 6 mmol/l produced a 10 per cent reduction in death rates.

Meta-analysis was used as individual trials did not give enough information to support the conclusion because:

• the drugs used produced only modest reductions in cholesterol
• there were too few patients in the individual trials
• the patients were not at particularly high risk from CHD (coronary heart disease) and therefore from the number of cardiac events.

The results of clinical trials and statins

More recently, powerful cholesterol-lowering drugs, known as statins, have been introduced into general practice and several individual clinical trials have demonstrated clear survival benefits from treatment.

The first trial was the Scandinavian Simvastatin Survival Study (4S), in which 4,444 patients with angina or previous myocardial infarction and blood cholesterol levels of 5.5 to 8.0 millimoles per litre (mmol/l) were given either active treatment with a statin or treatment with a placebo.

There was a reduction of CHD deaths of 42 per cent and overall mortality fell 30 per cent; blood cholesterol fell by almost 30 per cent in those who received simvastatin. Both men and women benefited equally and the relative decrease in CHD was similar in younger and older age groups. These results have been confirmed in other trials in which an alternative statin, pravastatin, has been used.

Trials have also shown that benefits are similar in both smokers and non-smokers, patients with high blood pressure and those with normal blood pressure, patients with and without diabetes and elderly people. Most of these trials have been in patients with existing CHD although one, in Scotland, looked at people without existing CHD. This showed that treatment reduced the incidence of CHD, although the results for survival were not as clear cut, possibly because the study population was at lower risk than in other statin trials.

A further important study using statins has been published recently (the Heart Protection Study). Over 20,000 individuals were included who had arterial disease or diabetes. The death rate was reduced by a third in those who received the drug for up to five years. For patients with diabetes (but without existing vascular disease), there was a reduction of about 25 per cent in the incidence of heart attacks and strokes. The CARDS study also showed that statins prevented heart attacks in patients with diabetes. Atorvastatin was used in this trial.

Statin trials have had a profound effect in emphasising the importance of cholesterol as a risk factor for CHD. There is no doubt that effective reduction of blood cholesterol levels by using these drugs, at least in patients who are at high risk, reduces the incidence of CHD and improves overall survival.

The trials have also shown benefits in preventing ischaemic stroke.

Does cholesterol lowering do any harm?

This question has received considerable attention in the newspapers and medical press over the years, more so than for related treatments such as the management of hypertension. A related question is whether patients who naturally have a low blood cholesterol level are at increased risk of other diseases, such as cancer, as a result.

Safety and clinical trials

Initial doubts about the safety of lowering cholesterol related to clinical trials undertaken in the 1980s, which showed that the number of heart attacks was reduced, although there was no overall reduction in the death rate (mortality). Some of these trials even suggested that there were more deaths from suicide and violent deaths in those receiving active intervention compared with the control patients, but the numbers were extremely small and the difference between the two groups was not statistically significant. Despite this, the possibility of a link received some support, particularly as the findings were linked with results of experiments in laboratory animals, which showed that modifying fat intake leads to behavioural changes.

It is obviously important to establish that any disadvantages of a particular treatment are outweighed by the benefits. The issue of suicide and violent deaths has now been looked at in individual studies and by pooling the results of a number of trials using meta-analysis. Individual studies and meta­analysis have not shown any significant increase in the broad category of deaths caused by accidents and suicides, and have failed to show any link between mood and cholesterol lowering. Similarly, no excess deaths from cancer have been shown by meta-analysis.

Naturally occurring low cholesterol levels

There is a U-shaped relationship between total mortality (death from all causes) and blood cholesterol levels. This graph relates to cholesterol levels without any treatment and could be interpreted as indicating that the overall death rate was higher in people with blood cholesterol levels of 4 mmol/l than in those with a level of 5 mmol/l.

Such an interpretation is incorrect. The reason for the apparently higher mortality in those with low cholesterol levels was early deaths from cancer. Cancer is known to lower cholesterol (see page 65) and therefore the most probable explanation is that the patients already had an undiagnosed malignant disease when the blood sample for cholesterol was taken.

There are other reasons for concluding that low blood cholesterol levels are not harmful and may be beneficial:

• In long-term follow-up (30 years) the higher mortality associated with low cholesterol levels disappears. If low cholesterol levels caused cancer, it would persist.
• Some populations, such as rural Chinese people, have naturally occurring low cholesterol levels without showing excess deaths from malignant disease, suicide or violence.
• Recent clinical trials, including the Heart Protection Study and CARDS, have shown that patients at high risk of CHD benefit from cholesterol reduction with statins even if their cholesterol levels are relatively low (total cholesterol less than 5.0 mmol/l, LDL-cholesterol less than 3.0 mmol/l).

KEY POINTS

• Cholesterol reduction prevents heart disease

• Cholesterol reduction increases length of life

• Cholesterol reduction does not increase your likelihood of suffering other diseases