Drug treatment of hypercholesterolaemia

Drug treatment for hypercholesterolaemia is considered when lifestyle and dietary changes have been tried but failed to reduce the absolute risk of CVD (cardiovascular disease) sufficiently. The decision to start treatment should be made after a discussion between you and your doctor, during which benefits and possible risks can be aired. Treatment should be considered where the risk is more than 20 per cent over a 10-year period or above 2 per cent per year. In general, you will fall into this category if you have CVD, diabetes or more than one risk factor.

Two main groups of drugs lower blood lipid levels: statins and fibrates. Other drugs are used more rarely, including resins and nicotinic acid (see box on page 99).

Statins

Statins are good at lowering blood cholesterol levels, often by 40 per cent or more, but have less activity against triglycerides (see page 107). They work by reducing the amount of cholesterol made inside body cells, especially in the liver, which in turn increases their production of LDL receptors because they have to obtain a greater proportion of their cholesterol needs from the circulation. As a result, more LDL particles are taken up through cell walls. This removes more cholesterol-rich LDL particles from the blood, and reduces blood cholesterol levels.

Statins are not very good at reducing blood triglyceride levels or increasing HDL-cholesterol concentrations. It is possible that statins have other beneficial effects, including improving the state of arterial walls. Statins are normally taken as tablets or capsules once a day in the evening, because our bodies make slightly more cholesterol at night than during the day. Treatment is adjusted to bring your total cholesterol level to below 4 millimoles per litre (mmol/l) and the LDL-cholesterol to below 2 mmol/l.

There are some differences between the statins that may lead your doctor to choose a particular drug. Those prescribed most frequently are simvastatin and atorvastatin.

Side effects of statins

Statins are generally well tolerated, producing few side effects. A small number of people develop muscle aches and pains, as a result of inflammation. Very occasionally this reaction may be severe, in which case treatment should be changed. Frequently, use of an alternative statin will solve this problem.

A mild type of liver inflammation (hepatitis) may also occur when treatment is started, but it usually clears by itself. Occasionally, more severe hepatitis can occur which requires a change in treatment. Some patients suffer from indigestion. A very rare side effect in men is erectile dysfunction. Some people suffer disturbance of their sleep pattern which may be resolved by taking their tablets in the morning instead of the evening.

Statins should not be taken during pregnancy or breast-feeding. Avoid grapefruits and grapefruit juice if you are taking statins.

Statins over the counter

Simvastatin is now available over the counter at pharmacies. This is not suitable if you have heart disease, diabetes, familial hypercholesterolaemia or other risk factors because you need to be under the care of your GP who will ensure that treatment is appropriate for your level of risk.

Over-the-counter statins are appropriate if you have a moderate risk, for example, a single risk factor. The dose (10 mg) is lower than is usually given by a doctor and you need to bear in mind that simvastatin is not a magic bullet. It doesn’t replace a sensible diet and lifestyle. However, the availability does offer an option to those of some, but not high, risk of CVD.

Ezetimibe

A new class of cholesterol-lowering drugs, absorption inhibitors, has been introduced recently. The first drug in this class, ezetimibe, lowers LDL-cholesterol levels by 10 to 20 per cent as a single therapy, but it can also be prescribed with statins. The cholesterol-lowering effect of ezetimibe adds to that of statins, with reductions in LDL-cholesterol of 60 per cent being found with the combination.

Ezetimibe appears to be safe from published studies. It is unclear how much of its cholesterol-lowering effect is the result of a reduction in the absorption of dietary cholesterol and how much results from blockage of recycling of cholesterol between the liver and the gut.

It is recommended as a single treatment when patients can’t tolerate statins, or combined with statins when the cholesterol level needs to be lowered further.

Fibrates

Fibrates lower cholesterol levels less than statins, but are more effective in reducing blood triglyceride concentrations. They work by reducing the rate at which lipoprotein-rich particles found in the blood are produced, and by increasing the rate at which they are removed. They also increase circulating levels of ‘good’ HDL-cholesterol.

Fibrates are taken as tablets or capsules. For people with very severe hyperlipidaemia they are occasionally given with statins, although this does increase the risk of side effects. They can reduce LDL-cholesterol levels by up to 18 per cent.

Side effects of fibrates

Fibrates are usually well tolerated although they can sometimes cause indigestion or nausea. Skin rashes and impotence are rare side effects. The risk of inflamed muscles with statin treatment is a little greater if fibrates are also given.

Other drugs

Statins and fibrates are the main drugs used to treat hypercholesterolaemia although others are used occasionally.

Resins are taken as powder or granules dissolved in water. They stay in the gut, binding bile acids so that they can no longer be reabsorbed. As a result of this, more cholesterol is converted to bile acids in the liver, so draining cholesterol from the body.

Before statins became available, the resins were the main drug treatment for hypercholesterolaemia and high doses were used. In general, they were tolerated poorly causing digestive upsets such as indigestion and diarrhoea. Despite this, they still have a place in treating very severe hypercholesterolaemia, most commonly as an additional treatment to statins in low doses. They complement the cholesterol-lowering effect of statins and there are fewer side effects with the lower doses. However, side effects still occur and the use of resins in this role has now been largely superseded by the use of ezetimibe (cholesterol absorption inhibitor).

Nicotinic acid

Nicotinic acid is less widely used. This is a type of vitamin B that is required in small amounts. It reduces both cholesterol and triglyceride levels if used in extremely high doses and also raises HDL-cholesterol levels. It is not used much in this country because it can produce frequent, unpleasant side effects, particularly flushing affecting the face, and indigestion. A slow release form, acipimox, is available as is an extended release form, Niaspan. These produce fewer side effects, although they still occur.

New drug treatments

Interest is developing in drugs that raise HDL-cholesterol levels and a clinical trial of one such agent, torcetrapib, has been reported recently. It was used with a statin and raised HDL-cholesterol levels in people in whom they were low. However, treatment with torcetrapib did not improve life expectancy; indeed more patients died early when receiving the drug. This shows the importance of treating risk rather than just trying to improve blood lipid levels.

Drugs used to treat hypercholesterolaemia in the UK

Hormone replacement therapy

Over 40 million women worldwide use hormone replacement therapy (HRT), primarily as treatment for menopausal symptoms. There are other health benefits from HRT, including the prevention of osteoporosis, and there is considerable interest in whether HRT reduces the incidence of CVD.

The incidence of CVD in women rises after the menopause and it is therefore plausible that HRT could prevent CVD. In addition, oestrogens reduce LDL-cholesterol and increase HDL-cholesterol. Some studies, comparing the incidence of CVD in women taking HRT with that in women on no treatment, suggested that it was lower in those receiving HRT. These studies were not designed to investigate the effects of HRT on CVD incidence, however, and the result was a chance finding.

A clinical trial was set up specifically to investigate whether HRT reduces CVD incidence in 2,700 women who already had heart disease and were therefore at extremely high risk of recurrence. Participants were assigned to receive either HRT or inactive placebo and followed for five years. There was no difference in outcome between the two groups.

So the specific trial did not support the previous chance findings of lower rates of CVD in women taking HRT. This is important because this type of randomised trial, in which patients receive either active treatment or a dummy tablet, is viewed as the gold standard for judging the benefits of drug treatment.

The position at present with regard to a possible role for HRT in preventing CVD is that it is not proven.

KEY POINTS

• The main purpose in treating hypercholes­terolaemia is to reduce CVD risk

• Statins are the most powerful cholesterol-lowering drugs

• Addressing other CVD risk factors is also important

• A recent trial suggests that HRT may not protect against CVD as was previously thought