Blood lipids and lipoproteins

Blood lipids form part of, and are transported within, various plasma lipoproteins. Chylomicrons are lipoproteins that transport lipids, mainly triglycerides, derived from the diet. Triglycerides synthesised in the liver are transported within very-low-density lipoproteins (VLDLs). Plasma cholesterol is carried predominantly within low-density lipoproteins (LDLs). Although some plasma cholesterol comes from food, most is synthesised by the liver in a process controlled by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. High-density lipoproteins (HDLs) carry cholesterol derived from tissues to the liver. Some cholesterol is eliminated in the bile unchanged or is secreted following metabolic conversion to bile salts. Raised blood concentrations of another lipoprotein particle, lipoprotein (a), are found in some people, in particular those with CHD. The lipid components in blood that are usually measured are serum total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides. These serum levels are about 3% higher than those in plasma.

Lipid concentrations and CHD

Cholesterol levels

In men, the risk of having a myocardial infarct or dying from CHD within a given time is higher the greater the circulating total cholesterol concentration.2^,3 At any serum total cholesterol concentration, the 10-year mortality rate due to CHD is particularly high in men who already have cardiovascular disease.4 Hypercholesterolaemia is also a risk factor for CHD in women.5 The main determinant of the increased risk is the LDL cholesterol concentration: oxidised LDL components are thought to promote atherosclerosis. HDL appears to be protective and so the risk of CHD tends to be inversely related to the serum HDL cholesterol concentration. The relative overall influences of LDL cholesterol and HDL cholesterol can be expressed by calculating the ratio of serum total cholesterol concentration to that of HDL cholesterol. In men who are middle-aged or older, the risk of developing a first myocardial infarct is much increased in those in whom the ratio is over 5.3

Triglyceride levels

A raised plasma triglyceride concentration is a risk factor for fatal and non-fatal cardiovascular events (in particular, myocardial infarction) independent of the levels of other blood lipids.6^,7 A 1mmol/L rise in the fasting plasma triglyceride concentration is associated with an increased risk for cardiovascular disease (principally CHD) of about 14% in men and 37% in women.6

Genetically determined lipid disorders

In people with heterozygous familial hypercholesterolaemia, serum LDL cholesterol concentrations are elevated from birth. Without treatment, over half of men with this disorder die from CHD before the age of 60; CHD is also very common in women with the disease. People with the rarer, more severe, homozygous form of the disease commonly develop angina and myocardial infarction in childhood. In other lipid/lipoprotein disorders with a definable genetic component, there may be elevations of cholesterol and/or triglyceride concentrations and premature atherosclerosis. Patients with these diseases usually require specialist management.

Absolute risk of CHD

The concentration of lipids in the blood is only one of the factors that determine a patient's chance of developing or dying from CHD. Other influences include age, gender and a family history of CHD. Ethnic background can be important: for example, CHD incidence and mortality rates are particularly high in British south Asians. These underlying characteristics are further influenced by whether the person smokes cigarettes or has diabetes mellitus, hypertension or left ventricular hypertrophy. Patients who have had a previous myocardial infarction or who have angina or other overt atherosclerotic disease (peripheral vascular disease, cerebrovascular disease) are particularly at risk of developing CHD events. Knowledge of such risk factors allows estimates to be made of the absolute risk of developing CHD within a given time.8

Rationale of lipid-lowering therapy

The main aim of treating hyperlipidaemia is to prevent, slow or reverse the development of atheroma and its clinical sequelae. Treatment of severe hypertriglyceridaemia (over 10mmol/L) may help to prevent acute pancreatitis.

Diet and other lifestyle measures

Lipid-lowering diets

Attempts to lower elevated levels of serum total cholesterol and thereby LDL cholesterol are often based on dietary modification. Typically, diets restrict total fat intake to under 30% of all calories (with no more than 10% from saturated fat), limit cholesterol intake to under 300mg/day and encourage daily consumption of 35g of fibre.9 Fibre binds bile acids in the intestine and leads to increased conversion of cholesterol to bile acids in the liver. Such diets often have marginal effects with serum total cholesterol concentrations typically falling by about 2% (0.13mmol/L).10 Greater falls in the levels of serum total cholesterol (16-22%) and LDL cholesterol (18-25%) are achieved by further restrictions in saturated fat and cholesterol intake11 or by increasing intake of vegetable-derived fibre and protein,12 but such diets may be difficult to adhere to.

Weight control and exercise

In patients who are very overweight (e.g. body mass index of 30kg/m), weight reduction of about 10kg can reduce the concentration of LDL cholesterol by 7% and raise that of HDL cholesterol by 13%.13 Regular exercise appears to enhance the effects of weight reduction.14

Drugs

Statins

Statins inhibit the enzyme HMG CoA reductase and so limit synthesis of cholesterol. Three drugs are available: ▼fluvastatin, pravastatin and simvastatin. In patients with hypercholesterolaemia, these drugs reduce levels of serum LDL cholesterol15^,16 and, in this respect, are generally more effective than other drugs. They can also produce modest falls in triglyceride and rises in HDL levels.16^,17

Unwanted effects - These are uncommon but include minor gastrointestinal disturbances (e.g. nausea, constipation, diarrhoea), headache, rash and elevations in liver enzymes. Raised levels of the muscle enzyme creatine phosphokinase may occur, sometimes with myositis. Rhabdomyolysis occurs rarely (1 case per 100,000 treatment-years).18 The risk of muscle damage is higher if the patient has renal impairment or, possibly, hypothyroidism, or is also taking either an immunosuppressant such as cyclosporin, a fibrate or nicotinic acid. Simvastatin may enhance the anticoagulant effect of coumarin anticoagulants, pravastatin and fluvastatin do not.

Contraindications - These include pregnancy, breast-feeding, lactation, porphyria, active liver disease and unexplained persistent elevation of serum transaminases.

Fibrates

These drugs lower elevated serum total cholesterol, LDL cholesterol and triglyceride concentrations and raise HDL cholesterol concentrations.19^,20 They include bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil.

Unwanted effects - Fibrates can cause gastrointestinal disturbances (e.g. nausea and anorexia), headache and itching. As with statins, muscle damage can occur with fibrates.18 Clofibrate may increase the risk of developing gallstones.

Contraindications - These include severe hepatic and renal impairment, hypoalbuminaemia, gall bladder disease, pregnancy, breast-feeding, nephrotic syndrome and primary biliary cirrhosis.

Anion-exchange resins

These drugs bind to, and so prevent intestinal reabsorption of, bile acids. Cholestyramine and colestipol are the two drugs licensed. In patients with hypercholesterolaemia, they reduce LDL cholesterol levels, cause modest or no elevation of HDL cholesterol and raise levels of triglyceride.21^,22

Unwanted effects - Resins often cause gastrointestinal disturbances (e.g. nausea, abdominal discomfort, diarrhoea) severe enough to limit adherence to therapy. They produce or aggravate hypertriglyceridaemia and may also reduce absorption of fat-soluble vitamins and drugs such as paracetamol, digoxin and thiazide diuretics. They should be given at least 1 hour before, or 4-6 hours after, other medication.

Contraindications - The resins should not be given to patients who have complete biliary obstruction.

Nicotinic acid and acipimox

In patients with hypertriglyceridaemia, nicotinic acid and its analogue, acipimox, can reduce serum triglyceride concentrations.19^,23 In patients with hypercholesterolaemia, nicotinic acid also raises serum HDL cholesterol concentrations and lowers those of serum total and LDL cholesterol.24

Unwanted effects - These are common and occur particularly with nicotinic acid. They include flushing, rash, gastrointestinal disturbances, hyperuricaemia and hyperglycaemia. Rarely, nicotinic acid impairs liver function.

Contraindications - Both drugs are contraindicated during pregnancy. Nicotinic acid is contraindicated in women who are breast-feeding and acipimox in patients with peptic ulcer.

Omega-3 fatty acids

Omega-3 fatty acids, present in certain fish oil supplements such as Maxepa,25 can lower elevated triglyceride levels in patients with hypertriglyceridaemia but do not have a reliable effect on cholesterol concentrations.26

Unwanted effects - These include nausea and belching.

Benefits of lipid lowering

Angiographic studies

A meta-analysis of angiographic trials, lasting 1-10 years and involving patients with various forms of atherosclerosis, indicated that therapy which lowers serum LDL cholesterol levels by about 30% also reduces the chances of atheromatous progression by about one-third and slows narrowing of already diseased vessels.27 Results from a second meta-analysis of studies lasting 1-4 years showed that changes in atheromatous narrowing correlated better with the percentage reduction in LDL cholesterol concentration than with the absolute concentration achieved following therapy.28

Morbidity and mortality studies

A meta-analysis of clinical trials of lipid-lowering therapy in patients with (secondary prevention) and without CHD (primary prevention) indicates that a 10% (about 0.6 mmol/L) fall in serum total cholesterol concentration reduces the risk of death from CHD by 10% (95% confidence interval = 3-16%) and of non-fatal myocardial infarction by 21% (95% CI = 15-27%).29 These trials were conducted before statins were in common use. Of the drugs now available, evidence for the clinical efficacy and safety of the statins (in particular, pravastatin and simvastatin) is much greater than that for other drugs. Some specialists use fibrates to treat patients with markedly elevated serum triglyceride and raised serum cholesterol levels. There is, however, much less evidence to suggest that the reduction of serum triglyceride levels per se improves clinical outcome with regard to CHD.

West of Scotland Coronary Prevention Study (WOSCOPS)

This primary prevention trial involved the randomisation of over 6500 men (aged 45-64 years, with a plasma total cholesterol above 6.5mmol/L and LDL cholesterol of 4.5-6mmol/L) either to pravastatin 40mg daily or to placebo, for an average of 4.9 years.30 Pravastatin decreased plasma total cholesterol by 20% and LDL cholesterol by 26%. It also reduced the risk of non-fatal myocardial infarction or death from CHD by 31% (95% CI = 17-43%) and overall mortality by 22% (p = 0.051, 95% CI = 0-40%). These results suggest that treatment of 1000 such patients with pravastatin 40mg daily for 5 years would prevent seven deaths from cardiovascular causes and 20 non-fatal myocardial infarcts.

Scandinavian Simvastatin Survival Study (4S)

In this secondary prevention study over 4000 patients (81% men) aged 35-70 years, with previous myocardial infarction or angina and serum total cholesterol concentration of 5.5-8.0 mmol/L, were randomised to receive either simvastatin 20mg/day or placebo.31 The dose of simvastatin was titrated against the serum total cholesterol concentration during the early part of the trial. Simvastatin lowered the concentration of serum total cholesterol by 25% and LDL cholesterol by 35%, and increased that of serum HDL cholesterol by 8%. Treatment continued for a median of 5.4 years and produced a 30% reduction in the risk of death, accounted for by a 42% reduction in the risk of death from CHD. Even in patients whose initial LDL cholesterol level was below 4.4mmol/L, simvastatin reduced the risk of a major coronary event by 35%.32 Deaths from other causes, such as cancer or trauma, were not increased. The benefits of simvastatin were accompanied by a substantial reduction in admissions to hospital for either acute cardiovascular events or coronary revascularisation procedures.33 The trial findings suggest that treating 100 patients with simvastatin 20-40mg daily for 6 years would prevent four deaths from CHD and seven non-fatal myocardial infarcts.

Cholesterol and Recurrent Events (CARE) trial

This secondary prevention trial investigated over 4000 patients (86% men) aged 21-75 years with a past history of myocardial infarction and a plasma total cholesterol concentration below 6.2mmol/L (plasma LDL concentration 3.0-4.5mmol/L). This secondary prevention trial investigated over 4000 patients (86% men) aged 21-75 years with a past history of myocardial infarction and a plasma total cholesterol concentration below 6.2mmol/L (plasma LDL concentration 3.0-4.5mmol/L).34 Patients were randomised to treatment for 5 years with either pravastatin 40mg daily or placebo. Pravastatin reduced mean plasma cholesterol concentration by 20% and LDL cholesterol by 28%. It also reduced the risk of either death from CHD or non-fatal myocardial infarction by 24%, the need for either coronary artery bypass grafting or coronary angioplasty by 27% and the risk of developing a stroke by 31%. The trial data suggest that treatment of 1000 patients with pravastatin 40mg daily for 5 years would prevent 11 deaths from CHD and 26 non-fatal myocardial infarcts.

Deciding when to treat

Primary prevention

For patients in whom there is no evidence of CHD, the Sheffield tables for men and women35^,36 offer workable advice and have the advantage of being clear and implementable. These tables identify patients likely to benefit from treatment with a statin and in whom serum total cholesterol concentration should be measured. We enclose copies of these tables with this issue. Despite their advantages, the tables have their limitations. They do not, for instance, give specific advice on how to manage patients from ethnic minorities or those with genetically determined lipid disorders; for these people, GPs and specialists will need to develop local protocols. As a general rule, when managing a patient with a family history of premature CHD and/or hyperlipidaemia, serum total cholesterol concentration should be measured and, if it is elevated, specialist advice sought. The tables can also be criticised because they take as their treatment threshold a risk of developing CHD of 3% per year. Cost is an important consideration in deciding whom to treat with a statin37 and the tables take this into account.38 Similar tables based on a 1.5% risk have been published and could be adopted instead by those who consider the 3% figure too high.38 Others may prefer a different, possibly lower, threshold for treatment. The tables do not adjust for the effect of HDL cholesterol concentration on risk of CHD. However, HDL cholesterol concentration is not usually measured routinely in non-specialist practice; screening and treatment guidelines must take this into account. Where HDL cholesterol concentration is known to be abnormal, and the serum total cholesterol level found to be raised, it would be appropriate to seek specialist advice on further management. If adopted, the tables should be used to review patients periodically since risk of CHD generally increases with age.

Secondary prevention

People who have had a myocardial infarction are particularly likely to benefit from statin therapy. In these patients, blood lipids (including concentrations of serum total and LDL cholesterol, HDL cholesterol and fasting triglyceride) should be measured routinely as part of the management and follow-up of the acute event. Cardiac rehabilitation should also include prophylactic aspirin therapy, a lipid-lowering diet, and advice on stopping smoking and on taking regular exercise.

Patients at similar high risk of developing CHD, and therefore likely to be helped by a statin, include those who have undergone coronary artery bypass grafting, coronary angioplasty or cardiac transplantation, and/or those with angina or other atherosclerotic disease. These patients should have their blood lipid profiles measured.

For secondary prevention, we suggest starting treatment with a statin (pravastatin or simvastatin) in any patient with a serum LDL cholesterol level above a threshold of 3.3 mmol/L (equivalent to a serum total cholesterol level of about 4.8mmol/L). This figure is compatible with the findings of the CARE trial.34 Lifestyle measures should also be instituted but this should not unnecessarily delay treatment with a statin.

As more trial data and results from the implementation of treatment policies become available, advice will need to be modified. We plan to review our advice on primary and secondary prevention in 2 years.

Conclusion

Patients with raised levels of blood cholesterol are at risk of developing and dying from coronary heart disease (CHD). These risks can be reduced by treatment. As general measures, individuals should not smoke, should eat food that does not elevate circulating cholesterol concentrations unduly or promote obesity, and should exercise regularly. In a patient without evidence of coronary heart disease, the need to measure blood cholesterol should be determined by the patient's CHD risk factors, as should decisions on when to treat if levels are found to be abnormal. Figures collating these factors are given in the Sheffield tables. The tables do not include specific advice for patients from ethnic minorities or for identifying and treating those with genetically determined hyperlipidaemias; protocols for management in these circumstances should be devised locally by GPs and specialists. Where there is a family history of premature CHD and/or of hyperlipidaemia or if the level of high-density-lipoprotein cholesterol is known to be low, we suggest that serum total cholesterol concentration should be measured and if raised, specialist advice sought. If hypercholesterolaemia is to be treated, a statin is the drug of choice. In a patient with evidence of atherosclerotic disease (e.g. angina, previous myocardial infarction, stroke), treatment with a statin should be started if the serum low-density-lipoprotein cholesterol levels are 3.3mmol/L or above. Other risk factors, such as hypertension and diabetes mellitus will also need treating.