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1University of Manchester Cardiovascular Research Group, Core Technology Facility, Manchester M13 9NT
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2Diabetes Centre, Royal Oldham Hospital, Oldham OL1 2JH
Correspondence to: D Bhatnagar, Diabetes Centre, Royal Oldham Hospital, Oldham OL1 2JH d.bhatnagar@man.ac.uk
Cite this as: BMJ 2008;337:a993
<DOI> 10.1136/bmj.a993
http://www.bmj.com/content/337/bmj.a993
Hypercholesterolaemia is one of the major causes of atherosclerosis. Although there are many causes, hypercholesterolaemia is the permissive factor that allows other risk factors to operate.1 The incidence of coronary heart disease is usually low where population plasma cholesterol concentrations are low.2 In Britain coronary heart disease is a major cause of mortality, and a recent Department of Health survey suggested that the average plasma cholesterol concentration in the United Kingdom was 5.9 mmol/l, much higher than the 4 mmol/l seen in rural China and Japan, where heart disease is uncommon.3 Many studies before and after the introduction of statins have indicated that reducing the prevalence of hypercholesterolaemia is an important means of decreasing coronary risk.
Cholesterol plays an important role as the precursor for steroid hormones and bile acids and it is essential for the structural integrity of cell membranes. It is transported in the body in lipoproteins. Figure 1 shows the role of cholesterol in lipoprotein metabolism.
Conventionally the upper limit for laboratory reference ranges is based on the 95th or 90th centile for a healthy population. This does not apply to plasma cholesterol, however, as several studies show that the epidemiological relation between plasma cholesterol and risk of coronary heart disease extends to the lower end of the cholesterol distribution. Although the relation becomes progressively steeper, there is no obvious threshold below which it ceases to exist.5 Therefore, it is more rational to base a desirable or healthy concentration of plasma cholesterol on the value at which coronary risk is considered unacceptably high. Most patients developing coronary heart disease have plasma cholesterol concentrations that are likely to be between the 30th and 90th centile for their population of origin.6 A population is considered to be unhealthy when its average plasma cholesterol concentration exceeds 5 mmol/l (equivalent to low density lipoprotein (LDL) cholesterol of 3 mmol/l).7
SOURCES AND SELECTION CRITERIA
We selected references if they included a recent meta-analysis or provided a useful, objective, and comprehensive account including extensive recent references. We chose them from a search of PubMed, personal reference lists, and three textbooks26, 27, 28
SUMMARY POINTS
The Joint British Societies (JBS2) guidelines on prevention of cardiovascular disease recommend that the optimal levels of plasma cholesterol should be ≤4 mmol/l (LDL cholesterol ≤2 mmol/l) in patients with pre-existing atherosclerotic disease or diabetes or in those who have a combination of other risk factors that produce a risk of cardiovascular disease (coronary heart disease and stroke) of 20% or more over the next 10 years.8 These risk factors include male sex, increased age, cigarette smoking, high blood pressure, impaired fasting glucose concentration, low concentrations of high density lipoprotein (HDL) cholesterol, raised triglycerides, Indian subcontinent ancestry, and low socioeconomic class.
Hypercholesterolaemia usually results from nutritional factors such as obesity and a diet high in saturated fats combined with an underlying polygenic predisposition. There is overproduction of LDL,9 and its genetic component is unlikely to be monogenic, unless it is extreme. Hypercholesterolaemia can also have an entirely genetic cause. A common example of this is monogenic familial hypercholesterolaemia, an autosomal dominant disorder in which the LDL cholesterol is raised from birth (table 1).10 It is characterised by a dominant pattern of inheritance of premature coronary disease and/or tendon xanthomata.11
Raised plasma triglyceride concentration in association with hypercholesterolaemia is common (table 2) and poses an additional risk of coronary heart disease.12 Usually such patients have an increase in both low density lipoprotein (VLDL) cholesterol and LDL cholesterol and a decrease in HDL cholesterol. This condition is called combined hyperlipidaemia or, if there is a strong familial tendency, familial combined hyperlipidaemia. Usually the disorder is polygenic with a strong overlap with glucose intolerance, diabetes, and the metabolic syndrome and may precede the onset of diabetes.13
Occasionally patients with hypercholesterolaemia have a plasma triglyceride concentration of >10 mmol/l owing to an increase in both chylomicrons and VLDL. The plasma has a milky appearance and eruptive xanthomata, and other features such as acute pancreatitis may occur. Such patients should be referred to lipid clinics for treatment.
Remnant removal disease (type III hyperlipoproteinaemia) leads to combined hyperlipidaemia.14 Although rare, it carries a high risk of both coronary heart disease and peripheral vascular disease early in life. Typically striate palmar and tuberoeruptive xanthomata occur.15 Chylomicron remnants accumulate in the circulation owing to homozygosity for the apo E2 isoform of apolipoprotein E, the ligand important for their hepatic clearance. It has variable penetrance, suggesting that some other cause such as obesity or insulin resistance is necessary for its expression.
Fig 1 The role of cholesterol in the metabolism of lipoprotein. Adapted from Charlton-Menys4
Table 1 Diagnostic criteria for heterozygous familial hypercholesterolaemia, taken from the Simon Broome familial hypercholesterolemia register (www.primarycare.ox.ac.uk/research/vascular/research/simon_broome)
A + B or A + C, constitutes a definite diagnosis of heterozygous familial hypercholesterolaemia.
A + D or A + E constitutes possible heterozygous familial hypercholesterolaemia.
Table 2 and box 1 outline the diagnostic classification of hypercholesterolaemia. Before primary hypercholesterolaemia is diagnosed underlying secondary causes should be excluded.
Before treatment is started for hypercholesterolaemia a detailed history, clinical examination, and baseline laboratory tests are needed to discover causes of secondary hypercholesterolaemia, manifestations of primary lipoprotein disorders, and any complications related to atherosclerosis. A family and occupational history—including a history of smoking, alcohol intake, and dietary preferences—will help to indicate the extent to which these factors contribute to hypercholesterolaemia and/or to risk of cardiovascular disease and to gauge the patient’s ability to change lifestyle. The physical examination should include blood pressure, body weight, height, waist circumference, and a search for xanthomata. A family history is essential to facilitate cascade testing in primary hypercholesterolaemia.16
Table 2 Most commonly encountered causes of primary hypercholesterolaemia
Prevalence is approximate and refers to the adult population in the UK (Durrington, see “Additional education resources” box).
*Defined as plasma cholesterol ≥5 mmol/l in middle age.
†Defined as plasma cholesterol ≥5 mmol/l and fasting plasma triglycerides ≥1.7 mmol/l in the absence of diagnostic features of heterozygous familial hypercholesterolaemia (table 1).
Laboratory assessment in hypercholesterolaemia
When screening for hypercholesterolaemia it is advisable to take blood samples after a fast of at least 10 hours to avoid the postprandial contribution to plasma triglycerides. If plasma triglycerides do not exceed 4.5 mmol/l, the LDL cholesterol concentration can be calculated by the Friedewald formula (box 2). If low density lipoprotein cholesterol cannot be measured owing to hypertriglyceridaemia, then non-HDL cholesterol can be used as a target for statin treatment. Biological and laboratory variations in plasma cholesterol concentrations mean that tests should be done more than once before treatment is started. Laboratory reports should also provide HDL cholesterol values and the total cholesterol:HDL ratio to help assess risk of cardiovascular disease, but LDL cholesterol should be used as the target for treatment where possible. The targets for non-HDL cholesterol are 0.75 mmol/l higher than for LDL cholesterol.
In assessing risk of cardiovascular disease it is also essential to measure fasting glucose concentration. Before lipid lowering treatment is started, liver function tests, creatine kinase activity, serum creatinine, and dipstick urine protein should be measured. In some patients specialised assays may be needed to identify the cause of hypercholesterolaemia.
The introduction of cholesterol lowering drugs should always be based on an assessment of risk of cardiovascular disease. In patients without diabetes, the pre-existing risk can be estimated using the JBS2 charts8 or the JBS2 cardiovascular risk assessor computer program (www.heartuk.org.uk/new/pages/prof/jbs_cv_riskassessor.html) (figure 2).
Cholesterol lowering drugs are intended for use in people between the age of 40 and 70 years. The assessment tables are likely to underestimate risk in people with adverse family history, impaired fasting glucose, or impaired glucose tolerance; people from the Indian subcontinent; people with hypertriglyceridaemia or renal dysfunction; and in the presence of multiple comorbidities. The computer program makes adjustments for these. The footnote to the tables recommends multiplying the cardiovascular risk by 1.3-1.5 when one or more of these factors are present. In certain groups of patients—for example, those with inherited dyslipidaemia—treatment through diet and with appropriate drugs should be started without calculating cardiovascular risk (box 3).8, 17 The charts and computer program are designed to assist clinical judgment not to replace it. They should be used along with the clinical approach described above.
BOX 1 CAUSES OF HYPERLIPIDAEMIA
Some causes of secondary hyperlipidaemia
Some causes of mixed hyperlipidaemia*
*Increase in plasma cholesterol and triglycerides
BOX 2 CALCULATING LDL CHOLESTEROL AND NON-HDL CHOLESTEROL CONCENTRATIONS*
*All values in mmol/l
The targets to which plasma cholesterol should be lowered have changed over the years, but the near linear relation between the log of the risk and cholesterol reduction described by the Cholesterol Trialists Collaboration18 forms part of the evidence for setting targets. The JBS2 guidelines8 advocate an optimal total cholesterol target of <4.0 mmol/l (or a 25% reduction) or an LDL cholesterol concentration of <2.0 mmol/l (or a 30% reduction) for both primary and secondary prevention and for people with diabetes mellitus.
Fig 2 Summary of the Joint British Societies’ guidelines on preventing cardiovascular disease in clinical practice 8
BOX 3 STARTING STATIN TREATMENT WITHOUT FORMAL ESTIMATION OF CARDIOVASCULAR RISK
Statin treatment should be considered in the following people without formal estimation of cardiovascular risk8, 17:
The 2008 guidelines from the National Institute for Health and Clinical Excellence (NICE) on lipid modification19 agree with the JBS2 guidelines on secondary prevention targets but do not advise any targets for primary prevention. They recommend that when the decision to prescribe a statin for primary prevention has been made patients should be given 40 mg of simvastatin without further monitoring of serum lipids, unless clinical judgment or patient preference indicate a review of drug treatment or lipid profile. The JBS2 and NICE guidelines both advise an “audit” concentration of total cholesterol of 5 mmol/l or an LDL cholesterol concentration of <3 mmol/l as the minimum standard of care for high risk individuals.
Clinicians should be aware that cholesterol lowering treatment can reduce the cholesterol content of an atheromatous plaque, which may be too small for angioplasty or bypass surgery but which can rupture, enabling clot formation, arterial occlusion, and the acute clinical syndromes associated with atherosclerosis.20
The strength of the evidence that cardiovascular risk can be decreased by treatment with statins18 means that the most appropriate approach to treating people at the highest risk combines lifestyle advice with use of statins.
Lifestyle measures
Lifestyle measures such as stopping smoking, decreasing excess alcohol consumption, increasing physical activity, losing weight, and following a low fat saturated diet will all decrease the risk of cardiovascular disease. However, dietary advice given by health professionals often produces inadequate lowering of cholesterol, typically by about 3%, although reductions of 10% or more have been seen in studies carried out in controlled conditions on a metabolic ward.21
Plant sterols
A recent systematic review suggests that margarines and drinks containing plant sterols or stanols rather than saturated fat can decrease plasma cholesterol by up to 10%.22
Statins
Several large trials of primary and secondary prevention of coronary heart disease using statins have established their efficacy. A meta-analysis of 14 statin trials using data from 90 056 participants showed that for each 1 mmol/l lowering of plasma LDL cholesterol coronary and stroke events fell by about 21% and this was accompanied by a decrease in all cause mortality.18
This linear decrease extends down to current LDL cholesterol targets of 2 mmol/l. Patients in clinical trials whose pretreatment LDL cholesterol concentrations were <3 mmol/l showed the same reduction in relative risk of cardiovascular disease with statin treatment as those with higher LDL cholesterol concentrations.18
Statins are generally well tolerated and efficacious. However, efficacy varies: at a maximum dose of 40 mg, pravastatin reduces LDL cholesterol by 29%, and at a maximum dose of 80 mg, simvastatin, atorvastatin, and rosuvastatin reduce LDL cholesterol by 42%, 55%, and 58% respectively.23 Each doubling of dose with a statin results in a further 5-6% reduction in LDL cholesterol.
About 1-3% of patients complain of side effects such as tiredness, indigestion, or change in bowel habit. Some patients develop increases in liver transaminase or creatine kinase activity. Tests for liver function should be done before and about three months after statins are started. If serum transaminase activity increases to three times the upper limit of normal then treatment should be stopped.
However, a substantial number of patients with dyslipidaemia already have abnormal serum liver function tests owing to non-alcoholic steatohepatitis, with increases in alanine aminotransferase and γ glutamyl transpeptidase being particularly common in patients with hypertriglyceridaemia. This is not a reason to withhold statin treatment. Fluctuations in alanine aminotransferase may create the impression that it has risen as a result of statin treatment. But hepatotoxicity induced by statins is rare, and in patients at high risk of cardiovascular disease statins should not be discontinued because of abnormal liver function tests without firm proof of causality.24
ADDITIONAL EDUCATIONAL RESOURCES FOR HEALTHCARE PROFESSIONALS
TIPS FOR NON-SPECIALISTS
ADDITIONAL EDUCATIONAL RESOURCES FOR PATIENTS
Myositis induced by statins is also uncommon,24 and minor fluctuation in creatine kinase activity and in muscle discomfort should not lead to discontinuation of statins. People who are physically active or are of African origin can have creatine kinase levels as high as 1000 U/l regardless of statin treatment. Untreated hypothyroidism and certain drugs when used with statins can increase the possibility of myositis.25 Nevertheless, when patients complain of tiredness or muscle pain then liver function tests and measuring creatine kinase activity should be part of the routine investigations. If patients are convinced that the symptoms are linked to statin use, then it is worth trying another statin.
Other pharmacological agents
For patients who are unable to tolerate statins, bile acid sequestrants or alternatives such as nicotinic acid can be used, but these are more likely than statins to cause side effects. Fibrates increase HDL cholesterol and lower plasma triglycerides but have marginal effect in lowering LDL cholesterol. Moreover, several large trials of fibrates have shown that although non-fatal cardiovascular events are decreased, total mortality increases.
Combination treatments
In patients who do not achieve target cholesterol levels when they are taking statins, combination treatment can be used. It is usual to combine a statin with ezetimibe, which will lower LDL cholesterol by a further 15%. Nicotinic acid, fibrates, and the fish oil preparation Omacor (Solvay), which have the advantage of lowering plasma triglycerides too, can also be used in combination with statins to lower LDL cholesterol. Currently large randomised controlled trials are looking at whether statins and fibrates combined are more beneficial than statins alone.
Combination treatments are associated with more side effects and must be used with caution. Gemfibrozil, in particular, interferes with the conjugation of statins, increasing the chances of myositis, and it should not be combined with statins. Combinations of statins with fibrates or nicotinic acid should not be used in secondary hyperlipidaemia, elderly people, or those being treated long term with ciclosporin, tacrolimus, macrolide antibiotics, or antifungals. Lipid lowering drugs should be stopped at least three months before a woman plans to conceive because of potential teratogenicity.
Contributors: DB, HS, and PND have contributed equally to the preparation of this article. DB and PND are the guarantors.
Competing interests: DB has received lecture fees and fees for consultancies from pharmaceutical companies making lipid lowering drugs and treatments for diabetes mellitus. HS has received lecture fees from a pharmaceutical company making insulin and lipid lowering drugs. PND has an independent research grant to the University of Manchester from Pfizer and has also received lecture fees from pharmaceutical companies.
Provenance and peer review: Commissioned; externally peer reviewed.
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