The management of hyperlipidaemias should be viewed against the background of the following observations.
• Hyperlipidaemias are common; 66% of the adult UK population have a plasma cholesterol concentration in excess of 5.2 mmol/1, the lowest concentration generally associated with cardiovascular risk (in fact, statistical correlation can be shown with cholesterol concentrations well below this value).
• Investigation of hyperlipidaemia must be directed initially at excluding contributory causes, i.e. secondary hyperlipidaemias (see above). None of these should be assumed to be the sole cause, even if present. Long-term decisions on management should be initiated only on the basis at least two fasting blood samples.
• All patients (and their spouses/partners, if appropriate) should receive advice on lifestyle, diet and weight control, which are important components of overall macrovascular risk prevention. Dietary treatment of hypercholesterolaemia has a modest effect at best but diet and weight reduction are more effective for hypertriglyceridaemia. Total fat, especially saturated fat should be reduced (and partially replaced with mono- and polyunsaturated fats); spreads containing plant sterols and stands, e.g. Benecol, Flora Proactiv, are useful as they can reduce plasma cholesterol by up to 10%. In some individuals, especially those with mixed hyperlipidaemia (elevated cholesterol and triglycerides), successful adherence to dietary advice, and weight loss, produces very significant improvements. Patients with remnant lipaemia (RRD hyperlipidaemia) may respond excellently to diet, weight loss (and possibly the addition of a fibrate).
• Much of the work of lipid clinics is taken up with attending to multiple interacting risk factors such as hypertension, diabetes, thyroid disease and smoking, as well as to the lipid abnormality.
• The decision to use lipid-lowering drugs is made on the basis of the overall absolute CHD risk (see below and footnote 3), e.g. evidence of existing CHD, hypertension, diabetes mellitus, positive family history. The justification is easiest in two cases. Firstly, as primary prevention in the relatively small number of patients who are asymptomatic but have significant abnormalities of their lipid profiles; patients with FH and remnant lipaemia are at high risk. The decision to treat is made on the patient's absolute risk as well as the degree of lipid abnormality. Secondly, as secondary prevention in patients who have evidence of CHD (previous myocardial infarction, angina pectoris), cerebrovascular or peripheral vascular disease or diabetes mellitus. The Scandinavian '4S' Study1 of 4444 patients with a total cholesterol 5.8-8.0 mmol/1 after a myocardial infarction randomised to receive simvastatin (median dose 27 mg) or placebo found that active treatment reduced total mortality by 30%, deaths from coronary heart disease by 42% and recurrent myocardial infarction risk by 34%. The authors estimated that addition of simvastatin to the treatment regimens of 100 patients with coronary heart disease would, over 6 years, preserve the lives of 4 out of 9 patients who would otherwise die and would prevent a nonfatal myocardial infarction in 7 of an expected 21 cases.
• Consensus minimum targets for primary and secondary prevention of CHD with statins are a total plasma cholesterol of < 5 mmol/1 (or a reduction of 20-25% if the result is lower) or a LDL-cholesterol of < 3 mmol/1 (or a reduction of 30% if that is lower).2 These may be revised in the light of the Heart Protection Study (see p. 486).
• There is evidence that statins protect against stroke. The benefit is seen in patients with
1 Scandinavian Simvastatin Survival Study Group 1994 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383-1389.
plasma cholesterol > 5.0 mmol/1 (or LDL cholesterol >3.0 mmol/1) who have a history of ischaemic stroke or transient ischaemic attacks, or CHD or diabetes mellitus.
More controversial is the extent to which primary prevention (treatment of clinically unaffected patients with moderate elevation of cholesterol levels) should include drugs, and whether secondary prevention should ever start with drugs rather than diet. Dietary treatment can lower cholesterol levels in committed subjects, and is obviously less costly than drug treatment. Unfortunately numerous studies have shown that over any substantial period of time (e.g. one year) diet has no clinically significant influence on plasma cholesterol; and the wait for diet to have an effect often results in patients being lost from hospital follow-up after their initial myocardial infarction. Evidence comes from the WOSCOPS study® in which pravastatin 40 mg/day and placebo were compared in 6590 men age 50-70 with LDL cholesterol 4-6 mmol/1; pravastatin reduced coronary heart disease (fatal and nonfatal events) by 31%. The authors estimated that treatment of 1000 such subjects each year would prevent 20 myocardial infarctions. Concerns that primary prevention could have a net adverse outcome (that cholesterol reduction increased the risk of cancer or violent deaths) have been laid to rest by a number of outcome trials.
The decision to offer a patient primary prophylaxis is influenced by the absolute risk for the individual, the potential risks from the statin therapy and costs to the health provider. As statins so far have an excellent safety record, costs will escalate with a decision to treat lower and lower levels of absolute risk. Current UK recommendations suggest treating patients with a CHD risk of at least 30% over 10 years, and an aspiration to treat those with a 15%
2 Wood D et al 1998 Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 80(Suppl): Sl-29. (British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association).
3 WOSCOPS = West of Scotland Coronary Prevention Study. Shepherd J et al 1995 Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New England Journal of Medicine 333:1301-1307.
10-year risk if resources allow. The large number of additional patients involved by treating at the lower level raises issues of funding and resources (but not the cost-effectiveness of the treatment, which is clear).
The absolute CHD risk is computed using risk equations based on the Framingham cohort;4 in reality this means consulting a simple colour-coded chart armed with data about the patient including age, sex, smoking status, pretreatment blood pressure and plasma total and LDL cholesterol, and presence or absence of diabetes.4
Management may proceed as follows:
1. Any medical disorder that may be causing hyperlipidaemia, e.g. diabetes, hypothyroidism, should be treated first.
2. Dietary adjustment. The following applies to all patients:
• Those who are overweight should reduce their total caloric intake, ideally until they have returned to the weight that is appropriate for their height (i.e. body mass index) but realistically with an initial aim of reducing body weight by 10% (see Appetite control p. 696); this automatically assumes reduced intake of alcohol and total (especially animal) fat. Elevated triglyceride concentrations may respond particularly well to alcohol withdrawal.
• Those who fail to achieve adequate weight reduction or who are already at their ideal weight should reduce their total fat intake; poly- and monounsaturated fats or oils may be taken partially to substitute for the reduction in animal fats. Reduction in dietary cholesterol is a much less important element of the diet, but excess egg yolks should be avoided. Benecol or Flora Proactiv should be added.
3. Specific types of hyperlipidaemia are treated thus:
• Familial hypertriglyceridaemia responds best to dietary modification and weight reduction
4 The cardiac risk program (actually an Excel spreadsheet) and risk assessment charts can be downloaded from the BHS website at http: / /www.hyp.ac.uk/bhsinfo. They may also be found in the British National Formulary.
(above) together with a fibrate; nicotinic acid may be added.
• Familial combined hyperlipidaemia should be treated with dietary modification and weight reduction (above) together with a statin; nicotinic acid and/or a fibrate may be added in resistant cases.
• Remnant removal disease (remnant lipaemia) responds to dietary modification and weight reduction (above) and a fibrate; nicotinic acid and/or a statin may be added where there is failure to respond.
• Familial or polygenic hypercholesterolemia is treated by dietary modification and a statin; an anion-exchange resin and/or a fibrate and/or nicotinic acid may be added.
• Familial hypoalphalipoproteinaemia may respond to exercise, weight loss, and nicotinic acid; a fibrate and/or a statin may be added for a small HDL-raising effect but primarily to lower triglycerides and LDL.
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