Diagnosis, Management and Prevention of the Common Dyslipidaemias in South Africa-Clinical Guideline 2000

South African Medical Association and LASSA working group

Principal Authors: GMB Berger, AD Marais

1 Summary

suffer from familial hypercholesterolaemia (FH) or equivalent severe, monogenic disorder, or

have a 10 year risk of an acute clinical coronary event of >20% — or > 30% risk if extrapolated to the age of 60 years — due to the presence of the hyperlipidaemia alone or in combination with contributory risk factors.

Table 1: Classification of dyslipidaemia and its common causes

1. Concentrations are expressed in mmol/l.

2. In this context the definition of 'primary' includes those dyslipidaemias due to a major, identifiable single-gene mutation and those disorders in which genetic factors are important in causation. In the latter category secondary and lifestyle mechanisms are also significant. 'Secondary' dyslipidaemias include those in which an identifiable non-lipid disorder is mainly responsible for the abnormal plasma lipid profile.

3. The atherogenic lipoprotein phenotype (ALP): elevated TG and low HDLC levels in the presence of normal or slightly raised LDLC concentrations. The TC/HDLC ratio is >5. Other abnormalities include an increased number and abnormally small and dense LDL, but these need not be measured in clinical practice. Type III hyperlipidaemia may also be known as dysbetalipoproteinaemia and type I hyperlipidaemia is familial chylomicronaemia or lipoprotein lipase deficiency.

2 Abbreviations:

ALP atherogenic lipoprotein phenotype
AMI acute myocardial infarction
BAS bile acid sequestrants
BMI body mass index
BP blood pressure
CABG coronary artery bypass graft
CHD coronary heart disease
CQC Centre for Quality Care of the SA Medical Association
DM diabetes mellitus
EDTA ethylenediaminetetraacetic acid
FCH familial combined hyperlipidaemia
FDB familial defective binding apolipoprotein B
FH familial hypercholesterolaemia
HDLC high density lipoprotein cholesterol
LASSA Lipid & Atherosclerosis Society of Southern Africa
LDL low density lipoprotein
LDLC low density lipoprotein cholesterol
LMD(s) lipid-modifying drug(s)
MI myocardial infarction
SAMA South African Medical Association
SEMDSA Society for Endocrinology, Metabolism & Diabetes of Southern Africa
TC total cholesterol
TG total triglycerides
VLDL very low density lipoprotein

3 Introduction:

Dyslipidaemia is defined as a clinically significant alteration in the circulating lipids and lipoproteins predisposing to CHD and related disorders. In practice the most important and common is hypercholesterolaemia. The term hyperlipidaemia emphasises the importance of excess lipid in generating the adverse consequences of the common lipid (lipoprotein) disorders. The chief exception is a low HDLC concentration which is independently atherogenic whereas a high HDLC level (> 1.5 mmol/L) is generally protective.
Dyslipidaemia is common in Westernised, industrialised communities (1-3). In South Africa, CHD is most prevalent in the Indian and white groups, with a somewhat lower incidence in the coloured community (4). CHD in the black population is still relatively uncommon but risk-factors for the possible emergence of future CHD are already apparent including hypertension, diabetes, hyperlipidaemia, obesity and tobacco smoking (5). While the bulk of CHD occurs in persons without major gene defects of lipid metabolism, some genetic disorders such as FH, powerfully predispose to CHD and should be considered in all severe hyperlipidaemias. FH and other severe genetic defects have been well described in many South Africans communities, including blacks.
The chief objective of this guideline is to assist health care providers in the effective diagnosis and management of the more common dyslipidaemias. It reflects advances in the diagnostic approach and drug therapy of dyslipidaemias since the previous guidelines published in 1986 (6). A holistic approach to cardiovascular risk factors and prevention of CHD is adopted which goes beyond cholesterol reduction, though this remains an important, quantifiable component of therapy. There is evidence that hyperlipidaemia is both inappropriately and undertreated in South Africa (7).

4 Approach to diagnosis:

The most common and clinically significant lipid abnormality is hypercholesterolaemia. Total plasma cholesterol concentration is minimally affected by recent food intake. Thus, in the absence of clinical risk factors or evidence of pre-existing CHD or atherosclerotic vascular disease elsewhere, determination of non-fasting cholesterol level will suffice to detect most clinically significant hyperlipidaemias in new patients. Screening for hypercholesterolaemia should be undertaken in any person considered to be at risk for CHD, and probably at least once in the life of each adult. A full serum or plasma lipoprotein profile should be done for the following indications: hypercholesterolaemia of > 5 mmol/L on screening, patients with existing clinical CHD and in the presence of physical signs of a lipid disorder. It is useful to view the plasma cholesterol concentration in three broad categories of risk (Table 2).

An approach to diagnosis and treatment is outlined in Figure 1, which emphasises the need to interpret cholesterol values in the context of other relevant clinical and laboratory data. A systematic assessment of overall risk in persons who have no clinical evidence of CHD is outlined in Table 3. This assessment should be performed on all patients under consideration for LMD. Some of the key decisions required of the practitioner are whether:

Table 2: Broad Categories of CHD risk according to cholesterol concentration

CATEGORY DESCRIPTION
1: Cholesterol level < 5.0 mmol/L

• In an otherwise healthy individual the level of cholesterol value is considered to contribute insignificant risk.

• Other than general advice concerning a health-promoting life-style such patients do not require further specific diagnostic investigation or individualised attention, but follow-up in 5 years is recommended.

• If overt CHD or obvious additional risk factors are present, further evaluation is required.

2: Cholesterol level 5.0 – 7.5 mmol/L

• This range carries an elevated and increasing risk for which, in the absence of additional risk factors, generally introduction of LMD therapy is NOT merited.

• More vigorous non-pharmacologic intervention and more frequent follow-up is warranted, as is careful clinical and laboratory assessment for additional risk factors and for the possible cause of the hyperlipidaemia.

• A significant proportion of patients in this category have additional risk factors which elevate the overall likelihood of future CHD sufficiently to merit the use of appropriate LMDs – the high risk group.

• A smaller number will have an underlying clinical disorder predisposing toward hyperlipidaemia, the so-called "secondary hyperlipidaemias" (Table 1). Treatment of the underlying illness may mitigate the severity of the lipid abnormality.

3: Cholesterol level > 7.5 mmol/L

• Above this level the use of drug therapy should be considered in all patients in whom life-style modification does not achieve the desired lipid profile (Table 1).

• A variable proportion of patients will have conditions listed below all of which further increase the need for effective management:

FH or

overt CHD or

other additional clinical risk factors.

 

• As for category 2 some patients will be hyperlipidaemic secondary to an independent underlying clinical disorder. A full lipoprotein profile and general diagnostic work-up is required

Table 3: Calculation of absolute risk of MI over 10 years in individuals without ischaemic heart disease by combining several conventional risk factors
Adapted from Kannel and Wilson, (8)

To derive the absolute risk as percentage of subjects who will develop MI over 10 years, add the points for each risk category. For men consult section A and for women, section B. For the BP score, use the highest score of either diastolic or systolic pressure. The risk associated with the total points is derived from section C for men and for women. The average population risk from which the data were derived is given in section D over various age intervals. The following risk factors are not included: obesity, family history, definite diagnosis of FH (to be considered in cases where cholesterol concentration is >7.5 mmol/L), sedentary lifestyle. These factors add to risk and should be borne in mind when assessing global risk.

Note 1: % = risk per 100 individuals with a specified point score of developing AMI within 10 years. The score is gender dependent: a score of 7 for men and 13 for women both have a 13% risk. To extrapolate the risk to age 60 years in a younger person, simply add the difference in age points to the total score. E.g., women of 30-34 years have -9 age points whereas women of age 60-64 have +8 age-related points. The difference, 17 points, should be added to a 30-34 year-old female, patient's score when calculating her risk at age 60 years.

4.1 Risk factors for CHD

These are clinical or biochemical markers of increased risk for CHD. Many risk factors represent about a 2 to 3 fold increase in risk while major risk factors (established CHD, major genetic defect) have worse risk implications. The most important risk factors in common clinical practice are used in the risk calculation in Table 3. Some risk factors are modifiable while others are not modifiable. A combination of risk factors may enhance risk many fold.

Table 4: Categories of risk factors

4.2 Classification of dyslipidaemia (Table 1)
Although it is not a pre-requisite to management to make an accurate aetiologic or phenotypic diagnosis, greater diagnostic precision does improve ability to determine risk, to tailor treatment including drugs, and to counsel the family. The lipoprotein phenotype is most conveniently classified in terms of hypercholesterolaemia, hypertriglyceridaemia or as a mixed picture in which cholesterol and triglyceride levels are more-or-less equally elevated. In addition, the ALP is a clinically significant dyslipidaemia in which triglyceride, cholesterol and HDLC are all variably abnormal. Pure hypertriglyceridaemia is the least atherogenic, but not totally innocuous form of the different profiles, but severe hypertriglyceridaemia can result in acute pancreatitis and other clinically adverse outcomes. Causally,dyslipidaemia is defined as either primary or secondary, though in many disorders the aetiology is significantly mixed; an important consideration in treatmentKH feels this is not clear enough. What does it mean?.

4.2.1 Primary dyslipidaemias
These were defined in Table 1. In the more common, clinically important monogenic disorders the inheritance is autosomal dominant. In FH and similar dyslipidaemias one may expect half the children in an affected family to present with hyperlipidaemia. In the rarer autosomal recessive disorders, such as familial lipoprotein lipase defect, only 25% of the children are generally affected and both parents carry the abnormal gene. Evidence for a familial cause is not always easy to elicit in this group. In those families in which the genetic basis may be multiple or in which lifestyle and secondary contributions to pathogenesis are significant — the so-called mixed or polygenic category — the family history does not manifest a Mendelian pattern, but is important in assessing the total risk in the affected patient. Some important examples of primary dyslipidaemias should be borne in mind in management.

4.2.2 Secondary dyslipidaemias
The genetic constitution of the person is normal or contains only minor gene defects but the environment or underlying incidental disease brings out the dyslipidaemia.

5 Laboratory procedures:

The determination of the lipoprotein profile is an essential component of the diagnostic process for patients in cholesterol categories 2 and 3, and for the patient with a cholesterol <5.0 mmol/L but established CHD.
A specimen for a lipoprotein profile requires a 12 hours overnight fast (water is permitted) in adults and older children. Blood should be taken between 08:00 and10:00. The patient should be sitting and it is important to avoid undue venestasis. Blood should be collected into tubes without anticoagulant and allowed to clot (serum), or into tubes containing heparin or EDTA (plasma) and mixed carefully by inversion. If EDTA is used, the tubes should be filled to the top to avoid dilution errors. Plasma or serum should ideally be separated from the cells within 2 hours of sampling but definitely within 6 hours. The separated plasma/serum can be stored at 4EC for four days; otherwise freeze at below –20EC if possible.
Care should be taken to avoid preanalytical errors (recent or current illness, non-fasting state, delayed processing). Normal biological variation of between 5-10% for TC, LDLC, HDLC and apolipoprotein B and 25% for triglycerides must also be considered in assessing results. Bearing this in mind, the clinician should base decisions to initiate treatment with LMDs, where possible, on at least 2 separate results obtained 1 week or more apart, using a single laboratory to minimise variability. If there is a discrepancy > 10% between these two, a third sample is advisable. The acute phase response seen with severe illnesses sets in within a day and results in a lower cholesterol measurement for at least 6 weeks. This is particularly important in the diagnosis of dyslipidaemia after myocardial infarction. Severe hypertriglyceridaemia may also be underestimated and renders cholesterol estimations less accurate too. Note that laboratory investigations for exclusion of secondary dyslipidaemia should include thyroid, renal and liver function tests as well as a random or fasting glucose, serum albumin and protein electrophoresis, and a urinary screen for protein, glucose and bilirubin and urobilinogen.

6 Management of hyperlipidaemia

The two key elements in the management of hyperlipidaemia are:

6.1 Lifestyle modification
The main targets of lifestyle or behavioural modification are: cessation of tobacco use, a healthy diet, regular aerobic exercise, and, where indicated, loss of weight. The principles of a prudent diet and exercise are outlined below. The enthusiastic endorsement of desirable lifestyle changes by the practitioner is most important. The initiation and maintenance of the appropriate changes may be promoted by the use of qualified dieticians and by referring the patient to an exercise group or gymnasium with some expertise in preventative cardiology. The use of support groups can assist patients attempting to stop smoking or curtail alcohol intake.

6.1.1 Cessation of tobacco use
This is the single most important therapeutic action in patients with hyperlipidaemia and may require considerable motivation and reinforcement; consider support groups with relevant expertise in selected cases. Risk falls rapidly with cessation.

6.1.2 Prudent diet
The main elements of a prudent or anticoronary diet are a reduction of saturated fat, cholesterol and energy intake relative to the typical Westernised intake. This may be achieved by substitution of low fat or zero-fat dairy products for full cream varieties, by the use of plant oils and soft margarine in place of butter, coconut oil and palm oil, by avoiding pastries and by grilling or steaming food rather than frying it. It is important to reduce or minimise the intake of fatty meats including, especially, sausages and other processed meats (salami, polony, pies). Poultry (without skin), small cuts of lean beef and fish can replace meat dishes with a high fat content. Reduce egg yolk intake to 1 or 3 times per week or less, depending on the fat content of the rest of the of the diet. Increased fruit, vegetables and fibre are important components of a healthy diet. In addition to lowering total fat intake, reduce alcohol if clinically indicated and in hypertriglyceridaemic states and also simple carbohydrates – in sugar, sweetened soft drinks, white bread and rolls – especially where weight loss is required. Ideal weight may be defined by a BMI < 25 kg/m2 in the general population. A body mass index can be calculated as mass/height2 where mass is described in kg and height in m. A figure around 23 kg/m2 is desirable for patients with DM or hypertriglyceridaemic, low HDLC profiles.
If there is a poor response to these measures or in more severe cases of hypercholesterolaemia, it is advisable to make use of a dietitian who may aim for a more restrictive, but still palatable diet along the following lines:

Nevertheless, evidence from large-scale, prospective, double-blind, randomised clinical trials clearly indicates a reduction of total and cardiovascular morbidity and mortality for both pravastatin (Prava®) and simvastatin (Zocor®) (10-12). Similar trials have demonstrated a reduction in cardiovascular mortality, but not total mortality, using gemfibrozil (Lopid®) (13) and cholestyramine (Questran®) (14). Less rigorous additional studies (15, 16) provide evidence to suggest that other statins and fibrates on the market may have similar beneficial clinical outcomes.
The use of medication must balance cost against clinical efficacy and risk of CHD. No general consensus has been reached on the use of a universal threshold, but the recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention are proposed: namely, that the introduction of LMDs should mainly be confined to patients with a ten year risk of an overt CHD event of $ 20%, projected to the age of 60 years (17). A more conservative approach would use a threshold of >30% at age 60 years. Clinical judgement should be exercised, but all commentators agree that patients with FH or a related monogenic dyslipidaemia or the presence of established CHD, especially a previous AMI, should be candidates for LMDs – unless LDL cholesterol is drastically lowered by non-pharmacologic means alone to #3.0 mmol/l, in the case of established CHD cases. Use Table 2 to calculate the risk of MI based on defined risk factors, bearing in mind the risk factors not included in the table in borderline cases. Careful consideration should be given in this setting to correcting modifiable risk factors and the healthcare context in which the patient is being managed.
In most circumstances, LMDs should not be introduced without a prior trial of vigorous lifestyle modification; more rarely it may be appropriate to initiate drug therapy concurrently with non-pharmacologic management in severely hyperlipidaemic subjects or those at high risk due to the presence of overt CHD. Titrate the drug dose so that the minimal amount may be used to achieve the desirable profile of Table 1. The central aim is to reduce LDLC to # 3 mmol/L. There is considerable variation in the average responses to drugs as given in Table 5. Only the LDLC responses are given in detail while a general range of response is given for TG and HDLC. In general, the lipoprotein response will be complete by 4 weeks. Given below is a brief summary of the drugs that are available on the South African market. For more detailed information about the drugs larger texts or package inserts should be consulted.
The response to medication varies from individual to individual. The Table has rounded off responses and is a guide to the average that can be expected in the majority of patients. An anticoronary diet, weight loss and exercise can significantly enhance the effects of LMDs. Statins were compared directly in one study (18) while fibrate comparisons were pooled for miscellaneous common dyslipidaemic patterns (19). Fibrates should be used in lower doses if there is impairment of renal function. Responses to older drugs are summarised (20) while information was incomplete for acipimox (21).

6.2.1 Statins (Table 5)
The statins, or HMG CoA reductase inhibitors, are the drugs of first choice in patients with pure hypercholesterolaemia and in those with mixed hyperlipidaemia in whom cholesterol elevation is prominent. In addition to reducing cholesterol and LDLC levels by increasing the number of hepatic LDL receptors, they variably elevate HDLC and lower triglyceride concentrations. Statins may also reduce coronary atherosclerosis by effects other than lipoprotein modulation (22). Maximal cardiovascular benefit has been demonstrated with LDLC lowering as little as 24% in primary prevention (23) and it appears that there is little gain from their use below LDLC concentrations of about 3 mmol/L in secondary prevention except for CABG (24). Nevertheless, additional evidence suggests that the degree of cholesterol lowering does influence the angiographic change and clinical outcome (25)
Statins vary in potency, as defined by the capacity to lower plasma cholesterol level per unit mass of drug (Table 5). The statins have a non-linear dose-response curve so that most of the benefit occurs at the lower dose range, with diminishing returns as the maximal dose is approached. With the exception of atorvastatin, the statins are better taken at night when most of the de novo synthesis of cholesterol occurs. Side effects are generally mild. Attention should be paid to transaminase levels, to creatine kinase and to symptoms of muscle pain and stiffness. Rhabdomyolysis is a rare complication, but may be facilitated by the concurrent administration of fibrates, immunosuppressive drugs and erythromycin. In many cases this is due to interactions of the other drugs with the catabolism of some of the statins by cytochrome P450. Occasionally patients complain of gastro-intestinal intolerance, headache and other vague symptoms which may be ameliorated by the use of a different statin. Insomnia may remit if the drug is taken in the morning.

6.2.2 Fibrates (Table 5)
Fibrates primarily lower triglyceride levels, and elevate HDLC concentrations. Total and LDLC values are generally reduced to a lesser extent and paradoxical increases in LDLC may occur in some hypertriglyceridaemic patients. Fibrates are chiefly indicated in predominantly hypertriglycerdaemic subjects with low HDLC levels. Many are obese with an atherogenic lipoprotein phenotype and possibly frank diabetes mellitus. Combining a fibrate with a low dose of a statin or BAS is often effective in normalizing all components of a mixed hyperlipidaemic phenotype.
While cardiovascular mortality was reduced on clofibrate (Atromid-S®) (26), non-cardiovascular and total mortality were not reduced. It is thus not recommended for treating hypercholesterolaemia. Later, the Helsinki Heart Trial (13), using gemfibrozil in hyperlipidaemic subjects with clinical features of CHD, reduced cardiovascular deaths, especially in the subgroup with an atherogenic lipoprotein phenotype (27). However, overall mortality was unaltered. Bezafibrate has achieved angiographic and clinical improvement in young hyperlipidaemic males with a prior acute myocardial infarction (16).
Side-effects include anorexia, alopecia, a reduced glomerular filtration rate, muscle pain and stiffness and increased transaminase levels. Creatinine and liver enzymes may be used to monitor potentially vulnerable or symptomatic patients. Substantially lower doses should be used in elderly patients or in patients with renal or hepatic disease. In general, loss of weight and vigorous non-pharmacologic intervention potentiates the action of fibrates, allowing the use of lower doses.

6.2.3 Bile Acid Sequestrants or Resins (Table 5)
These cannot be recommended as first line drugs, except in children with FH. They are useful as supplementary medication in combination with statins in severely hypercholesterolaemic patients, or, with fibrates in managing some mixed hyperlipidaemias. In the Lipid Research Clinics Primary Prevention Trial (14) on hyperlipidaemic males with overt CHD, cholestyramine was shown to reduce CHD end-points in a dose-dependent relationship.
The chief contra-indication is the high incidence of gastro-intestinal side-effects, notably gastric discomfort and bloating, constipation and nausea. Drugs of the BAS class should be thoroughly mixed with water, the total dose kept as low as possible and introduced slowly over a period of one to two weeks in a stepped fashion. Concomitant prescription of a bulk laxative and stool softener (e.g., psyllium) may ameliorate constipation. Since this class of medication interferes with the absorption of many other drugs, they should be administered some hours apart from other medication.

6.2.4 Nicotinic acid (Niacin) (Table 5)
Nicotinic acid has the advantage of being inexpensive and, when tolerated, is useful to reduce triglyceride levels and increase HDLC as well as lowering LDLC in larger doses. Unfortunately, usage is complicated by significant side-effects, including flushing and sensations of heat and cutaneous discomfort. Hyperuricaemia and gout, hyperglycaemia and diabetes, and hepatic and ophthalmic toxicity are described and may be more frequent with delayed-release preparations (18). A skilled and experienced practitioner may achieve considerable success if time is invested to give the patient a good understanding into the prescription. Flushing is reduced by taking a half or whole aspirin (dissolved in water) between half and one hour before the niacin is taken, this can later be reduced to half an aspirin per day in the morning. Niacin should always be taken with food. The dose should be gradually increased: 100 mg 3 or 4 times daily for a week, then 200 mg 3 or 4 times daily for a week, then further increases by 100 mg 3 or 4 times daily at weekly intervals. A good effect is seen on HDLC at about 1 g daily while LDLC will still improve at higher doses of up to about 3 g daily. If the regimen is interrupted, then the patient should build up the dose from the beginning again. Note that niacinamide or nicotinic acid amide is ineffective and also does not lead to flushing.
Acipimox is a drug derived from niacin with similar but weaker action and, unlike niacin, may be anti-diabetogenic.

6.2.5 Combination therapy
A patient whose lipoprotein concentrations are not controlled by dietary modification and compliance to a drug, should be evaluated at a referral clinic (Table 5). This table will be updated as necessary on the SAMA Centre for Quality Care Internet site: www.samedical.org/cqc
Occasionally severe hypercholesterolaemia may require combinations of a statin and a BAS or a statin together with niacin for better control. Severe hypertriglyceridaemia persisting after maximal dietary fat reduction and control of secondary causes may require the combination of a fibrate with niacin or a statin, but such patients should generally be referred to a Lipid Clinic. In severe mixed hyperlipidaemias a fibrate and a statin may also be combined with good effect.

6.3 Referral of patients
Table 6 lists the lipid clinics at referral hospitals that can provide expertise in lipid disorders in South Africa. This table will be updated as necessary on the SAMA Centre for Quality Care Internet site: www.samedical.org/cqc
Urgent referral is required if the plasma triglyceride concentration is >15 mmol/L while persistence of hypertriglyceridaemia of >5 mmol/L after all other measures have been attempted also merits referral.
Persistent hypercholesterolaemia of >7.5 mmol/L should also be referred, as should any patient with a TC $15 mmol/L. With the exception of xanthelasma, the presence of a cutaneous or tendon xanthoma indicates a potentially serious metabolic disorder and merits referral, this is especially true to children.