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PREFACE The necessity for a standardised consensus on clinical management of various medical conditions cannot be overemphasized. The idea for such consensus statements was first initiated by the Master of the Academy of Medicine of Malaysia in 1992. In collaboration with the Ministry of Health of Malaysia, this has now become a reality. In choosing the members of the expert panel, the Ministry placed emphasis on eligible representatives from the Universities, the public sector and the private sector. Grateful thanks must be given to these members for voluntarily sacrificing their valuable time in formulating the contents of this consensus statement. The expert panel met on several occasions to prepare the draft consensus which was then formally presented and discussed at a nationwide workshop held in December 1993. I would like to extend my appreciative acknowledgements also to the Academy of Medicine of Malaysia, the Ministry of Health of Malaysia and to the numerous members of the secretarial staff who shall, for the sake of brevity, remain nameless! Dato' Dr Robaayah Zambahari 1 MEMBERS OF THE EXPERT PANEL CHAIRPERSON Dato' Dr Robaayah Zambahari Consultant Cardiologist Institut Jantung Negara Kuala Lumpur COORDINATOR/EDITOR Dr Ridzwan Bakar Consultant Cardiologist Pantai Medical Centre Kuala Lumpur SECRETARY Dr Rosli Mohd Ali Consultant Cardiologist Institut Jantung Negara Kuala Lumpur PANELISTS Prof Dato' Dr Khalid Abdul Kadir Dato’ Dr Ismail Merican Professor of Medicine Consultant Endocrinologist Universiti Kebangsaan Malaysia Kuala Lumpur Consultant Physician Department of Medicine Hospital Kuala Lumpur Kuala Lumpur Prof Dr Amir Khir Dr R Jeyamalar Professor of Medicine Consultant Endocrinologist Universiti Malaya Kuala Lumpur Consultant Cardiologist Subang Jaya Medical Centre Subang Jaya Datuk Dr Joseph Ong Ah Soon Dr Khoo Kah Lin Consultant Physician Assunta Hospital Petaling Jaya Consultant Cardiologist Pantai Medical Centre Kuala Lumpur Datuk Dr Tarmizi Thayaparan Consultant Physician Department of Medicine Hospital Seremban Negri Sembilan 2 CONSENSUS STATEMENT ON MANAGEMENT OF HYPERLIPIDAEMIA 1. INTRODUCTION Cardiovascular disease is an increasingly important health problem in Malaysia. It is the most common cause of death reported in government hospitals.The majority of these cases are due to coronary artery disease (CAD), of which hyperlipidaemia is one of the main risk factors. The primary and secondary prevention of CAD should therefore be directed against hyperlipidaemia as well as the other risk factors. The above objective can be achieved by a two-fold strategy: a) to promote population-wide lifestyle recommendations for risk reduction. b) to identify individuals at high risk who require therapy. In this context, it is important to treat the patient as a whole and not to treat the individual risk factors in isolation - a global approach. In the light of recent studies, there is convincing evidence that cholesterol reduction in individuals with and without heart disease leads to a reduction in total mortality, CAD morbidity and mortality. Dietary modification, cessation of smoking, exercise and weight reduction form the cornerstone of any coronary prevention strategy. Where appropriate, pharmacotherapy with lipid-modifying drugs should be instituted. Treatment of hyperlipidaemia should be risk stratified. It is most cost effective in individuals with highest risks i.e. those with CAD, followed by individuals without CAD but with multiple risk factors. 2. MEASUREMENT OF LIPID LEVELS Measurement of plasma lipids should take into consideration various factors. The level would be affected if measured during or immediately after acute stress or illness eg. acute myocardial infarction, febrile illness, surgery. In acute MI the cholesterol level may be spuriously low between 24 hours post infarction to 3 months. Certain drugs would affect the lipid levels eg. thiazide diuretics, steroids. The total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) can be measured in both fasting and non-fasting states. The triglycerides (TG) should be measured after 10-12 hours of fasting. TG levels are influenced by alcohol intake in the preceding 24 hours and smoking during the fasting state. The low density lipoprotein cholesterol (LDL-C) level is derived by calculation from the Friedewald formula as follows: LDL-C (mmol/L) = TC - HDL-C - TG / 2.3 This formula cannot be used if the TG levels exceed 4.5 mmol/L. Plasma cholesterol is 3% lower than serum. Measurements made from whole blood differs slightly from that obtained from plasma or serum. Fingerprick method using a 3 desktop machine for the measurement of TC, TG and HDL-C, can produce satisfactory results. These machines however require well-trained operators, careful maintenance and calibration. Lipid levels especially TG show biological variability. Because of this and laboratory variability more than one measurement are usually required, particularly in borderline cases. 3. CLASSIFICATION OF HYPERLIPIDAEMIA Hyperlipidaemia can be classified based on therapeutic considerations as follows: Table 1. CLASSIFICATION OF HYPERLIPIDAEMIA INCREASED CONCENTRATION LIPOPROTEIN SERUM LIPID I. Hypercholesterolaemia LDL Cholesterol II. Mixed Hyperlipidaemia LDL + VLDL* Cholesterol and Triglyceride III. Hypertriglyceridaemia VLDL Triglyceride * VLDL - very low density lipoprotein. 4 The hyperlipidaemias may be primary or secondary in origin. Table 2. PRIMARY HYPERLIPIDAEMIAS Risk of CHD Risk of pancreatitis Plasma cholesterol Plasma triglyceride Physical signs (if present) Common ("polygenic") hypercholesterolaemia + - N Corneal arcus, xanthelasma Familial combined hyperlipidaemia ++ - or N or N Corneal arcus, xanthelasma Familial hypercholesterolaemia +++ - N or N Tendon xanthomata (finger extensor, Achilles' tendons), corneal arcus, xanthelasmas, aortic stenosis Remnant hypercholesterolaemia +++ ± Tuberous xanthomata (elbows), striate xanthomata (palm creases), tendon xanthomata Chylomicronaemia syndrome - +++ Eruptive xanthomata (buttocks, elbows), retinal lipaemia, hepatosplenomegaly Familial hypertriglyceridaemia ? ++ Eruptive xanthomata (buttocks, elbows), retinal lipaemia, hepatosplenomegaly High HDL - - N - 5 Table 3. CAUSES OF SECONDARY HYPERLIPIDAEMIA CONDITIONS MAIN LIPID ABNORMALITIES Diabetes mellitus Triglyceride, HDL Alcohol abuse Triglyceride Therapeutic drugs (diuretics, oral contraceptives, retinoids, corticosteroids, anabolic steroids, progestogens related to testosterone) Triglyceride and/or cholesterol, HDL Hypothyroidism Cholesterol Chronic renal failure Triglyceride Nephrotic syndrome Cholesterol, ± triglyceride Cholestasis Cholesterol Bulimia Triglyceride Anorexia nervosa Cholesterol Pregnancy Triglyceride Secondary causes of hyperlipidemia should be considered in the following situations: 1. TC exceeds 7.0 mmol/L, one should exclude primary hypothyroidism, nephrosis, obstructive liver disease. 2. TG exceeds 4.5 mmol/L, one should exclude secondary causes such as alcoholism. 3. High TG with low HDL usually indicates insulin resistance syndrome such as NIDDM and impaired glucose tolerance. 4. Failure to respond to therapy. 5. Special risk groups eg family history of diabetes mellitus, past history of thyroid disease. 6 4. HYPERLIPIDAEMIA AS A RISK FACTOR FOR CHD From available epidemiological and scientific data, hyperlipidaemia has been identified as one of the main risk factors of CHD. Specific lipid entities implicated are: 4.1 Elevated total cholesterol levels In epidemiological studies, a single total cholesterol measurement appears to be predictive of the risk of CHD. The evidence linking elevated total cholesterol levels with increased risk for CHD comes from: - animal experiments, - nature and dynamics of human atherosclerotic plaques, - occurrence of elevated total cholesterol levels in groups with clinically manifested atherosclerotic disease, - genetic hyperlipidaemias associated with premature CHD; - epidemiological studies of CHD risk in populations with differing total cholesterol levels. The risk for CHD appears to increase progressively with total cholesterol levels above 3.5 mmol/L. The relationship between CHD risk and total cholesterol levels is continuous and curvilinear. The higher the total cholesterol level, the greater the risk. People with the lowest total cholesterol levels are however not completely immune to the disease. The subfraction of cholesterol which correlates best with atheroma and CHD is LDL-C. It has been shown that reducing total cholesterol by 1% will reduce CHD risk by 2%. 4.2 Low plasma HDL-C levels There is substantial data linking a low HDL-C level with an increased risk of CHD. These include: - family studies of kindreds with familial forms of low HDL-C who have CHD. - epidemiological data all seem to show an inverse relationship between HDL-C levels and CHD risk. - angiographic studies of atherosclerosis regression in lipid intervention trials in which there was an increase in HDL-C levels. 7 Epidemiological data seem to consistently show that there is a 2-3% decrease in CHD risk for each 0.4 mmol/L rise in HDL-C levels after adjustment for other risk factors. 4.3 Elevated TG Levels The relationship between elevated TG levels and CHD risk is not that clear and the evidence appears mixed. Prospective cohort studies seem to indicate a strong positive relationship between hypertriglyceridaemia and elevated CHD risk. When subjected to multivariate analysis, the effect of TG is however diminished. In genetic hypertriglyceridaemias, many affected individuals do not have an increased CHD risk while others seem to be at risk. In most angiographic regression trials, lowering of TG levels was not associated with significant atherosclerotic regression. In some other studies however, the greatest benefit in terms of CHD risk reduction was seen in individuals with high LDL-C levels, low HDL-C levels and high TG levels. There is an inverse relationship between TG and HDL-C levels. Elevated TG also alter the coagulation and fibrinolytic systems. However, TG values in any one person are highly variable. The predictive value of TG is also low when compared to total cholesterol. At present, it would appear that there is inadequate data indicating increased risk of CHD with elevated TG levels per se. 5. OTHER RISK FACTORS FOR CHD 5.1 Age The incidence of CHD increases with age. 5.2 Gender The incidence of CHD is about 3-4 times higher in men than in women in the middle decades of life and approximately twice as high in the elderly. 8 5.3 Hypertension Both elevated systolic and diastolic blood pressures are linked with increased CHD risk. From epidemiological data, elevated systolic blood pressure appears to be more important when compared to elevated diastolic blood pressure as a risk factor. There is no single measurement of either systolic or diastolic blood pressure separating individuals with high risk from those who are at low risk. 5.4 Smoking This is an important risk factor in both men and women. The incidence and mortality of CHD is twice as high in male cigarette smokers compared to nonsmokers. The risk of developing CHD is directly related to the number of cigarettes smoked. In individuals who discontinue smoking, the risk decreases within a year or two of stopping although it remains slightly higher compared to non-smokers. 5.5 Diabetes Mellitus and Impaired Glucose Tolerance From prospective epidemiological data, the occurrence of CHD doubles in men with impaired glucose tolerance. In women, the incidence increases 3-4 fold particularly before the age of 50. Both insulin dependent and non-insulin dependent diabetics have an increased risk of developing CHD. It should be noted that in non-insulin dependent diabetes mellitus (NIDDM), there is an associated increase in TG, decrease in HDL-C, increase in serum insulin, obesity, high waist-to-hip ratio (WHR) and hypertension, all of which contribute to the increased risk of CAD. 5.6 Family History of Premature CHD Familial and genetic factors may play an important role in the determination of some major risk factors, especially hypertension, lipid abnormalities and glucose intolerance. In addition, there appears to be a familial predisposition to CHD per se that is independent of other known risk factors. The presence of premature CHD in first degree male relatives below the age of 55 years or female relatives below the age of 65 years is a recognised independent risk factor for CHD. 9 5.7 Others - Obesity - Sedentary Life-Style - Psychosocial Factors - Hyperinsulinaemia (features include high waist to hip ratio) Risk factors that are implicated in CHD but whose role in current clinical practice needs to be fully established include: - elevated fibrinogen levels - elevated Lipoprotein(a) [Lp(a)] levels - homocysteinaemia Table 4. RISK FACTORS FOR CHD Positive Risk Factors - Elevated total cholesterol - * Elevated LDL-C levels - HDL-C < 0.9 mmol/L - Hypertension - Cigarette smoking - Diabetes mellitus - Family history of myocardial infarction or sudden death prior to 55 years of age in a male parent or sibling and prior to 65 years of age in a female parent or other female first degree relative - Male 45 years of age - Female 55 years of age or premature menopause without hormonal replacement therapy HDL-C > 1.6 mmol/L is considered as a negative risk factor * LDL-C is a derived and not a measured value. NB. Obesity and sedentary life-style have not been included as risk factors because they operate through other risk factors that are already included (hypertension, diabetes mellitus, decreased HDL-C). 10 6. PREVENTION OF CHD Prevention can be divided into: a. Primary Prevention preventing the occurrence of CHD events in people without CHD. b. Secondary Prevention preventing the progression of CHD and its complications in people with established CHD. Evaluation and aggressive treatment for primary prevention especially for young adults i.e. men <35 years and premenopausal women is not well established and should be assessed on a case to case basis especially if there is a strong family history of CHD. Secondary prevention on the other hand requires aggressive management. 6.1 Primary Prevention The strategy would be based on:6.1.1 Population based strategy This strategy is aimed at educating the public concerning CHD, its presentation and complications, cardiac risk factors and the importance of maintaining a healthy life style. Mass screening for hyperlipidaemia is not advocated as it is not cost-effective and there may be inadequate follow-up and counselling. 6.1.2 Individual based strategy The aim is to identify individuals at risk of developing CHD and modify their risk factors. Individuals at high risk defined as those having 2 or more risk factors, especially in those with a family history of premature CHD, should have a full lipoprotein analysis after at least 10 hours of fasting. If the results are in the acceptable range it should be repeated every 3 years. If it is abnormal, a repeat analysis should be obtained in 23 weeks before deciding on further management. It should be strongly emphasized that management is based on treating the patient as a whole, modifying all the risk factors and not the hyperlipidaemia in isolation. The objective is to reduce the risk of CHD in the immediate and long term. 11 6.2 Secondary Prevention The population involved are patients with established CHD with or without other atherosclerotic disease, e.g. peripheral vascular disease, cerebrovascular disease. Recent clinical trials indicate aggressive lipid lowering therapy will : lead to stabilisation, reduce progression and induce regression of atherosclerotic plaques. decrease total and CHD mortality and morbidity. Drug therapy should be initiated together with non-pharmacological measures (NPM). 12 7. LIPID LEVELS FOR INITIATING TREATMENT The decision to initiate treatment is determined by target levels based on: a. b. Presence or absence of CHD. Presence or absence of non-lipid risk factors. . TARGET LEVELS FOR HYPERCHOLESTEROLAEMIA TARGET LEVEL GLOBAL RISK Risk mildly increased pretreatment total cholesterol of 5.2 7.8 mmol/L No risk factor of CHD Risk moderately increased pretreatment total cholesterol of 5.2 - 7.8 mmol/L plus 1 risk factor High risk presence of CHD or peripheral vascular disease OR presence of familial hypercholesterolaemia or plasma cholesterol > 7.8 mmol/L OR Diabetics with CHD OR plasma cholesterol 5.2-7.8 mmol/L plus 2 risk factors REDUCE PLASMA CHOLESTEROL TO (mmol/L) REDUCE LDL-C TO (mmol/L) 5.2 - 6.5 < 4.1 <5.2 < 3.4 4.5 - 5.0 < 3.0 (Note: 1. It is preferable to aim for the lower value. 2. TG target level is not yet determined; suggested value <2.3 mmol/L) 13 8. MANAGEMENT OF HYPERLIPIDAEMIA 8.1 Non-Pharmacological Measures Introduction Non-pharmacological measures (NPM) refer to dietary modification, weight reduction, regular exercise, cessation of smoking and alcohol restriction. NPM are the mainstay of treatment of hyperlipidaemia. They should precede or be initiated together with drug therapy and are directed especially at individuals who are obese, who smoke and who seldom exercise. The obvious advantages of NPM are the absence of adverse side effects that may complicate drug therapy and the minimal costs incurred. For patients without CHD, peripheral vascular disease or any other risk factors, emphasis should be placed on NPM especially dietary modification and exercise. 8.1.1 Dietary Modification This is aimed at optimising lipid levels while maintaining a balanced diet. It involves reducing high intake of saturated fats (SFA), cholesterol and calories. The lipid lowering diet includes the reduction of total fat, reduction of the proportion of SFA and increase in the proportion of mono (MUFA) and polyunsaturated fats (PUFA) and reduction of dietary cholesterol. SFA raise blood cholesterol levels whereas PUFA help to lower cholesterol. Dietary therapy can lower TC by 12-15%. 8.1.2 Weight Reduction This is of special importance in overweight and obese patients particularly those with central obesity. Obesity has been shown to be associated with higher levels of TG and lower levels of HDL-C and in some cases there may be a slight increase in TC and LDL-C. Weight reduction helps to lower TG and increase HDL-C, in addition to enhancing the cholesterol (TC and LDL-C )- lowering effect of dietary treatment. A weight reduction of 0.5-1.0 kg per week is recommended. The recommended BMI is <25kg/m2 and waist-to-hip ratio (WHR) is < 0.9 for males and < 0.8 for females. 14 8.1.3 Exercise Exercise and weight reduction will enhance the lipid-lowering effect of dietary treatment. Such exercises include aerobic exercises (eg brisk walking, jogging, cycling, swimming). Exercise will also increase HDL-C and decrease plasma TG. To achieve good lipid profiles, exercise needs to be regular and adequate (at least 30-45 minutes per session 3x a week). A regular exercise programme can counteract the low HDL-C observed in patients on a low cholesterol diet. 8.1.4 Cigarette Smoking Smoking is one of the major risk factors for CHD. Smoking reduces HDL-C level and increases lipid peroxidation products which is atherogenic. Passive smoking also decreases HDL-C levels. 8.1.5 Alcohol Restriction of alcohol is advised in patients with hyperlipidaemia as it increases plasma TG levels. Moderate alcohol consumption (not more than 21 units for males and 14 units for female per week) has been associated with higher levels of HDL-C, HDL3, apoproteins A-I and A-II. In general, alcohol consumption is not recommended as a means of improving lipid profile. 8.2 Monitoring Therapy The lipid profile should be measured 3-6 months after initiating NPM. Generally, NPM may reduce lipid levels by up to 25%. If these levels are not achieved, patient compliance should be assessed. For individuals at low risk, failure to achieve a defined target value for reduction of cholesterol does not mean that dietary therapy be replaced by drug therapy. Whatever reduction that is achieved will help lower the risk of CHD especially with the concomitant adoption of a healthy lifestyle. Drug therapy should be considered together with NPM from the outset in patients with established coronary heart disease or in those with severe primary hyperlipideamia. Those without CHD or who have mild to moderate hyperlipidaemia, could be managed by NPM. Drug therapy is presently not recommended for these groups of patients especially if they are males who are <35 years old or pre-menopausal females. 15 8.3 Miscellaneous Omega-3 fatty acid is useful in individuals with high TG and can be considered in addition to fibrates or nicotinic acid. The importance of the following in treating hyperlipidemia remains uncertain :- transfatty acids, essential fatty acids (linoleic acid, linolenic acid), anti-oxidants and lecithin. 16 8.4 Drug Therapy Non-pharmacological measures form the mainstay in the treatment of hyperlipidaemia. In secondary hyperlipidaemia, efforts should be made to correct the underlying cause. In those with established CHD, drug treatment will need to be initiated from the outset in conjunction with NPM. There are 4 major groups of drugs currently in use. They are: 8.4.1 Bile Acid Sequestrants (Resins) Bile acid sequestrants are effective in lowering LDL-C, both in familial hypercholesterolaemia (at full dosage) and in other forms of diet-resistant hypercholesterolaemia (often in lower, easily tolerated dosage). Resin increases HDL-C slightly. Combination with a statin may be necessary in severe hypercholesterolaemia. Resins are not suitable in combined (mixed) hyperlipidaemia as monotherapy. TG levels may increase unless used together with a TG-lowering drug. Recommended Dosage - cholestyramine (Questran) 4 - 24 g/day taken daily or twice daily with meals Side Effects * GIT symptoms eg. constipation (major single complaint), abdominal discomfort, flatulence, nausea, vomiting, anorexia, diarrhoea. Bleeding tendencies (Vitamin K deficiency), skin rash. Resins may reduce absorption of a number of oral medication. Contraindications * Hypersensitivity, complete biliary obstruction. * For more details, please look up for further reference. 17 8.4.2 HMG CoA Reductase Inhibitors (Statins) HMG CoA reductase inhibitors are highly effective in all conditions where LDLC elevation is the predominant disorder. They are suitable first-line agents in familial hypercholesterolaemia. They have moderate effect in lowering TG and in elevating HDL-C. Treatment is commenced at a minimum dosage and increased stepwise, if necessary. Serum lipids, creatinine kinase and alanine aminotransferase are measured at 6-8 weeks interval initially and thereafter as necessary. In patients with very high pretreatment cholesterol levels, combination therapy with resin may be needed. The safety of statins in pregnancy has not been established. 8 Recommended Dosage - lovastatin (Mevacor) 10-80 mg/day daily or - pravastatin (Pravachol) divided doses 10-40 mg daily or - simvastatin (Zocor) doses 5-40 mg daily or divided - fluvastatin (Lescol) divided doses 20-80 mg daily or divided doses Side Effects * These drugs are generally well-tolerated. Note side effects are flatulence, diarrhoea, constipation, nausea, myopathy, hepatitis. The risk of myopathy and rhabomyolysis may be increased in combination therapy with fibric acid derivatives, niacin and cyclosporin. Contraindications * Hypersensitivity, active liver disease, pregnancy and lactation. * For more details, please look up for further reference. 18 8.4.3 Fibric Acid Derivatives (Fibrates) Fibric acid derivatives are particularly useful in patients with combined (mixed) hyperlipidaemia and hypertriglyceridaemia as they reduce serum TG effectively, increase HDL-C substantially and can be used in mild to moderate hypercholesterolaemia, in which LDL-C may be lowered. Treatment is usually commenced with a recommended optimal dosage. Serum alanine aminotransferase should be monitored. Recommended Dosage - bezafibrate (Bezalip) divided doses or sustained release form, - fenofibrate (Lipanthyl) daily 200-600 mg daily or in 400 mg daily 100-300 mg daily or micronised form, 200 mg - gemfibrozil 600-1200mg daily or in divided doses (Lopid) - ciprofibrate (Modalim) 100 mg daily Side Effects * Most commonly reported are GIT symptoms, eg. diarrhoea, abdominal pain, nausea and flatulence. Abnormal liver function tests. Contraindications * Severe hepatic or renal dysfunction, gall bladder disease, hypersensitivity. 8.4.4 Nicotinic Acid and its derivatives Nicotinic acid effectively lowers both serum cholesterol and TG levels but its side effects tend to limit compliance, eg. cutaneous flushing and abdominal symptoms being the most common problems. Liver disease, gout and diabetes are relative contra-indications for its usage and therefore routine monitoring for signs of these diseases is necessary. Acipimox is a derivative of nicotinic acid which produces less cutaneous flushing and does not worsen glucose tolerance. * For more details, please look up for further reference. 19 Recommended Dosage Nicotinic acid (Niacin) is available as tablets of 50 mg or 500 mg, and sustained release form: - starting dose: 150-300 mg daily in divided doses titration of dose up to 2 - 6 g/day Acipimox (Olbetam) 750 mg daily in divided doses Side Effects * Cutaneous flushing, abdominal pain. Contraindications * Hypersensitivity. contraindications. Liver disease, gout and diabetes mellitus are relative * For more details, please look up for further reference. 20 8.5 Hypertriglyceridaemia In severe hypertriglyceridaemia, TG > 6 mmol/L which is refractory to 8-12 weeks of non-pharmacological therapy, drug therapy is recommended. In patients with a history of acute pancreatitis or with levels > 10 mmol/L, drug therapy should be started immediately. Table 6. RECOMMENDED DRUG THERAPY HYPERLIPIDAEMIA DRUG OF CHOICE Hypercholesterolaemia resin, statin Mixed Type fibrates, nicotinic acid, statin Hypertriglyceridaemia fibrates, nicotinic acid 21 8.6 Combination Drug Therapy This may be necessary to achieve target levels in severe hyperlipidaemia. Acceptable forms of combination therapy include: Table 7. COMBINATION DRUG THERAPY HYPERLIPIDAEMIA Severe Hypercholesterolaemia DRUG OF CHOICE statin + resin statin + fibrates * statin + nicotinic acid resin + nicotinic acid Severe Mixed Type statin + fibrates * statin + nicotinic acid resin + fibrates /nicotinic acid * there is an increased risk of myositis and rhabdomyolysis with this combination. 8.7 Monitoring and Duration of Therapy It should be stressed that these patients will be on long term therapy. It is therefore important to assess them on a regular basis, ie. in terms of the response to treatment by regular lipid measurements every 3-6 months and to look out for possible side effects related to the drugs. 22 9. TREATMENT OF SPECIAL GROUPS 9.1 Women CHD in women occurs principally in later life - it lags 10 years behind CHD in men and is the leading cause of death among women in developed countries. Management of CHD risk in women is as important. The lipid and non-lipid risk factors in men have similar predictive values in women. This CHD lag period in women is probably due to such protective factors as female sex hormones accounting for the differences in lipoprotein levels. Prior to menopause women have lower total and LDL cholesterol levels than men and higher HDL cholesterol as well. After menopause the TC and LDL-C increases and approaches the levels in similar aged men. Serum TG appears to be more important in women as a risk factor for CHD. Lipid lowering drug therapy can often be delayed in pre-menopausal women when LDL-C does not exceed 5.7 mmol/l and other risk factors are not present. In postmenopausal women and in premenopausal women with severe primary hyperlipidaemia non-pharmacological therapy together with drug therapy should be initiated. When lipid lowering trials with clinical event end-points are analysed separately, the degree of cholesterol lowering and reductions in CHD mortality have been about the same in men and women. If lipid lowering drugs are necessary in women with likelihood of pregnancy, bile-acid sequestrants are preferred. The choice of drugs for post-menopausal women is as for men. Diabetes mellitus in women removes the protective effect and in the diabetic women the CHD risk becomes similar to men. The threshold for treatment of lipid levels in diabetic women should therefore be as for men. Use of oestrogens appears to have a biphasic effect on CHD risk in women. Use of higher dose oestrogen in OCP especially in smokers have a marked effect on increasing the CHD risk. On the other hand the use of oestrogen replacement therapy may confer benefit in post-menopausal women by increasing HDL and lowering LDL cholesterol levels. Data from non-randomised studies suggest that oestrogen replacement is associated with lesser severity of atherosclerosis as shown by coronary angiography and a lower frequency of CHD. The effect of progestogen on lipids has been considered but it appears that adding medroxyprogesterone does not have adverse effects on LDL and HDL. The use of progestogen is important in those with intact uterus to protect against endometrial carcinoma but has not been shown to be protective against breast carcinoma. The use of the second generation selective oestrogen receptor modulators eg. raloxifene which has agonist activity on the bone and cholesterol metabolism but without action on the breast or uterus may offer a safer alternative. Long-term trial results are yet to be seen. 23 9.2 Elderly In the elderly the relative risk of CHD conferred by raised cholesterol is only moderate or mild but the attributable risk is high. This is because the prevalence of CHD is much higher in the elderly compared to younger groups. A high cholesterol level leads to more CHD in the elderly and therefore the need to treat also exists in this age group. Clinical trials in the elderly are limited but sub-group analysis of recent trials support aggressive lipid lowering treatment in the healthy elderly. It is important to consider functional age rather than chronological age. In the elderly the presence of other risk factors and secondary causes of hyperlipidaemia, eg. drugs should be actively sought and treated. Target lipid levels in the elderly are those used for the general adult population. Dietary therapy needs to be individualised. They should be encouraged to exercise appropriately. The elderly are prone to adverse effects of all drugs therefore caution should be exercised. Fibrates and the statins are generally well tolerated. 9.3 Children Screening of children should be selective and confined to those above two years of age whose parents have premature CHD or primary hyperlipidaemia. Non-pharmacological measures are advocated in children between the age of 2 - 18 years but calorie levels must take into account growth and development and desirable body weight. Drug therapy should be started in children above the age of 12 years where LDL-C remains very high despite lifestyle change. When indicated, the drug of choice should be a resin. The other drugs should be avoided unless absolutely necessary as the safety of these drugs in children have not been established. 9.4 Diabetes mellitus Atherosclerotic disease is a major cause of mortality and morbidity in diabetics and occurs earlier in younger individuals and in women when compared to the nondiabetic population. Diabetics especially NIDDM have lipid abnormalities especially hypertriglyceridaemia, decreased HDL-C. They have a higher proportion of small dense LDL as well as other atherogenic abnormalities eg. elevated Lp(a), glycated LDL (which is more susceptible to peroxidation), increased fibrinogen and reduced plasminogen activation inhibitor-1 (PAI-1). Treatment by lifestyle change and glycaemic control (optimisation of body weight, exercise and drug therapy) will have a positive impact on the lipid indices. In view of data from recent studies, more aggressive cholesterol lowering in diabetics is necessary as compared to non diabetics to reduce the risk of CHD events. Statins have also been shown to beneficially influence diabetic nephropathy. 24 9.5 Renal Disease In nephrotic syndrome elevated serum total and LDL-C occurs. Treatment of the underlying cause for the nephrotic syndrome should be given first as the lipid problem may resolve. In those with persistent hyperlipidaemia especially with the presence of other risk factors anti lipid treatment should be considered. Chronic renal failure is associated with dyslipidaemia and hypertension. It has been shown that treating hyperlipidaemia may slow down the progression of renal impairment. Caution must be exercised when starting statins watching out for acute deterioration in renal function and myopathy. A lower starting and maintenance dose is recommended. In haemodialysis patients, the main abnormalities are elevated levels of TG and lower levels of HDL-C. In CAPD patients more severe disturbances of lipid profile can occur. In these patients on renal replacement therapy there is inadequate data at present to make definite recommendations regarding drug therapy. There are at present no good control studies to show reduction of cardiac events following anti lipid treatment. 25 10. CONCLUSIONS Interpretation of lipid profiles should take into consideration variability and modifying factors including secondary causes. Elevated TC, LDL-C, low HDL-C and the combination of high TG - low HDL-C are proven risk factors of CHD. Primary prevention reduces CHD events, cardiac and total mortality. Secondary prevention will lead to stabilisation, reduce progression and induce regression of atherosclerotic plaques. Aggressive lipid lowering therapy reduces strokes, cardiac events, cardiac and total mortality. The threshold for initiating therapy depends on the presence or absence of coronary risk factors and atherosclerotic diseases. Management of the risk factors for CHD should be global in approach including NPM and where appropriate, drug therapy should be initiated. For those without CHD, emphasis should be on NPM. In those with no other risk factors, treatment should be initiated to achieve a target level of LDL-C of less than 4.1 mmol/L. In those with one other risk factor, treatment should be initiated to achieve a target level of LDL-C of less than 3.4 mmol/L. In those with two or more other risk factors, or presence of atherosclerotic disease, treatment should be initiated to achieve a target LDL-C level of less than 3.0 mmol/L. For those with CHD or with two or more other risk factors, drug therapy should be initiated together with NPM. In diabetics, aggressive lipid lowering therapy is advocated. In post-menopausal or diabetic women, a similar treatment strategy should be followed. In the elderly, treatment is still beneficial with similar target values as in the younger age group. In children, if drug treatment is necessary, it should be started after the age of 12 years using resins. 26 APPENDIX 1 LIPID LOWERING DIET Principle Decreased total fat/oil. Amount Comment < 30% energy. Modify cooking methods grill/steam/boil/microwave/bake to reduce use of oil and fats. a) Saturated fat. Avoid. eg. butter, hard margarine, whole milk, cream, high fat cheese, fatty meals, bacon and sausages, coconut oil, santan, products containing hydrogenated oils eg. some coffee whitener. b) Mono and polyunsaturated oils/margarine. Not more than 2 tablespoons per day (including the amount in products based on these). eg. olive oil, sunflower oil, corn oil, palm oil, soyabean oil, peanut oil, polyunsaturated margarine. Types: Use food high in protein but low in saturated fat Skinned chicken, fish, bean curd (tofu), egg white, legumes. Increased intake of complex carbohydrate; increased fruit, vegetables and legumes for fibre 20-25gm fibre/day - half All fruits, fresh vegetables, legumes derived from fruit and (lentils, peas, beans) unrefined cereals vegetables. including oats, wholemeal flour, tubers. Decreased dietary cholesterol. < 300 mg/day Allow up to 2 egg yolks per week. Avoid organ meat (offal) eg. liver, heart, brains, kidney. 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