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Hypercholesterolaemia
Highlights
Summary Overview
Basics
Definition Epidemiology Aetiology Pathophysiology Classification
Prevention
Primary Screening Secondary
Diagnosis
History & examination Tests Differential Step-by-step Criteria Guidelines Case history
Treatment
Details Step-by-step Emerging Guidelines Evidence
Follow Up
Recommendations Complications Prognosis
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History & exam

Key factors

presence of risk factors FHx of early onset of CHD or dyslipidaemia in firstdegree relatives hx of cardiovascular disease consumption of saturated fats, trans-fatty acids, and cholesterol excess body weight (especially abdominal obesity) xanthelasmas tendinous xanthomas
Other diagnostic factors

arcus corneae with onset before the age of 45 years tuberous xanthomas History & exam details
Diagnostic tests
1st tests to order

lipid profile serum TSH Diagnostic tests details
Treatment details
Ongoing
o o o o o o o o o o o o
<2 cardiac risk factors LDL 4.1 to 4.9 mmol/L (160 to 189 mg/dL) lifestyle modification statin + lifestyle modification nicotinic acid and/or bile acid sequestrants continued statin + lifestyle modification fibric acid derivative ezetimibe continued statin + lifestyle modification fibric acid derivative LDL 4.921 mmol/L (190 mg/dL) statin + lifestyle modification nicotinic acid and/or bile acid sequestrants continued statin + lifestyle modification fibric acid derivative
o o o
ezetimibe continued statin + lifestyle modification fibric acid derivative 2 cardiac risk factors LDL <3.367 mmol/L (<130 mg/dL) lifestyle modification statin + lifestyle modification nicotinic acid and/or bile acid sequestrants continued statin + lifestyle modification fibric acid derivative ezetimibe continued statin + lifestyle modification fibric acid derivative LDL 3.367 mmol/L (130 mg/dL) statin + lifestyle modification nicotinic acid and/or bile acid sequestrants continued statin + lifestyle modification fibric acid derivative ezetimibe continued statin + lifestyle modification bile acid sequestrant and/or nicotinic acid fibric acid derivative CHD or CHD equivalent LDL <2.59 mmol/L (<100 mg/dL) lifestyle modification statin + lifestyle modification nicotinic acid and/or bile acid sequestrants continued statin + lifestyle modification fibric acid derivative
o o o o o o o o o o o o o o o o
o o o o o
o o o o o o o o o o o o
ezetimibe continued statin + lifestyle modification bile acid sequestrant and/or nicotinic acid fibric acid derivative LDL 2.59 mmol/L (100 mg/dL) statin + lifestyle modification nicotinic acid and/or bile acid sequestrants continued statin + lifestyle modification fibric acid derivative ezetimibe continued statin + lifestyle modification bile acid sequestrant and/or nicotinic acid fibric acid derivative isolated low HDL-cholesterol statins + management of primary cause Treatment details
Summary
Elevation of total cholesterol or elevation of cholesterol in circulating lipoproteins, including chylomicrons, LDL, VLDL, and intermediate-density lipoprotein. May be accompanied by a decrease in HDL. Usually symptomatically quiescent until significant degrees of atherosclerosis have occurred. Complications include MI, ischaemic cardiomyopathy, sudden death, stroke, erectile dysfunction, peripheral vascular disease, and acute limb ischaemia. Risk factors for secondary hypercholesterolaemia in industrialised populations include a sedentary lifestyle and a diet characterised by the excessive consumption of saturated fats, trans-fatty acids, and cholesterol. Other
causes include diabetes, excess body weight mainly in abdominal region, hypothyroidism, nephrotic syndrome, and cholestatic liver disease. Low HDL-cholesterol levels are associated with smoking and abdominal obesity. Diagnosed by fasting lipid profile, consisting of measurements of total cholesterol, LDL (estimated or direct), HDL, and triglycerides. Treated with lifestyle modifications such as dietary changes and exercise, as well as pharmacological intervention with statin therapy, nicotinic acid, bile acid sequestrants, or cholesterol absorption inhibitors (ezetimibe).
Definition
Hypercholesterolaemia, an elevation of total cholesterol (TC) and/or LDLcholesterol in the blood, is also often referred to as dyslipidaemia, to encompass the fact that it might be accompanied by a decrease in HDLcholesterol or an increase in triglycerides. Dyslipidaemia is classified as serum TC, LDL-cholesterol, triglyceride, apolipoprotein B (apoB), or lipoprotein (a) concentrations above the 90th percentile, or HDL-cholesterol or apolipoprotein A-I concentrations below the 10th percentile, for the general population.
Definition
Hypercholesterolaemia, an elevation of total cholesterol (TC) and/or LDLcholesterol in the blood, is also often referred to as dyslipidaemia, to encompass the fact that it might be accompanied by a decrease in HDLcholesterol or an increase in triglycerides. Dyslipidaemia is classified as serum TC, LDL-cholesterol, triglyceride, apolipoprotein B (apoB), or lipoprotein (a) concentrations above the 90th percentile, or HDL-cholesterol or apolipoprotein A-I concentrations below the 10th percentile, for the general population.
Epidemiology
The prevalence of the disorder varies depending on the definition of dyslipidaemia and the population studied. In patients with coronary heart disease (CHD), the prevalence of dyslipidaemia is as high as 80% to 88%, compared with approximately 40% to 48% in age-matched controls without coronary disease. [3] There is a strong correlation between BMI and incidence of hypercholesterolaemia. [4] The incidence is therefore higher in industrialised countries compared with developing countries. A worrisome development is the increase in the rate of risk factors, in developing countries, for CHD ( including hypercholesterolaemia), while the risk factors for CHD decrease in prevalence in industrialised countries. [5] However, while there has been a steady decline in mortality from heart disease in the US since the early 1960s, it still remains the leading cause of death for both men and women of all races and ethnicities. [6]
Aetiology
The aetiology can be classified into primary and secondary causes. Primary causes are due to single or multiple gene mutations, resulting in a disturbance of LDL and triglyceride production or clearance. They vary in location of genetic defect, inheritance pattern, prevalence, clinical features, and treatment. At least 18 separate entities have been described. [7] The suspicion for a primary lipid disorder should be especially high in patients with premature atherosclerotic disease, a family history of early atherosclerotic disease, a significantly elevated serum cholesterol level (>6.2 mmol/L [>240 mg/dL]), and physical signs of hyperlipidaemia. Primary dyslipidaemias are most commonly seen in children and young adults and cause only a small percentage of cases in adults. Most adult cases of dyslipidaemia are secondary in nature. In Western civilisations, sedentary lifestyle and excessive consumption of saturated fats, trans-fatty acids, and cholesterol are the most important secondary causes. Certain medical conditions are commonly associated with dyslipidaemia, including chronic renal insufficiency, renal failure, diabetes mellitus, hypothyroidism, cholestatic liver disease, and alcohol dependency. Certain drugs, including high-dose thiazide diuretics, oral oestrogens, glucocorticoids, anabolic steroids, and atypical antipsychotics such as olanzapine and clozapine have also been implicated in causing mild to moderate degrees of dyslipidaemia. [8] Use of atypical antipsychotics, such as olanzapine and
clozapine, and of beta-blockers without intrinsic sympathomimetic or alphablocking activities are associated with reduced HDL-cholesterol levels.
Pathophysiology
Hypercholesterolaemia develops as a consequence of abnormal lipoprotein metabolism, mainly reduction of LDL receptor expression or activity, and consequently diminishing hepatic LDL clearance from the plasma. It is a major predisposing risk factor for the development of atherosclerosis. This mechanism is classically seen in familial hypercholesterolaemia and when excess saturated fat or cholesterol is ingested. In addition, excessive production of VLDL by the liver, as seen in familial combined hyperlipidaemia and insulin resistance states such as abdominal obesity and type 2 diabetes, can also induce hypercholesterolaemia or mixed dyslipidaemia. A current theory for the initiating event in atherogenesis is that apoprotein B100-containing lipoproteins are retained in the subendothelial space, by means of a charge-mediated interaction with extracellular matrix and proteoglycans. [9] This allows reactive oxygen species to modify the surface phospholipids and unesterified cholesterol of the small LDL particles. Circulating LDL can also be taken up into macrophages through unregulated scavenger receptors. As a result of LDL oxidation, isoprostanes are formed. Isoprostanes are chemically stable, free radical-catalysed products of arachidonic acid, and are structural isomers of conventional prostaglandins. Isoprostane levels are increased in atherosclerotic lesions, but they may also be found as F2 isoprostanes in the urine of asymptomatic patients with hypercholesterolaemia. [10] A strong association exists between elevated plasma concentrations of oxidised LDL and CHD.[11] The mechanisms through which oxidised LDL promotes atherosclerosis are multiple and include damage to the endothelium, induction of growth factors, and recruitment of macrophages and monocytes. Vasoconstriction in the setting of high levels of oxidised LDL seems to be related to a reduced release of the vasodilator nitric oxide from the damaged endothelial wall as well as increased platelet aggregation and thromboxane release. Smooth muscle proliferation has been linked to the release of cytokines from activated platelets. [12]
The state of hypercholesterolaemia leads invariably to an excess accumulation of oxidised LDL within the macrophages, thereby transforming them into "foam" cells. The rupture of these cells can lead to further damage of the vessel wall due to the release of oxygen free radicals, oxidised LDL, and intracellular enzymes.
Classification
WHO/Fredrickson classification [1] Classically, dyslipidaemia can be classified phenotypically by lipid electrophoresis based on which lipoprotein is raised. Classification was devised before the importance of HDL as a prognostic indicator was recognised. Type:
I - elevated chylomicrons; associated with lipoprotein lipase deficiency, apolipoprotein C-II deficiency IIa - elevated LDL; associated with familial hypercholesterolaemia, polygenic hypercholesterolaemia, nephrosis, hypothyroidism, familial combined hyperlipidaemia IIb - elevated LDL and VLDL; associated with familial combined hyperlipidaemia III - elevated intermediate-density lipoprotein; associated with dysbetalipoproteinaemia
IV - elevated VLDL; associated with familial hypertriglyceridaemia, familial combined hyperlipidaemia, sporadic hypertriglyceridaemia, diabetes V - elevated chylomicrons and VLDL; associated with diabetes. Clinical classification [2] In a more simple and practical way, dyslipidaemia can also be classified as:
Isolated hypercholesterolaemia: mostly due to LDLcholesterol elevation Mixed or combined dyslipidaemia: elevations in total or LDL-cholesterol, and in triglycerides Isolated hypertriglyceridaemia: elevation in triglycerides only Low HDL-cholesterol: either isolated or in association with hypercholesterolaemia or hypertriglyceridaemia. Causes of low HDL-cholesterol include abdominal obesity with insulin resistance, hypertriglyceridaemia, smoking, and genetic diseases such as apoA-I or lecithin-cholesterol acyltransferase (LCAT) deficiency.
Monitoring
The optimal method of monitoring the effects of lipid-lowering therapy has yet to be defined. Lipid levels should be monitored every 6 weeks initially until the LDL target is achieved. [27]This interval can be extended to every 6 to 12
months in patients adherent to lifestyle modifications and after lipid levels have stabilised. Baseline liver and muscle enzymes should be measured in patients starting statin therapy, despite the low incidence of toxicity (0.5% to 2%). Liver enzymes should be repeated 4 to 8 weeks after statin therapy is commenced. In the absence of hepatobiliary symptoms, annual measurements of liver enzymes are sufficient. Statin therapy can be continued unless liver enzymes increase to more than 3 times the upper limit of normal. After initiation of statin therapy, muscle enzyme levels need not be checked regularly unless patients develop myalgias or other muscle symptoms. [69]
Patient Instructions
A reduced intake of saturated fats and cholesterol should be advised, as well as increased consumption of dietary fibre, complex carbohydrates, and unsaturated and monounsaturated fats. Aerobic exercise, at least 3 times per week, is recommended.
Complications
Complicationhide all
erectile dysfunction see our comprehensive coverage of Erectile dysfunction Endothelial dysfunction is the underlying mechanism of ED, an with elevated levels of LDL. [67] Nonpharmacological interven improving quality of diet, and increasing physical activity can im risk. [68]
ischaemic heart disease see our comprehensive coverage of Stable ischaemic heart dis The likelihood of progression to ischaemic cardiomyopathy due relatively low. Aggressive risk factor control and management
peripheral vascular disease (PVD) see our comprehensive coverage of Peripheral vascular disea PVD manifests as insufficient tissue perfusion caused by exist narrowing of the vessel lumen, which may be acutely affected very common condition that has the potential to cause loss of l control of all existing risk factors is the mainstay of treatment fo
acute coronary syndrome see our comprehensive coverage of Overview of acute corona Long-term lipid-lowering therapy with a statin is recommended syndrome.
An LDL-cholesterol goal of <1.813 mmol/L (<70 mg/dL) is cons these high-risk patients. [43] [63] [64] Statin therapy reduced LDL by up to 55% and produced small decreases in triglycerides. [42]
stroke see our comprehensive coverage of Overview of stroke For patients with thrombotic stroke, the LDL goal is defined by Program (NCEP) as <2.59 mmol/L (<100 mg/dL).
Recently it has been shown that many patients hospitalised wi LDL levels higher than recommended. Patients at the greatest the least likely to be at guideline-recommended LDL levels. [65 only modestly reduce stroke recurrence after TIA or ischaemic reductions were seen in cardiovascular events in these patient
Prognosis
Since statins were introduced in the treatment of hypercholesterolaemia, the rate of adverse outcomes has been significantly reduced. If the treatment plan includes detection and management of other factors that contribute to the development of coronary heart disease (CHD), such as HTN, diabetes mellitus, and smoking, the overall prognosis of hypercholesterolaemia is improved. Cholesterol reduction is useful as a CHD risk-reduction strategy and for primary prevention in people at high risk for CHD or other forms of atherosclerosis.
Case history
A 43-year-old pilot presents for a stress test required by his employer. He states that there is a strong history of premature cardiac disease in his family and 2 of his older brothers are currently being treated for high cholesterol. System review is negative except for some mild SOB with exercise. Examination demonstrates moderate abdominal obesity with a BMI of 31 kg/m^2 and waist circumference of 102 cm (40 inches). The remainder of the examination is normal.
Other presentations
Many patients present with symptomatic cardiovascular disease, such as angina, MI, TIAs, or stroke, and claudication. Patients with very high levels of LDL may present with eyelid xanthelasmas, arcus corneae with onset before 45 years of age, and tendinous xanthomas in the Achilles, elbow, and knee tendons as well as over the metacarpophalangeal joints (familial hypercholesterolaemia).
Differential diagnosis
Condition Obstructive liver Differentiating signs/symptoms
Differentiating tests
Stigmata of liver
Elevated ALT, A
disease
disease, such as jaundice and abdominal tenderness, may be present.
bilirubin.
Imaging studies show dilated bili
With significant elevations of bilirubin the patient may also complain of pruritus. The hyperlipidaemic response is triggered at least in part by the reduction in plasma oncotic pressure, and the severity of the hyperlipidaemia is inversely and closely related to the fall in oncotic pressure. Spontaneous or drug-induced resolution of nephrotic syndrome reverses
Nephrotic syndrome
Marked elevatio triglycerides (TG
HDL-cholestero
Abnormal serum
Elevated 24-hou
hyperlipidaemia. Chronic renal insufficiency Dyslipidaemia normally presents as hypertriglyceridaemi a (due to diminished clearance). Patients undergoing peritoneal dialysis are more likely to have an atherogenic lipid profile than those undergoing haemodialysis. There may be lethargy, cold intolerance, constipation, dry hair or skin, goitre, or delayed return of deep tendon reflexes. In a study investigating people
About half of pa mg/dL), about o mg/dL), and 10% mg/dL).
TC concentratio malnutrition in th
Abnormal serum
Elevated 24-hou
Hypothyroidism
Serum TSH is h
referred for the evaluation of hyperlipidaemia, hypothyroidism was found to be present in 4.2% of patients.
A significant reduction in the serum cholesterol concentration during thyroid hormone replacement was only seen in those patients with a serum TSH concentration >10 milliunits/L. [26]
History & examination

Key diagnostic factorshide all
presence of risk factors (common) Key risk factors include excess body weight, type 2 diabetes mellitus, hypothyroidism, and cholestatic liver disease. FHx of early onset of CHD or dyslipidaemia in firstdegree relatives(common) Given the paucity of early signs and symptoms of hypercholesterolaemia, it is crucial to perform a
thorough family history. A significant family history (for example, of early-onset CHD) suggests primary hypercholesterolaemia. hx of cardiovascular disease (common) Many patients with hypercholesterolaemia are not diagnosed until premature cardiovascular disease becomes symptomatic. It is important to assess lipid profiles in patients presenting with angina, MI, stroke, and peripheral vascular disease. consumption of saturated fats, trans-fatty acids, and cholesterol(common) Sedentary lifestyle and a diet characterised by excessive consumption of cholesterol, saturated fats, and trans-fatty acids. excess body weight (especially abdominal obesity) (common) A BMI >25 kg/m^2 and a waist circumference that is >94 cm in white and black men, >80 cm in white and black women, >90 cm in Asian men, and >80 cm in Asian women is associated with a variety of unfavourable changes in lipid metabolism. [15] [16] xanthelasmas (common) Yellow plaques that occur most commonly near the inner canthus of the eyelid.View image Half of these lesions are associated with elevated plasma lipid levels. [22] Some occur with altered lipoprotein composition or structure, such as lowered HDL levels.
They frequently occur in patients with type II and IV hyperlipidaemia. tendinous xanthomas (uncommon) Slowly enlarging subcutaneous nodules related to the tendons or the ligaments. The extensor tendons of the hands, feet, and Achilles tendons are the most common locations.View imageView image A relationship to previous trauma to the site often exists. Associated with severe hypercholesterolaemia and elevated LDL levels (familial hypercholesterolaemia). They are also associated with some of the secondary hyperlipidaemias, such as cholestasis.
Other diagnostic factorshide all

arcus corneae with onset before the age of 45 years (uncommon) White or grey opaque ring in the corneal margin. The result of cholesterol deposits in the hyalinosis of the corneal stroma; can be seen in patients with ocular defects or familial hyperlipidaemia. tuberous xanthomas (uncommon) Firm, painless, red-yellow nodules. Multilobated tumours can develop once individual lesions coalesce. Usually related to pressure areas, such as the extensor surfaces of the knees, elbows, and buttocks. Particularly associated with hypercholesterolaemia and increased levels of LDL. They can be associated with familial dysbetalipoproteinaemia and familial
hypercholesterolaemia, and they may be present in some of the secondary hyperlipidaemias.
Risk factorshide all

Strong insulin resistance and type 2 diabetes mellitus Hypercholesterolaemia due to increased VLDLcholesterol and expressed by high total cholesterol but not LDL-cholesterol can be seen in the context of mixed dyslipidaemia, and is associated with the state of insulin resistance. [13] LDL-cholesterol levels are not increased in insulin resistance. However, the number of apolipoprotein Bcontaining lipoproteins is increased. HDL-cholesterol and the number of apolipoprotein A-I particles are usually reduced in insulin resistance. In addition, a correlation exists between severity of insulin resistance and degree of lipoprotein abnormalities: the greater the degree of insulin resistance, the greater is the VLDL triglyceride production and reduction in clearance, larger are the VLDL particles, and smaller are the LDL and HDL particles. [14] The total number of LDL, intermediate-density lipoprotein, and VLDL particles is also increased in patients with insulin resistance. excess body weight (BMI >25 kg/m^2) Weight gain is associated with increased LDLcholesterol levels. However when abdominal obesity is present, it is associated with a variety of unfavourable changes in lipid metabolism, similar to those found in
insulin resistance and type 2 diabetes. [14] [15] This includes a waist circumference that is >94 cm in white and black men, >80 cm in white and black women, >90 cm in Asian men, and >80 cm in Asian women. [15] [16] Loss of body fat may partially reverse hypercholesterolaemia and hypertriglyceridaemia. hypothyroidism In a study of patients with primary hypothyroidism, 56% had isolated hypercholesterolaemia and another 34% had combined hypercholesterolaemia with hypertriglyceridaemia. [20] In another study of patients referred to a lipid disorder speciality clinic, the rate of overt hypothyroidism was found to be 2.8%, and 4.4% of patients had subclinical hypothyroidism. [21] The severity of lipid abnormalities increases with the severity of the hypothyroidism. Because of this association, it is appropriate to assess TSH in any patient presenting with dyslipidaemia. cholestatic liver disease Lipoprotein-X (an abnormal LDL in cholestatic conditions) plays a major role in the pathogenesis of hypercholesterolaemia observed with primary biliary cirrhosis and similar hepatic disorders. In these disorders, serum cholesterol concentrations may exceed 12.95 mmol/L (500 mg/dL) and physical stigmata such as xanthomas may be found.
Weak
cigarette smoking Patients smoking 2 packs of cigarettes per day had a mild reduction of HDL-cholesterol. [17] This reduction may be more pronounced in the setting of concomitant alcohol intake. [18] It has been suggested that smoking may induce insulin resistance, with associated increases in the size and number of LDL and VLDL particles. [19] nephrotic syndrome Hyperlipidaemia observed in patients with nephrotic syndrome is partially due to a reduction in lipid catabolism. The low oncotic pressure seen in these patients is thought to lead to increased hepatic synthesis of lipoproteins. use of certain medications Mild alterations of lipid metabolism can occur with drug therapy for other medical conditions. The mechanism for this differs for each class of drug. Medications commonly implicated are high-dose thiazide diuretics, oral oestrogens, glucocorticoids, anabolic steroids (also reduce HDL-cholesterol), and also atypical antipsychotics, such as olanzapine and clozapine. The use of protease inhibitors in HIV infection is associated with a class-related adverse effect termed lipodystrophy syndrome, which has marked abnormalities of lipid and glucose metabolism. The acne treatment drug isotretinoin is also associated with hypercholesterolaemia and hypertriglyceridaemia.
Diagnostic tests
1st tests to orderhide all
Test
lipid profile Consists of TC, triglycerides, and LDL- and HDL-cholesterol.
TC and HDL can be measured in the non-fasting state, but mo while fasting to minimise variability. Fasting for 12 hours is opt postprandial hyperlipidaemia.
TC values vary by 10% and triglycerides by up to 25% from da disease. [23] Plasma or serum can be used, with plasma cholesterol being a value. [24] Acute illnesses can influence the lipid profile. Triglycerides incr inflammatory states. In particular, lipid profiles change significa measurement should either be performed acutely or postponed
serum TSH TSH may be low in secondary hypothyroidism.
Step-by-step diagnostic approach

Patients with hypercholesterolaemia may be incidentally diagnosed on routine blood testing and have no presenting clinical features.
History
In most cases the clinician is presented with the consequences of longstanding dyslipidaemia. It is therefore wise to carry out a systemic review for vascular disease, focusing on symptoms of coronary artery disease, cerebrovascular disease, and peripheral arterial disease, such as chest pain, SOB, weakness, dysphasia, or claudication. It is also helpful to take a detailed family history for early onset of CHD and dyslipidaemia in firstdegree relatives, and ask the patient about their level of exercise and diet at this stage.
Examination
The patient can be examined for direct signs of hypercholesterolaemia, such as eyelid xanthelasmas,View image arcus corneae (with onset before 45 years of age), and xanthomata. Tendinous xanthomas at the Achilles,View image elbow, and knee tendons, and over metacarpophalangeal joints,View image are characteristics of heterozygous and homozygous forms of familial hypercholesterolaemia.
Palmar or cutaneous xanthomas may be present in the homozygous form of familial hypercholesterolaemia. Eruptive xanthomas over the trunk, back, elbows, buttocks, knees, hands, and feet may be present in severe elevations of triglycerides. Palmar and tuberous xanthomas are seen in patients with dysbetalipoproteinaemia.
There may also be evidence of vascular disease, such as elevated neck veins or bibasal crepitations on lung auscultation (heart failure), hemiplegia (stroke), or diminished pulses (peripheral arterial disease).
Investigations
A fasting serum lipid profile should be taken; this includes total cholesterol, triglycerides, HDL, and LDL. Extremely high lipid levels may give a lactescent (milky) appearance to blood plasma. Routine TSH rules out most cases of hypothyroidism. Additional tests may be indicated by the history and
examination findings to identify complications of hypercholesterolaemia. These may include creatinine levels, fasting blood glucose, urinalysis, ECG, echocardiogram, cardiac stress testing, cardiac computed tomography to measure coronary calcium scores, cardiac catheterisation, and vascular studies, such as Doppler examination or ankle-brachial indices.
Click to view diagnostic guideline references.
Diagnostic
criteria
Adult treatment panel III classification of LDL, total, and HDL cholesterol[27]
LDL-cholesterol:
Optimal: <2.6 mmol/L (<100 mg/dL) Near or above optimal: 2.6 to 3.3 mmol/L (100 to 129 mg/dL) Borderline high: 3.367 to 4.1 mmol/L (130 to 159 mg/dL) High: 4.1 to 4.9 mmol/L (160 to 189 mg/dL) Very high: >4.9 mmol/L (190 mg/dL).
Total cholesterol:
Desirable: <5.2 mmol/L (<200 mg/dL) Borderline high: 5.2 to 6.2 mmol/L (200 to 239 mg/dL) High: >6.2 mmol/L (240 mg/dL).
HDL-cholesterol:
Low: 1 mmol/L (<40 mg/dL) High: >1.554 mmol/L (60 mg/dL).
Treatment Options
Patient group <2 cardiac risk factors LDL 4.1 to 4.9 mmol/L (160 to 189 mg/dL) 1st Treatment Treatmenthide all line
lifestyle modification Risk factors include cigarette smoking, HTN, family history of premature CHD, and age >45 years in men or >55 years in women. Patients can be allowed 3 to 6 months of lifestyle modification before considering lipid-lowering drugs. [41] This length of time, however, is still controversial; 2 to 3 followup visits over 2 to 3 months should be arranged to
Patient group <2 cardiac risk factors
Treatment Treatmenthide all line
assess motivation and adherence. There is clear evidence that dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDLcholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence] Recommendations should include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36] Significant reductions in
LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40]
2nd
statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in
primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to
one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of
commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol.[B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant
reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR
rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily
3rd
nicotinic acid and/or bile acid sequestrants Beneficial effects of nicotinic acid are additive to statins and bile acid sequestrants. However, nicotinic acid and bile acid sequestrants in addition to lifestyle changes may be an alternative initial therapeutic option for patients intolerant to statins. Lipids, glucose, LFTs, and uric acid should be checked after 6 weeks. Bile acid sequestrants are also used in conjunction
with statins and nicotinic acid, and display a synergistic treatment effect. Colesevelam is tolerated better overall than the other bile acid sequestrants, and no timing intervals with other medications are generally needed. Bile acid sequestrants are the first choice for children <10 years old as an alternative to statins. Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR -colestyramine : 4 g orally once daily initially, increase
by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided doses plus [?] continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total
mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to
55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide
antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the
diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses
OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients
with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
4th
ezetimibe
Ezetimibe can be added in addition to statin therapy and lifestyle changes. Adverse effects include hepatic transaminase elevation, myalgia, rhabdomyolysis, hepatitis, acute pancreatitis, and thrombocytopenia. [58] Primary Options ezetimibe : 10 mg orally once daily
plus [?]
continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause
mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is
at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin,
fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation
s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally
once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done
with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
LDL 4.921 mmol/L (190 mg/dL)
1st
statin + lifestyle modification Risk factors include cigarette smoking, HTN, family history of premature CHD, and age >45 years in men or >55 years in
women. Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of
LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may
occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be commenced. Dietary reduction in total and
saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40]
Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally
once daily
2nd
nicotinic acid and/or bile acid sequestrants Beneficial effects of nicotinic acid are additive to statins and bile acid sequestrants. However, nicotinic acid and bile acid sequestrants in addition to lifestyle changes may be an alternative initial therapeutic option for patients intolerant to statins. Lipids, glucose, LFTs, and uric acid should be checked after 6 weeks. Bile acid sequestrants are also used in conjunction with statins and nicotinic acid, and display a synergistic treatment effect. Colesevelam is tolerated
better overall than the other bile acid sequestrants, and no timing intervals with other medications are generally needed. Bile acid sequestrants are the first choice for children <10 years old as an alternative to statins. Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR -colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response,
maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided doses plus [?] continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol
of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most
potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin,
simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B
Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR
simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This
association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
3rd
ezetimibe Ezetimibe can be added in addition to statin therapy and lifestyle changes. Adverse effects include
hepatic transaminase elevation, myalgia, rhabdomyolysis, hepatitis, acute pancreatitis, and thrombocytopenia. [58] Primary Options ezetimibe : 10 mg orally once daily plus [?] continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary
revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than
atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from
one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of
total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80
mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be
used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
2 cardiac risk factors LDL <3.367 mmol/L (<130 mg/dL) 1st
lifestyle modification Risk factors include cigarette smoking, HTN, family history of premature CHD, and age >45 years in
men or >55 years in women. Patients can be allowed 3 to 6 months of lifestyle modification before considering lipid-lowering drugs. [41] This length of time, however, is still controversial; 2 to 3 followup visits over 2 to 3 months should be arranged to assess motivation and adherence. There is clear evidence that dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDLcholesterol and an increase in HDLcholesterol. [33] [34] [35] [B
Evidence] Recommendations should include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36] Significant reductions in LDL but no increase in HDL were found in the diet and exercise group compared with control or diet alone. [40]
2nd
statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL)
reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and
atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some
statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDL-
cholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily
OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily
3rd
nicotinic acid and/or bile acid sequestrants Beneficial effects of nicotinic acid are additive to statins and bile acid sequestrants. However,
nicotinic acid and bile acid sequestrants in addition to lifestyle changes may be an alternative initial therapeutic option for patients intolerant to statins. Lipids, glucose, LFTs, and uric acid should be checked after 6 weeks. Bile acid sequestrants are also used in conjunction with statins and nicotinic acid, and display a synergistic treatment effect. Colesevelam is tolerated better overall than the other bile acid sequestrants, and no timing intervals with other medications are generally needed. Bile acid sequestrants are the first choice for children <10 years old as an alternative to statins.
Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR -colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day increments every 1-2 months according to response, maximum 30 g/day
or colesevelam : 3.75 g/day orally given in 1-2 divided doses plus [?] continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in
primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to
one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of
commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant
reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR
rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients
intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
4th
ezetimibe Ezetimibe can be added in addition to statin therapy and lifestyle changes. Adverse effects include hepatic transaminase elevation, myalgia, rhabdomyolysis, hepatitis, acute pancreatitis, and thrombocytopenia. [58] Primary Options ezetimibe : 10 mg orally once daily
plus [?]
continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which
leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without
enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary
reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40]
Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally
once daily adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present.
Primary Options fenofibrate micronised : 67200 mg orally once daily

LDL 3.367 mmol/L (130 mg/dL) 1st
statin + lifestyle modification Risk factors include cigarette smoking, HTN, family history of premature CHD, and age >45 years in men or >55 years in women. Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal
MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better
HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of
warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be commenced. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a
trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally
once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily
2nd
nicotinic acid and/or bile acid sequestrants Beneficial effects of nicotinic acid are additive to statins and bile acid sequestrants. However, nicotinic acid and bile acid sequestrants in addition to lifestyle changes may be an alternative initial therapeutic option for patients intolerant
to statins. Lipids, glucose, LFTs, and uric acid should be checked after 6 weeks. Bile acid sequestrants are also used in conjunction with statins and nicotinic acid, and display a synergistic treatment effect. Colesevelam is tolerated better overall than the other bile acid sequestrants, and no timing intervals with other medications are generally needed. Bile acid sequestrants are the first choice for children <10 years old as an alternative to statins. Primary Options nicotinic acid : 375-2000 mg orally (modified-release)
once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR -colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided
doses plus [?] continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA
reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and
myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year.
Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group
compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR
pitavastatin : 1-4 mg orally once daily adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present.
Primary Options fenofibrate micronised : 67200 mg orally once daily

3rd
plus [?]
continued statin + lifestyle modification Statin therapy reduces LDL
levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance.
Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that
inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic
exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day
orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] bile acid sequestrant and/or nicotinic acid
In cases of severe hypercholesterolaemia and in patients with high risk of coronary heart disease, when LDL-cholesterol goals are not attained, generally in familial hypercholesterolaemia patients, bile acid sequestrants such as colestyramine and colesevelam, and also nicotinic acid, can be used as adjuvant therapies to statins and ezetimibe. Ezetimibe blocks about 50% of cholesterol absorption, and bile acid sequestrants can work on the remaining cholesterol in the intestinal lumen. There is evidence that both colesevelam and colestyramine potentiate the
lowering effect of ezetimibe on cholesterol levels. Also, in rare cases of sitosterolaemia, bile acid sequestrants can be added to ezetimibe to reduce phytosterol and cholesterol levels. Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR -colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day
More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided doses adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done
with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative to statins in intolerant patients when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
CHD or CHD equivalent LDL <2.59 mmol/L 1st
lifestyle modification CHD risk equivalents
Patient group <2 cardiac risk factors (<100 mg/dL)
include patients with clinical manifestations of noncoronary forms of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease (e.g., transient ischaemic attacks, stroke of carotid origin, or >50% obstruction of a carotid artery), or diabetes, in the presence of 2 cardiac risk factors. Risk factors include cigarette smoking, HTN, family history of premature CHD, and age >45 years in men or >55 years in women. Patients can be allowed 3 to 6 months of lifestyle modification before considering lipid-lowering drugs. [41] This length of
time, however, is still controversial; 2 to 3 followup visits over 2 to 3 months should be arranged to assess motivation and adherence. There is clear evidence that dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDLcholesterol and an increase in HDL-cholesterol.[B Evidence] Recommendations should include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from
food should be limited to <300 mg/day. [36] Significant reductions in LDL but no increase in HDL were found in the diet and exercise group compared with control or diet alone. [40]
2nd
statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic
stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both
atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may
relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from
food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR
atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily
3rd
nicotinic acid and/or bile acid sequestrants Beneficial effects of nicotinic acid are additive to statins and bile acid sequestrants. However, nicotinic acid and bile acid sequestrants in addition to lifestyle changes may be an alternative initial therapeutic option for patients intolerant to statins. Lipids, glucose, LFTs, and uric acid should be checked
after 6 weeks. Bile acid sequestrants are also used in conjunction with statins and nicotinic acid, and display a synergistic treatment effect. Colesevelam is tolerated better overall than the other bile acid sequestrants, and no timing intervals with other medications are generally needed. Bile acid sequestrants are the first choice for children <10 years old as an alternative to statins. Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day
-- AND/OR -colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided doses plus [?] continued statin + lifestyle modification
Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and
increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, whereas both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins
are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in
overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options
lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct fibric acid derivative
[?]
Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
4th
plus [?]
continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol
simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] bile acid sequestrant and/or nicotinic acid In cases of severe hypercholesterolaemia and in patients with high risk of coronary heart disease, when LDL-cholesterol goals
are not attained, generally in familial hypercholesterolaemia patients, bile acid sequestrants such as colestyramine and colesevelam, and also nicotinic acid, can be used as adjuvant therapies to statins and ezetimibe. Ezetimibe blocks about 50% of cholesterol absorption, and bile acid sequestrants can work on the remaining cholesterol in the intestinal lumen. There is evidence that both colesevelam and colestyramine potentiate the lowering effect of ezetimibe on cholesterol levels. Also, in rare cases of sitosterolaemia, bile acid sequestrants can be added
to ezetimibe to reduce phytosterol and cholesterol levels. Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR -colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day
increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided doses adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the
association with a statin. Fibrates may be an alternative to statins in intolerant patients when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
LDL 2.59 mmol/L (100 mg/dL)
1st
statin + lifestyle modification CHD risk equivalents include patients with clinical manifestations of noncoronary forms of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease (e.g., transient ischaemic attacks, stroke of carotid origin, or >50%
obstruction of a carotid artery), or diabetes, in the presence of 2 cardiac risk factors. Risk factors include cigarette smoking, HTN, family history of premature CHD, and age >45 years in men or >55 years in women. Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published
in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and
rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs
should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be commenced. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to
<300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg
orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily
2nd
nicotinic acid and/or bile acid sequestrants Beneficial effects of nicotinic acid are additive to statins and bile acid sequestrants. However, nicotinic acid and bile acid sequestrants in addition to lifestyle changes may be an alternative initial therapeutic option for patients intolerant to statins. Lipids, glucose, LFTs, and uric acid should be checked after 6 weeks.
Bile acid sequestrants are also used in conjunction with statins and nicotinic acid, and display a synergistic treatment effect. Colesevelam is tolerated better overall than the other bile acid sequestrants, and no timing intervals with other medications are generally needed. Bile acid sequestrants are the first choice for children <10 years old as an alternative to statins. Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR --
colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided doses plus [?] continued statin + lifestyle modification Statin therapy reduces LDL
levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects. [31] Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance.
Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Rosuvastatin and atorvastatin are the most potent statins; fluvastatin is at the lower end of the potency spectrum. Rosuvastatin has better HDL-raising properties than atorvastatin when used in high doses, while both atorvastatin and rosuvastatin can decrease triglycerides (TGs) by up to one third. Adverse effects include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation may occur when some statins are used with drugs that
inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Changing from one statin to another or lowering the dose may relieve the problem. LFTs should be carried out before and within 1 to 3 months of commencing treatment and then at intervals of 6 months for 1 year. Lifestyle modification should be continued. Dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic
exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence]Recommendation s include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36]Significant reductions in LDL but no increase in HDL were found in a diet and exercise group compared with control or diet alone. [40] Primary Options lovastatin : 10-80 mg/day
orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] fibric acid derivative
Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
3rd
plus [?]
continued statin + lifestyle modification Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. There is a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction in LDL-cholesterol
simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily adjunct [?] bile acid sequestrant and/or nicotinic acid In cases of severe hypercholesterolaemia and in patients with high risk of coronary heart disease, when LDL-cholesterol goals
are not attained, generally in familial hypercholesterolaemia patients, bile acid sequestrants such as colestyramine and colesevelam, and also nicotinic acid, can be used as adjuvant therapies to statins and ezetimibe. Ezetimibe blocks about 50% of cholesterol absorption, and bile acid sequestrants can work on the remaining cholesterol in the intestinal lumen. There is evidence that both colesevelam and colestyramine potentiate the lowering effect of ezetimibe on cholesterol levels. Also, in rare cases of sitosterolaemia, bile acid sequestrants can be added
to ezetimibe to reduce phytosterol and cholesterol levels. Primary Options nicotinic acid : 375-2000 mg orally (modified-release) once daily at bedtime according to response, maximum 2000 mg/day -- AND/OR -colestyramine : 4 g orally once daily initially, increase by 4 g increments every week to 12-24 g/day given in 1-4 divided doses according to response, maximum 36 g/day More or colestipol : 5 g orally once or twice daily initially, increase by 5 g/day
increments every 1-2 months according to response, maximum 30 g/day or colesevelam : 3.75 g/day orally given in 1-2 divided doses adjunct [?] fibric acid derivative Fibrates may be added to the treatment for patients with mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the
drug of choice for the association with a statin. Fibrates may be an alternative for patients intolerant to statins when mixed dyslipidaemia is present. Primary Options fenofibrate micronised : 67200 mg orally once daily
isolated low HDLcholesterol
1st
statins + management of primary cause Currently it is recommended that statins should be the initial treatment in subjects with isolated low HDL cholesterol. Since low HDL is usually secondary to abdominal obesity,
hypertriglcieridemia, smoking, insulin resistance and genetic causes, these also should be managed. Primary Options lovastatin : 10-80 mg/day orally (immediate-release) given in 1-2 divided doses OR pravastatin : 10-80 mg orally once daily OR simvastatin : 5-40 mg orally once daily OR fluvastatin : 20-40 mg orally once daily, maximum 80 mg/day OR atorvastatin : 10-80 mg orally once daily
OR rosuvastatin : 5-40 mg orally once daily OR pitavastatin : 1-4 mg orally once daily
Ongoing
Treatment approach
Several treatment options exist for hypercholesterolaemia, which may be instituted individually or in combination. They include lifestyle changes to diet and exercise, medications, and dietary supplements. Rarely, experimental therapies or procedural interventions can be applied.
Risk stratification
Risk category may guide treatment options; risk factors include cigarette smoking, HTN, low levels of high density lipoprotein (HDL), family history of premature coronary heart disease (CHD), and age >45 years in men or >55 years in women. Diabetes is considered to be of equivalent risk to CHD. Recent evidence suggests that the detection of subclinical atherosclerosis by either coronary calcium quantification by computed tomography or carotid intima medial thickness/plaque by B-mode ultrasound, as well as the detection of subclinical inflammation by determining CRP levels, might be useful to re-classify risk and start lipid-modifying treatment. This strategy is
apparently more effective in patients considered at intermediate level of risk by clinical evaluation (CHD risk 10% to 20% in 10 years) but without clinical manifestation of atherosclerosis. [30] Patients with clinical manifestation or at high risk of cardiovascular disease must be treated with lipid-modifying therapies, usually a statin if not contraindicated, in addition to lifestyle modifications. In people at lower levels of risk, pharmacological therapy is usually indicated if lifestyle changes are ineffective in the short term (3 to 6 months). There is evidence that statin therapy reduces cardiovascular events in people without clinical cardiovascular disease but with risk factors. [31] [32] Recently the updated meta-analysis of the Cholesterol Treatment Trialists (CTT) has shown reduction in both mortality and cardiovascular disease by lowering low density lipoprotein (LDL) independently of the presence of cardiovascular disease. [32] This meta-analysis evaluated either the effects of statins versus placebo or more potent versus less potent or higher versus lower dose statins for approximately 5 years.[A Evidence] It clearly showed the benefits of LDL lowering for the prevention of cardiovascular disease and mortality, even in people without overt hypercholesterolaemia but in the presence of risk factors for cardiovascular disease or the presence of previous cardiovascular disease. The cost effectiveness of statin treatment will depend on an adequate risk stratification in people without evidence of cardiovascular disease.
Lifestyle modification
Lifestyle changes should be started in all patients. There is clear evidence that dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol and an increase in HDLcholesterol. [33] [34] [35] [B Evidence] The implementation of dietary change can be difficult for many patients, and it may be helpful to include a dietician in the patient's care. A reduced intake of cholesterol and saturated fats should be advised, as well as increased consumption of dietary fibre, complex carbohydrates, and unsaturated fats. Recommendations should include an intake of total fat between 25% and 35%, saturated fat of <7%, and a trans fat intake of <1% of total daily calories. The intake of cholesterol from food should be limited to <300 mg/day. [36] A large English study in more than 2500 patients found that with diet alone, LDL-cholesterol was lowered by 5% to 7% in 60% of patients, who also achieved a mean reduction in body weight of 1.8%. [37] A meta-analysis
of 37 studies testing step I and step II diets (concentration of saturated fat <10% and <7%, respectively) showed an average 13% reduction in LDLcholesterol. A meta-analysis of 23 controlled trials showed a 7% reduction of LDL-cholesterol with soya supplementation and 19% reduction in LDLcholesterol with a Mediterranean diet. Diets rich in soluble fibre reduce LDLcholesterol 2% per gram of ingested fibre per day. [38] Other low-fat diets have shown LDL-cholesterol reduction of up to 30%. [39] The effect of aerobic exercise and diet has been studied in 377 men and women with low HDL- and high LDL-cholesterol. Significant reductions in LDL but no increase in HDL were found in the diet-and-exercise group compared with control or diet alone. [40] Patients with average or low cardiovascular risk can be allowed 3 to 6 months of lifestyle modification before considering lipid-lowering drugs. [41] This length of time, however, is still controversial; 2 to 3 follow-up visits over 2 to 3 months should be arranged to assess motivation and adherence.
Drug therapy (statins)

Drugs are the next step when lifestyle changes are not effective. In patients with extremely elevated LDL-cholesterol and those at high cardiovascular risk, drug therapy may accompany diet and exercise as an initial therapeutic approach. [25] Statin therapy reduces LDL levels, cardiovascular morbidity, and total mortality. Recently the updated meta-analysis of the Cholesterol Treatment Trialists (CTT) has shown a relative risk reduction for every 1 mmol/L (39 mg/dL) reduction of LDL-cholesterol of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for non-fatal MI, 25% for coronary revascularisation, and 21% for ischaemic stroke. [32] Data published in 2009 showed reduction of all-cause mortality in primary prevention subjects.[31] Higher doses are used in patients with acute coronary syndrome because of the effect that statins have on plaque stabilisation. Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, which leads to up-regulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type of statin chosen. [42] Statin therapy should be started in patients who fall into the following groups:
Lower-risk category (0 to 1 risk factors) and LDL >4.9 mmol/L (>190 mg/dL) (drug therapy optional for LDL of 4.1 mmol/L [160 to 189 mg/dL]).[B Evidence] Moderate- to high-risk category (2 risk factors) and LDL 3.367 mmol/L (130 mg/dL).[C Evidence] High-risk category (CHD or CHD equivalent) if LDL 2.6 mmol/L (100 mg/dL) (drug therapy optional for LDL of 1.8 to 2.6 mmol/L [70 to 99 mg/dL]). [27] [43] [C Evidence] CHD equivalents include patients with clinical manifestations of non-coronary forms of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease (e.g., transient ischaemic attacks, stroke of carotid origin, or >50% obstruction of a carotid artery), or diabetes, or in the presence of 2 cardiac risk factors.
Adverse effects are uncommon but include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation has also been reported; this seems to be most common when some of the statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, azole antifungals, and ciclosporin [cyclosporine]). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Caution is advised when using statins with these drugs, and lower doses of the statin (or the interacting drug) may be required. Also, the FDA now recommends that the dose of simvastatin not exceed 40 mg/day due to the increased risk of myopathy with the 80 mg/day dose. They recommend that the 80 mg/day dose only be used in patients who have been using this dose for 12 months or longer with no ill effect. For patients who do not respond to 40 mg/day, the FDA recommends changing to an alternative statin rather than increasing the dose. Two meta-analyses, one comparing statins with placebo, [44] and the other comparing more intensive versus less intensive statin treatment, [45] report an increased risk of new-onset type 2 diabetes associated with statin use. Another study, which looked at 3 large trials, found an increased risk of developing new-onset type 2 diabetes with high-dose atorvastatin, and that
baseline fasting glucose and features of the metabolic syndrome are predicitive of new-onset type 2 diabetes. [46] Adverse effects are more common in older patients, those with multiple diseases, and those on multiple drugs. In some people, changing from one statin to another or lowering the dose relieves the problem.
Approach to people with intolerance to statins

Statins are a very safe class of drugs; however, up to 10% of people are intolerant, especially where muscular symptoms are concerned. [47] There is no consensus how these patients must be treated; initially changing from one statin to another might be enough for improved tolerance. Alternate-day dose therapy, in association or not with daily ezetimibe (a cholesterol-blocking inhibitor), has been proposed for these patients. A systematic review of every other day administration of statins suggests that when more potent statins such as atorvastatin and rosuvastatin are used, similar LDL-c reductions to every-day treatment are attained. [47]However, tolerance was not adequately evaluated in most of these studies. In addition, studies are hindered by the small numbers of subjects and short-term follow-ups. Finally, alternate-day therapy may lead to either missed or extra doses. Fibrates may be an alternative to statins in intolerant patients when mixed dyslipidaemia is present. A recent meta-analysis has shown a reduction of 13% in coronary events; however, no changes in mortality were shown. [48] Another meta-analysis of people with high triglycerides and low HDL suggests a risk reduction of 35% in this sub-group of patients. [49] Nicotinic acid and bile acid sequestrants in addition to lifestyle changes may be an alternative initial therapeutic option for patients intolerant to statins.
Other lipid-lowering drug therapies

1. Nicotinic acid[C Evidence]
Beneficial effects are additive to statins and bile acid sequestrants. Effective in raising HDL as well as in lowering LDL and VLDL. The effect is highly dose-dependent, with the HDLraising properties seen with doses as low as 1 g/day;
lowering of LDL is typically observed at doses exceeding 1 to 2 g/day. [50] Adverse effects are relatively common, especially with the shorter-acting crystalline form of nicotinic acid. Flushing occurs in 80% of patients; pruritus, paraesthesias, and nausea each occur in about 20%. Elevations of hepatocellular enzymes are commonly seen, although it is very rarely associated with fulminant hepatitis. Additional adverse effects include induction of insulin resistance, precipitation of gout, elevation of homocysteine levels, and hypotension in patients treated with vasodilators. Pretreatment with aspirin 325 mg, 30 minutes prior to dosing, can minimise flushing and other prostaglandinmediated adverse effects. After 6 weeks check lipids, glucose, LFTs, and uric acid. Nicotinic acid (modified-release) was available in a combination formulation with the selective prostaglandin D(2) receptor-1 antagonist, laropiprant, which decreased flushing associated with nicotinic acid; however, the manufacturer is withdrawing the combination drug from the market due to an increased risk of non-fatal serious adverse effects seen in the HPS2-THRIVE (Heart Protection Study 2Treatment of HDL to Reduce the Incidence of Vascular Events) trial.
2. Bile acid sequestrants
Effective in patients with mild to moderate elevations of LDL-cholesterol. Used in conjunction with statins and nicotinic acid, and display a synergistic treatment effect. Work by binding bile acids in the intestine and preventing their re-absorption. Through this process, about 90% of bile acids are extracted. The loss of cholesterol-rich bile acids leads to a lowering of intrahepatic cholesterol and an up-regulation of LDL receptors. Increased receptor density in the liver results in further reduction of blood cholesterol. LDL reductions ranging from 10% to 24% can be achieved depending upon the dose used. [51] Most adverse effects are related to the GI tract and include nausea, bloating, cramping, and increased hepatic transaminases. For many patients these adverse effects are very limiting. The absorption of other drugs can be significantly impaired. Take other drugs 1 hour before or 4 hours after bile acid sequestrants. Formally contra-indicated in patients with triglycerides >500 mg/dL (>5.5 mmol/L). May be first choice for children <10 years old with severe hypercholesterolaemia where statins are not approved.
3. Ezetimibe[C Evidence]
Can also be added in addition to statin therapy and lifestyle changes. Effective in patients with mild to moderate elevations of LDL-cholesterol. Impairs dietary and biliary cholesterol absorption at the intestinal brush border by interaction with specific receptors and, in contrast to bile acid resins, has systemic exposure. If used alone, LDL reductions of 15% to 20% have been reported. [52] In conjunction with simvastatin, LDL was lowered an additional 14% above the effect achieved with simvastatin alone. [53] Although clinical endpoint data have not yet determined whether the combination of ezetimibe-statin is clinically superior to statin alone, the combination may be useful in patients unable to tolerate higher doses of statins but in whom further LDL-lowering is warranted. Bile acid sequestrants such as colestyramine and colesevelam, and also nicotinic acid, can be used as adjuvant therapies to statins and ezetimibe in cases of severe hypercholesterolaemia, in patients with high risk of coronary heart disease, when LDL-cholesterol goals are not attained, and generally in familial hypercholesterolaemia patients. Ezetimibe blocks about 50% of cholesterol absorption, and bile acid sequestrants can work on the remaining cholesterol in the intestinal lumen. There is evidence that both colesevelam and colestyramine potentiate the lowering effect of ezetimibe on cholesterol levels. Also, in sitosterolaemia (a rare condition), bile acid sequestrants can be added to ezetimibe to reduce phytosterol and cholesterol levels.
4. Fibric acid derivatives
Fibrates may be added to statins, but only in the presence of mixed dyslipidaemia when reductions in both cholesterol and triglycerides are necessary. This association must be done with care since it increases the risk of rhabdomyolysis. Gemfibrozil is never to be used in association with a statin, and fenofibrate is the drug of choice for the association with a statin.
Treatment of older patients

There is controversy in the literature whether older patients should be treated with lipid-modifying therapy. Cholesterol loses its impact as a risk factor in older patients and there is no consensus whether statins should be prescribed to asymptomatic older patients with hypercholesterolaemia. The PROSPER study that evaluated the effects of pravastatin treatment in people 70 to 82 years old found that in primary prevention, statin treatment was effective only in those with HDL cholesterol <1.15 mmol/L (45 mg/dL), where a relative 33% reduction was found. [54] The larger updated CTT metaanalysis that included studies such as PROSPER and HPS found no heterogeneity on the effects of LDL lowering for prevention of cardiovascular disease among people <65 years, 65 to 75 years old, and > 75 years old. [32] Despite the controversy, it is recommended that statins are prescribed to prevent cardiovascular disease in older patients.
Treatment of patients with isolated low HDLcholesterol

Low HDL is an isolated risk factor for atherosclerosis and for recurrence of cardiovascular events even in patients treated with statins. [55] However, there is no proof that raising HDL levels will reduce cardiovascular events, especially in people treated with statins. Fibrates and niacin significantly raise HDL cholesterol in people with high triglycerides and imaging studies such as HATS and ARBITER 6 show that niacin potentiates the effects of statins on coronary plaque and carotid intima medial thickness. [56] Despite this, there is no evidence that the association of statins with nicotinic acid or fibrates
reduces cardiovascular events and this is still a question being tested in clinical trials. [57] Currently it is recommended that statins should be the initial treatment in subjects with isolated low HDL cholesterol. Since low HDL is usually secondary to a primary cause such as abdominal obesity, hypertriglcieridemia, smoking, insulin resistance and genetic causes, these also should be managed.
Emerging treatments
Microsomal triglyceride transfer protein inhibitor This is responsible for transferring triglycerides onto apolipoprotein B (apoB) within the liver, during the assembly of VLDL, the precursor to LDL. In the absence of this protein, as in the rare recessive genetic disorder abetalipoproteinaemia, the liver cannot secrete VLDL, leading to the absence of apoB-containing lipoproteins. Thus, the pharmacological inhibition of microsomal triglyceride transfer protein might be a useful strategy for reducing LDL production and plasma LDL-cholesterol levels. In a recent study of patients with homozygous familial hypercholesterolaemia, the microsomal triglyceride transfer protein inhibitor BMS-201038 was shown to be highly effective in reducing plasma LDL-cholesterol levels, with a reduction of more than 50% at the highest dose. [58] The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat. Plasma levels of all other apoB-containing lipoproteins were similarly reduced. Thus, inhibition of microsomal triglyceride transfer protein represents another strategy for reducing plasma levels of atherogenic apoBcontaining lipoproteins in patients lacking functional LDL receptors. Mipomersen A second-generation anti-sense oligonucleotide designed to inhibit apo B-100 protein synthesis. Studies in animal models and in familial hypercholesterolaemia patients have shown that mipomersen results in a 25% to 30% reduction in plasma levels of both apo B and LDL-cholesterol in people at already maximum tolerated doses of statins and ezetimibe. [59]In addition, mipomersen reduces lipoprotein(a) levels. It is injected subcutaneously once a week and is being extensively tested in people with severe hypercholesterolaemia and in statin-intolerant people.
Cholesteryl ester transfer protein inhibitors (CETP) Anacetrapib was associated with a 40% reduction in LDL and a 138% increase in HDL on top of statin therapy after 76 weeks of followup. [60] Evacetrapib was associated with a 11.2% to 13.9% reduction in LDL and a 78.5% to 88.5% increase in HDL on top of statin therapy (compared to statin monotherapy). [61] Compared to torcetrapib, no changes in blood pressure or aldosterone levels were found. [60] The development of dalcetrapib, a much less potent drug than anacetrapib and evacetrapib which did not have LDL-lowering effects, has been ceased due to a lack of effect on cardiovascular events. Both anacetrapib and evacetrapib are being tested in clinical trials to show their impact in clinical vascular events.

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Hypercholesterolaemia

History & exam

Other diagnostic factors

lipid profile serum TSH Diagnostic tests details

disease, such as jaundice and abdominal tenderness, may be present.

Imaging studies show dilated bili

Marked elevatio triglycerides (TG

About half of pa mg/dL), about o mg/dL), and 10% mg/dL).

History & examination

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hypercholesterolaemia, and they may be present in some of the secondary hyperlipidaemias.

Risk factorshide all

lipid profile Consists of TC, triglycerides, and LDL- and HDL-cholesterol.

serum TSH TSH may be low in secondary hypothyroidism.

Step-by-step diagnostic approach

Click to view diagnostic guideline references.

Low: 1 mmol/L (<40 mg/dL) High: >1.554 mmol/L (60 mg/dL).

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LDL 4.921 mmol/L (190 mg/dL)

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