Total cholesterol (TC)^a	<4.0 mmol/L
LDL cholesterol (LDL-C)^a	<2.0 mmol/L
Triglycerides^b	<1.7 mmol/L
HDL cholesterol (HDL-C)	>1.0 mmol/L in men
HDL cholesterol (HDL-C)	>1.2 mmol/L in women

a Target levels in individuals with established atherosclerotic disease, coronary heart disease, stroke, peripheral arterial disease, diabetes mellitus or where there is a cardiovascular disease risk >20% over 10 years. In these identified individuals, the aim is to achieve the value stated in the table or a 25% reduction in total cholesterol and a 30% reduction in LDL-C from their baseline levels should these set target levels lower than those stated in the table.

b Fasting levels.

Despite a 50% reduction in the death rate from CVD over the past 25 years, it remains the leading cause of premature death and morbidity in the UK (British Heart Foundation, 2008), and the higher the levels of TC in an individual the greater the chance of developing CVD. At the individual level there appears no level below which a further reduction of TC or LDL-C is not associated with a lower risk of CVD. The death rate from CVD is threefold higher in males than females, but because women live longer and are at increased risk of stroke after the age of 75 years their lifetime risk of disease is greater (National Institute of Health and Clinical Excellence, 2008a).

TC levels tend to increase with age such that 80% of British men aged 45–64 years have a level that exceeds 5 mmol/L and the population average is 5.6 mmol/L. In contrast, in rural China and Japan, the average is 4 mmol/L.

Population-based approaches to vascular screening have the potential to provide significant health gain for society as most deaths from CVD occur in individuals who are not yet identified as at increased risk. Moreover, a small reduction in average population levels of TC and LDL-C can potentially prevent many deaths. In England, a scheme was introduced in 2009 for everyone between 40 and 74 years of age to receive a free health check to include measurement of TC and the TC:HDL-C ratio. The intention was that individuals would be given the necessary information about their health to make changes to lifestyle and avoid preventable disease.

Lipid transport and lipoprotein metabolism

The clinically important lipids in the blood (unesterified and esterified cholesterol and triglycerides) are not readily soluble in serum and are rendered miscible by incorporation into lipoproteins. There are six main classes of lipoproteins: chylomicrons, chylomicron remnants, very low-density lipoproteins (VLDL-C), intermediate-density lipoproteins (IDL-C), low-density lipoproteins (LDL-C) and high-density lipoproteins (HDL-C).

The protein components of lipoproteins are known as apoproteins (apo), of which apoproteins A-I, E, C and B are perhaps the most important. Apoprotein B exists in two forms: B-48, which is present in chylomicrons and associated with the transport of ingested lipids, and B-100, which is found in endogenously secreted VLDL-C and associated with the transport of lipids from the liver (Fig. 24.1).

Fig. 24.1 Schematic representation of lipoprotein metabolism in plasma. Dietary cholesterol and fat are transported in the exogenous pathway. Cholesterol produced in the liver is transported in the endogenous pathway.

When dietary cholesterol and triglycerides are absorbed from the intestine they are transported in the intestinal lymphatics as chylomicrons. These are the largest of the lipoprotein particles of which triglycerides normally constitute approximately 80% of the lipid core. The chylomicrons pass through blood capillaries in adipose tissue and skeletal muscle where the enzyme lipoprotein lipase is located, bound to the endothelium. Lipoprotein lipase is activated by apoprotein C-II on the surface of the chylomicron. The lipase catalyses the breakdown of the triglyceride in the chylomicron to free fatty acid and glycerol, which then enter adipose tissue and muscle. The cholesterol-rich chylomicron remnant is taken up by receptors on hepatocyte membranes, and in this way dietary cholesterol is delivered to the liver and cleared from the circulation.

VLDL-C is formed in the liver and transports triglycerides, which again make up approximately 80% of its lipid core, to the periphery. The triglyceride content of VLDL-C is removed by lipoprotein lipase in a similar manner to that described for chylomicrons above, and forms IDL-C particles. The core of IDL-C particles is roughly 50% triglyceride and 50% cholesterol esters, acquired from HDL-C under the influence of the enzyme lecithin-cholesterol acyltransferase (LCAT). Approximately 50% of the body’s IDL particles are cleared from serum by the liver. The other 50% of IDL-C are further hydrolysed and modified to lose triglyceride and apoprotein E1 and become LDL-C particles. LDL-C is the major cholesterol-carrying particle in serum.

LDL-C provides cholesterol, an essential component of cell membranes, bile acid and a precursor of steroid hormones to those cells that require it. LDL-C is also the main lipoprotein involved in atherogenesis, although it only appears to take on this role after it has been modified by oxidation. For reasons that are not totally clear, the arterial endothelium becomes permeable to the lipoprotein. Monocytes migrate through the permeable endothelium and engulf the lipoprotein, resulting in the formation of lipid-laden macrophages that have a key role in the subsequent development of atherosclerosis. The aim of treatment in dyslipidaemia is normally to reduce concentrations of LDL-C (and consequently atherogenesis) and thus reduce TC at the same time.

While VLDL-C and LDL-C are considered the ‘bad’ lipoproteins, HDL-C is often considered to be the ‘good’ antiatherogenic lipoprotein. In general, about 65% of TC is carried in LDL-C and about 25% in HDL.

High-density lipoprotein

HDL-C is formed from the unesterified cholesterol and phospholipid removed from peripheral tissues and the surface of triglyceride-rich proteins. The major structural protein is apoA-I. HDL-C mediates the return of lipoprotein and cholesterol from peripheral tissues to the liver for excretion in a process known as reverse cholesterol transport.

Reverse cholesterol transport pathway

The reverse cholesterol transport pathway (Fig. 24.2) controls the formation, conversion, transformation and degradation of HDL-C and is the target site for a number of new, novel drugs and has recently been described (Chapman et al., 2010).

Fig. 24.2 Pathways of reverse cholesterol transport in man (Chapman et al., 2010 with kind permission from Oxford University Press, Oxford).

The reverse cholesterol transport system involves lipoprotein-mediated transport of cholesterol from peripheral, extra-hepatic tissues and arterial tissue (potentially including cholesterol-loaded foam cell macrophages of the atherosclerotic plaque) to the liver for excretion, either in the form of biliary cholesterol or bile acids. The ATP-binding cassette transporters, ABCA1 and ABCG1, and the scavenger receptor B1, are all implicated in cellular cholesterol efflux mechanisms to specific apoA-1/HDL acceptors. The progressive action of lecithin:cholesterol acyl transferase on free cholesterol in lipid-poor, apolipoprotein A-I-containing nascent high-density lipoproteins, including pre-β-HDL, gives rise to the formation of a spectrum of mature, spherical high-density lipoproteins with a neutral lipid core of cholesteryl ester and triglyceride. Mature high-density lipoproteins consist of two major subclasses, large cholesteryl ester-rich HDL₂ and small cholesteryl ester-poor, protein-rich HDL₃ particles; the latter represent the intravascular precursors of HDL₂. The reverse cholesterol transport system involves two key pathways: (a) the direct pathway (blue lines), in which the cholesteryl ester content (and potentially some free cholesterol) of mature high-density lipoprotein particles is taken up primarily by a selective uptake process involving the hepatic scavenger receptor B1 and (b) an indirect pathway (dotted blue lines) in which cholesteryl ester originating in HDL is deviated to potentially atherogenic VLDL, IDL and LDL particles by cholesteryl ester transfer protein. Both the cholesteryl ester and free cholesterol content of these particles are taken up by the liver, predominantly via the LDL receptor which binds their apoB100 component. This latter pathway may represent up to 70% of cholesteryl ester delivered to the liver per day. The hepatic LDL receptor is also responsible for the direct uptake of high-density lipoprotein particles containing apoE; apoE may be present as a component of both HDL₂ and HDL₃ particles, and may be derived either by transfer from triglyceride-rich lipoproteins, or from tissue sources (principally liver and monocyte-macrophages). Whereas HDL uptake by the LDL receptor results primarily in lysosomal-mediated degradation of both lipids and apolipoproteins, interaction of HDL with scavenger receptor B1 regenerates lipid-poor apoA-I and cholesterol-depleted HDL, both of which may re-enter the HDL/apoA-I cycle.

From the above it is evident that HDL-C plays a major role in maintaining cholesterol homeostasis in the body. As a consequence it is considered desirable to maintain both levels of the protective HDL-C and the integrity of the reverse cholesterol transport pathway. Low levels of HDL-C are found in 17% of men and 5% of women and may be a risk factor for atherogenesis that is comparable in importance to elevated levels of LDL-C. Drugs that reduce HDL-C levels are considered to have an undesirable effect on lipid metabolism and increase the risk of developing CVD.

Triglycerides

The role of hypertriglyceridaemia as an independent risk factor for coronary heart disease (CHD) is unclear because triglyceride levels are confounded by an association with low HDL-C, hypertension, diabetes and obesity, and a synergistic effect with LDL-C and/or low HDL-C. An isolated elevation of triglyceride may be the consequence of a primary disorder of lipid metabolism, it may be secondary to the use of medicines or it may be a component of the metabolic syndrome or type 2 diabetes mellitus. Many individuals have a mixed dyslipidaemia that includes elevated levels of triglycerides and LDL-C, but reduction of LDL-C normally remains the primary focus of treatment. A recent analysis, in over 73,000 individuals, of a genetic variant which regulates triglyceride concentrations has demonstrated a causal association between triglycerides and CHD (Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, 2010).

Aetiology

Primary dyslipidaemia

Up to 60% of the variability in cholesterol fasting lipids may be genetically determined, although expression is often influenced by interaction with environmental factors. The common familial (genetic) disorders can be classified as:

• the primary hypercholesterolaemias such as familial hypercholesterolaemias in which LDL-C is raised

• the primary mixed (combined) hyperlipidaemias in which both LDL-C and triglycerides are raised

• the primary hypertriglyceridaemias such as type III hyperlipoproteinaemia, familial lipoprotein lipase deficiency and familial apoC-II deficiency.

Secondary dyslipidaemia

Dyslipidaemias that occur secondary to a number of disorders (Box 24.1), dietary indiscretion or as a side effect of drug therapy (Table 24.2) account for up to 40% of all dyslipidaemias. Fortunately, the lipid abnormalities in secondary dyslipidaemia can often be corrected if the underlying disorder is treated, effective dietary advice implemented or the offending drug withdrawn.

Table 24.2 Typical effects of selected drugs on lipoprotein levels

On occasion, a disorder may be associated with dyslipidaemia but not the cause of it. For example, hyperuricaemia (gout) and hypertriglyceridaemia co-exist in approximately 50% of men. In this particular example, neither is the cause of the other and treatment of one does not resolve the other. There are, however, two notable exceptions to the rule with this example: nicotinic acid and fenofibrate. Both drugs reduce triglyceride levels but nicotinic acid increases urate levels while fenofibrate reduces them by an independent uricosuric effect.

Some of the more common disorders that cause secondary dyslipidaemias include the following.

Diabetes mellitus

Premature atherosclerotic disease is the main cause of reduced life expectancy in patients with diabetes. The atherosclerotic disease is often widespread and complications such as plaque rupture and thrombotic occlusion occur more often and at a younger age. The prevalence of CHD is up to four times higher among diabetic patients with more than 80% likely to die from a cardiovascular event. LDL levels are a stronger predictor of CV risk in diabetic patients than blood glucose control or blood pressure.

Type 1 diabetes

In patients with type 1 diabetes, HDL-C may appear high but for reasons which are unclear, it does not impart the same degree of protection against CVD as in those without diabetes. It is, therefore, not appropriate to use cardiovascular risk prediction charts that utilise the TC:HDL-C ratio in patients with type 1 diabetes. Patients with type 1 diabetes have a two- to three-fold increased risk of developing CVD.

Type 2 diabetes

Patients with type 2 diabetes typically have increased triglycerides and decreased HDL-C. Levels of TC may be similar to those found in non-diabetic individuals but the patient with type 2 diabetes often has increased levels of highly atherogenic small dense LDL particles.

Individuals with type 2 diabetes and aged over 40 years, but without CVD, are often considered to have the same cardiovascular risk as patients without diabetes who have survived a myocardial infarction. This assumption is generally appropriate but influenced by patient age, duration of diabetes and gender and holds better for women than men. This probably occurs because the impact of type 2 diabetes is more marked in women than men. In some guidelines, the criteria for at risk is age above 40 years but with one other risk factor present, for example, hypertension, obesity, smoker, etc.

National Institute of Health and Clinical Excellence (2008a) consider an individual with type 2 diabetes to be at high premature cardiovascular risk for their age unless he or she:

• is not overweight

• is normotensive (<140/80 mmHg in the absence of antihypertensive therapy)

• does not have microalbuminuria

• does not smoke

• does not have a high-risk lipid profile

• has no history of CVD and

• has no family history of CVD.

Where the individual is found to be at risk the patient is typically started on 40 mg simvastatin (or equivalent generic statin). Current guidance indicates the dose can be titrated up to simvastatin 80 mg a day if lipid levels are not reduced to less than 4 mmol/L for TC and less than 2 mmol/L for LDL-C on 40 mg simvastatin. In those who do not reach target with 80 mg simvastatin, 80 mg atorvastatin may be tried. However, with both drugs at the higher dose there is increasing concern about their side effect profile and consequently use is limited at these doses.

Individuals aged 18–39 with type 2 diabetes may also be at high risk and in need of treatment with a statin. Again at-risk individuals typically receive 40 mg simvastatin, or equivalent alternate statin, a day titrated up to 80 mg a day if levels for TC of less than 4 mmol/L and less than 2 mmol/L for LDL-C are not achieved. Again there are emerging concerns about use of these higher doses.

Hypothyroidism

Abnormalities of serum lipid and lipoprotein levels are common in patients with untreated hypothyroidism. Hypothyroidism may elevate LDL-C because of reduced LDL receptor activity and it frequently causes hypertriglyceridaemia and an associated reduction in HDL-C as a result of reduced lipoprotein lipase activity. Remnants of chylomicrons and VLDL-C may also accumulate. However, once adequate thyroid replacement has been instituted the dyslipidaemia should resolve.

Chronic renal failure

Dyslipidaemia is frequently seen in patients with renal failure in the predialysis phase, during haemodialysis or when undergoing chronic ambulatory peritoneal dialysis. The hypertriglyceridaemia that most commonly occurs is associated with reduced lipoprotein lipase activity and often persists despite starting chronic maintenance renal dialysis.

Nephrotic syndrome

In patients with the nephrotic syndrome, dyslipidaemia appears to be caused by an increased production of apoB-100 and associated VLDL-C along with increased hepatic synthesis of LDL-C and a reduction in HDL-C. The necessary use of glucocorticoids in patients with the nephrotic syndrome may exacerbate underlying lipoprotein abnormality.

Obesity

Chronic, excessive intake of calories leads to increased concentrations of triglycerides and reduced HDL-C. Obesity per se can exacerbate any underlying primary dyslipidaemia. Individuals with central obesity appear to be at particular risk of what has become known as the metabolic or DROP (dyslipidaemia, insulin resistance, obesity and high blood pressure) syndrome which represents a cluster of risk factors. Obesity and sedentary lifestyle coupled with inappropriate diet and genetic factors interact to produce the syndrome (Kolovou et al., 2005).

Alcohol

In the heavy drinker, the high calorie content of beer and wine may be a cause of obesity with its associated adverse effect on the lipid profile. In addition, alcohol increases hepatic triglyceride synthesis, which in turn produces hypertriglyceridaemia.

Light to moderate drinkers (1–3 units/day) have a lower incidence of CVD and associated mortality than those who do not drink. This protective effect is probably due to an increase in HDL-C, and appears independent of the type of alcohol. Men should be advised to limit their alcohol intake to 3–4 units a day, and not exceed 21 units a week. For women, the equivalent recommendation is 2–3 units a day with a maximum intake of 14 units a week. Everyone should be advised not to binge drink and have one or two alcohol free days a week.

Drugs

A number of drugs can adversely affect serum lipid and lipoprotein concentrations (see Table 24.2).

Antihypertensive agents

Hypertension is a major risk factor for atherosclerosis, and the beneficial effects of lowering blood pressure are well recognised. It is, however, a concern that, although treatment of patients with some antihypertensives has reduced the incidence of cerebrovascular accidents and renal failure, there has been no major impact in reducing the incidence of CHD. It has been suggested that some of these antihypertensive agents have an adverse effect on lipids and lipoproteins that override any beneficial reduction of blood pressure.

Diuretics

Thiazide and loop diuretics increase VLDL-C and LDL-C by mechanisms that are not completely understood. Whether these adverse effects are dose dependent is also unclear. Use of a thiazide for less than 1 year has been reported to increase TC by up to 7% with no change in HDL-C. However, there is evidence that the short-term changes in lipids do not occur with the low doses in current use. Studies of 3–5 years’ duration have found no effect on TC.

ß-Blockers

The effects of β-blockers on lipoprotein metabolism are reflected in an increase in serum triglyceride concentrations, a decrease in HDL-C, but with no discernible effect on LDL-C. β-Blockers with intrinsic sympathomimetic activity appear to have little or no effect on VLDL-C or HDL-C. Pindolol has intrinsic sympathomimetic activity but is rarely used as an antihypertensive agent since it may exacerbate angina. Alternatively, the combined α- and β-blocking effect of labetalol may be of use since it would appear to have a negligible effect on the lipid profile.

Overall, the need to use a diuretic or a β-blocker must be balanced against patient considerations. A patient in heart failure should receive a diuretic if indicated regardless of the lipid profile. Likewise, the patient with heart failure may also benefit from a β-blocker such as bisoprolol or carvedilol. Patients who have had a myocardial infarction should be considered for the protective effect of a β-blocker and again the benefits of use will normally override any adverse effects on the lipid profile.

If an antihypertensive agent is required, that is, without adverse effects on lipoproteins, many studies would suggest that angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers or α-adrenoceptor blockers could be used.

Oral contraceptives

Oral contraceptives containing an oestrogen and a progestogen provide the most effective contraceptive preparations for general use and have been well studied with respect to their harmful effects.

Oestrogens and progestogens both possess mineralocorticoid and glucocorticoid properties that predispose to hypertension and diabetes mellitus, respectively. However, the effects of the two hormones on lipoproteins are different. Oestrogens cause a slight increase in hepatic production of VLDL-C and HDL-C, and reduce serum LDL-C levels. In contrast, progestogens increase LDL-C and reduce serum HDL-C and VLDL-C.

The specific effect of the oestrogen or progestogen varies with the actual dose and chemical entity used. Ethinyloestradiol at a dose of 30–35 μcg or less would appear to create few problems with lipid metabolism, while norethisterone is one of the more favourable progestogens even though it may cause a pronounced decrease in HDL-C.

Corticosteroids

The effect of glucocorticoid administration on lipid levels has been studied in patients treated with steroids for asthma, rheumatoid arthritis and connective tissue disorders. Administration of a glucocorticoid such as prednisolone has been shown to increase TC and triglycerides by elevating LDL-C and, less consistently, VLDL-C. The changes are generally more pronounced in women. Alternate-day therapy with glucocorticoids has been suggested to reduce the adverse effect on lipoprotein levels in some patients.

Ciclosporin

Ciclosporin is primarily used to prevent tissue rejection in recipients of renal, hepatic and cardiac transplants. Its use has been associated with increased LDL-C levels, hypertension and glucose intolerance. These adverse effects are often exacerbated by the concurrent administration of glucocorticoids. The combined use of ciclosporin and glucocorticoid contributes to the adverse lipid profile seen in transplant patients. Unfortunately, the administration of a statin to patients treated with ciclosporin increases the incidence of myositis, rhabdomyolysis (dissolution of muscle associated with excretion of myoglobin in the urine) and renal failure. Use of a statin is, therefore, contraindicated in patients receiving ciclosporin.

Case reports of similar interactions between statins and other drugs used to prevent tissue rejection, including tacrolimus and sirolimus, have also been reported.

Hepatic microsomal enzyme inducers

Drugs such as carbamazepine, phenytoin, phenobarbital, rifampicin and griseofulvin increase hepatic microsomal enzyme activity and can also increase serum HDL-C. The administration of these drugs may also give rise to a slight increase in LDL-C and VLDL-C. The overall effect is one of a favourable increase in the TC:HDL-C ratio. It is interesting to note that patients treated for epilepsy have been reported to have a decreased incidence of CVD.

Risk Assessment

Primary prevention

In patients with no evidence of CHD or other major atherosclerotic disease, there are a number of CVD risk prediction charts, including those produced by the Joint British Societies (JBS2) (British Hypertension Society, 2009) for males (Fig. 24.3) and females (Fig. 24.4). JBS2 recommends that all adults from the age of 40 years, with no history of CVD or diabetes, and not receiving treatment for raised blood pressure or dyslipidaemia, should receive opportunistic screening every 5 years in primary care. The cardiovascular risk calculated using the JBS2 charts is based on the number of cardiovascular events expected over the next 10 years in 100 women or men with the same risk factors as the individual being assessed. Those with a cardiovascular risk >20% over 10 years are deemed to require treatment according to current national and international guidelines, although individuals with a risk as low as 8% over 10 years will gain some benefit, this will be small.

Fig. 24.3 Joint British Societies’ cardiovascular disease risk prediction chart for non-diabetic men 2009 (reproduced with kind permission of University of Manchester). SBP, systolic blood pressure mmHg; TC:HDL, serum total cholesterol to HDL cholesterol ratio.

Fig. 24.4 Joint British Societies’ cardiovascular disease risk prediction chart for non-diabetic women 2009 (reproduced with kind permission of University of Manchester). SBP, systolic blood pressure mmHg; TC:HDL, serum total cholesterol to HDL cholesterol ratio.

Risk assessment is not required when the individual is 75 years of age or older, or they have pre-existing CVD. These individuals are already assumed to have a 10-year risk of at least 20%.

When using the JBS2 risk prediction charts a number of factors need to be taken into account at screening and include:

• Age: in individuals under 40 years of age the charts overestimate risk; over the age of 70 years risk is underestimated by the charts and most have a 10-year risk >20%.

• Gender: there are separate charts for men and women.

• Ethnicity: the risk prediction charts have only been validated in white caucasians and underestimate risk in individuals from the Indian subcontinent (India, Pakistan, Bangladesh and Sri Lanka) by a factor of 1.5.

• Smoking history: individuals who have stopped smoking within 5 years of assessment should be considered as current smokers.

• Family history: risk increases by a factor of 1.5 when CHD has occurred in a first-degree relative (parent, offspring, sibling) male <55 years or female <65 years, when a number of family members have developed CHD risk increases by a factor of 2 (Box 24.2).

• Body mass index (BMI) and waist circumference: the charts do not adjust for either BMI or waist circumference; these factors need to be taken into account in the clinical decision-making process.

• Non-fasting blood glucose: if non-fasting glucose >6.1 mmol/L, the individual should be assessed for impaired glucose regulation or diabetes.

Box 24.2 Criteria that indicate familial hypercholesterolaemia

Family history of dyslipidaemia or cardiovascular disease:

• in first-degree female relative less than 65 years old

• in first-degree male relative less than 55 years old

Xanthelasma or corneal arcus under the age of 45

a Tendon xanthomata + TC >7.5 mmol/L at any age

a Tendon xanthomata + LDL-C >4.9 mmol/L

a Tendon xanthomata may not be readily apparent in younger people

Individuals with type 2 diabetes aged over 40 years and with an additional cardiovascular risk factor are considered to be at greater than 20% risk over 10 years and eligible for treatment. In those who are 40 years of age or older but without any additional risk factor, a specific risk engine is available (http://www.dtu.ox.ac.uk/riskengine/) based on data from the United Kingdom Prospective Diabetes Study.

Framingham

Up to 2008, risk charts and calculators based on Framingham data were the most widely used and researched approach for calculating cardiovascular risk, and are the data on which the risk charts discussed above are based. The Framingham data derive from a North American population studied in the 1960s to 1980s. The data generally overestimate risk in the UK population but underestimate risk, as discussed, in those with a family history of premature CVD, South Asian men, people with diabetes and those from a deprived socioeconomic background.

Assign

This is a risk calculator based on data from a Scottish population and includes many of the variables utilised in the Framingham-based model. It also takes into account social status, determined by postcode of residence in Scotland, and family history of CVD (Woodward et al., 2007). The calculator can be found at: http://www.assign-score.com.

QRISK2

This is a relatively new CVD risk calculator, based on a database of anonymised UK primary care patients established in 2003. It contains over 10 million sets of encrypted patient records. A cohort of 1.28 million patients without evidence of diabetes mellitus or CVD was identified, and followed up for more than 5 years looking for the first development of CVD as an endpoint.

The current version of the calculator (QRISK2) uses the following parameters with any missing values calculated by a complex averaging procedure:

• Patient age (35–74)

• Patient gender

• Current smoker (yes/no)

• Family history of heart disease aged <60 (yes/no)

• Existing treatment with blood pressure agent (yes/no)

• Postcode (postcode is linked to Townsend score measure of deprivation)

• BMI (height and weight)

• Systolic blood pressure (use current not pre-treatment value)

• Total and HDL cholesterol

• Self-assigned ethnicity (not nationality)

• Rheumatoid arthritis

• Chronic kidney disease

• Atrial fibrillation.

The QRISK2 calculator is available at http://www.qrisk.org/

The Department of Health and NICE endorse the use of either Framingham-based risk prediction tools or QRISK2.

Secondary prevention

Patients with CVD and levels of TC >4 mmol/L and LDL-C >2 mmol/L are the ones most likely to benefit from treatment with lipid-lowering agents. Typical of individuals who fall into this category are patients with a history of angina, myocardial infarction, acute coronary syndrome, coronary artery bypass grafting, coronary angioplasty or cardiac transplantation as well as patients with evidence of atherosclerotic disease in other vascular beds such as patients post-stroke or TIA, and those with peripheral arterial disease.

As in the situation with primary prevention outlined above, if an individual is to receive a lipid-lowering agent as part of a secondary prevention strategy, the possibility of a familial dyslipidaemia and the need to assess other family members must not be overlooked (National Institute of Health and Clinical Excellence, 2008b).

Treatment

Lipid profile

When a decision has been made to determine an individual’s lipid profile, a random serum TC and HDL-C will often suffice. If a subsequent decision is made to commence treatment and monitor outcome, a more detailed profile that includes triglycerides is required. Treatment should not be initiated on the basis of a single random sample.

Serum concentrations of triglycerides increase after the ingestion of a meal and, therefore, patients must fast for 12–15 h before they can be measured. Patients must also be seated for at least 5 min prior to drawing a blood sample. TC level and HDL are little affected by food intake, and this is, therefore, not a consideration if only these are to be measured. However, it is important that whatever is being measured reflects a steady-state value. For example, during periods of weight loss, lipid concentrations decline as they do following a myocardial infarction. In the case of the latter, samples drawn within 24 h of infarct onset will reflect the preinfarction state. In general, measurement should be deferred for 2 weeks after a minor illness and for 3 months after a myocardial infarction, serious illness or pregnancy.

Once the TC, HDL-C and triglyceride values are known it is usual to calculate the value for LDL-C using the Friedewald equation:

The Friedewald equation should not be used in non-fasting individuals, it is less reliable in individuals with diabetes and is not valid if the serum triglyceride concentration >4 mmol/L.

Although lipid target levels are normally only defined for TC and LDL-C, increasingly non-HDL-C is measured. The value for non-HDL-C is obtained by subtracting the value for HDL-C from TC. Non-HDL-C consequently represents the total of cholesterol circulating on apoprotein B particles, that is, both LDL and triglyceride-rich lipoproteins, and represents the main atherogenic particles. A desirable value is <3 mmol/L.

Lifestyle

When a decision is made to start treatment with a lipid-lowering agent, other risk factors must also be tackled as appropriate, such as smoking, obesity, high alcohol intake and lack of exercise (Box 24.3). Underlying disorders such as diabetes mellitus and hypertension should be treated as appropriate. Issues around body weight, diet and exercise will be briefly covered in the following sections.

Box 24.3 Lifestyle targets

• Do not smoke

• Maintain ideal body weight (BMI 20–25 kg/m²)

• Avoid central obesity

• Reduce total dietary intake of fat to ≤30% of total energy intake

• Reduce intake of saturated fats to ≤10% of total fat intake

• Reduce intake of dietary cholesterol to <300 mg/day

• Replace saturated fats by an increased intake of monounsaturated fats

• Increase intake of fresh fruit and vegetables to at least five portions per day

• Regularly eat fish and other sources of omega-3 fatty acids (at least two portions of fish each week)

• Limit alcohol intake to <21 units/week for men and <14 units/week for women

• Restrict intake of salt to <100 mmol day (<6 g of sodium chloride or <2.4 g sodium/day)

• Undertake regular aerobic exercise of at least 30 min/day, most days of the week

• Avoid excess intake of coffee or other caffeine-rich containing products

Body weight and waist measurement

The overweight patient is at increased risk of atherosclerotic disease and typically has elevated levels of serum triglycerides, raised LDL-C and a low HDL-C. This adverse lipid profile is often compounded by the presence of hypertension and raised blood glucose, that is, the metabolic syndrome. A reduction in body weight will generally improve the lipid profile and reduce overall cardiovascular risk.

It is useful to classify the extent to which an individual is overweight by calculating their BMI. The BMI (kg/m²) in all but the most muscular individual gives a clinical measure of adiposity.

• BMI 18.5: underweight

• BMI 18.6 to 24.9: ideal

• BMI 25 to 29.9: overweight (low health risk)

• BMI 30 to 40: obese (moderate health risk)

• BMI >40: morbidly obese (high health risk)

The distribution of body fat is also recognised as a factor that influences CVD risk. Measurement of waist circumference is perhaps the easiest and most practical indicator of central obesity and correlates well with CVD risk. Target waist circumference should be <102 cm in white caucasian men, <88 cm in white caucasian females and in Asians <90 cm in men and <80 cm in females.

Diet

Diet modification should always be encouraged in a patient with dyslipidaemia but is rarely successful alone in bringing about a significant improvement in the lipid profile. Randomised controlled trials of dietary fat reduction or modification have shown variable results on cardiovascular morbidity and mortality. In pragmatic, community-based studies, reductions in TC of only 3–6% have been achieved. The overall picture is that patients with dyslipidaemia should receive dietary advice and a small number of those who adhere to the advice will experience a fall in TC.

There is a common misconception that a healthy diet is one that is low in cholesterol. However, generally it is the saturated fat content that is important, although many components of a healthy diet are not related to fat content. For example, the low incidence of cardiovascular disease in those who consume a Mediterranean-type diet suggests an increased intake of fruit and vegetables is also important. The typical Mediterranean diet has an abundance of plant food (fruit, vegetables, breads, cereals, potatoes, beans, nuts and seeds) minimally processed, seasonally fresh, and locally grown; fresh fruit as the typical daily dessert, with sweets containing concentrated sugars or honey consumed a few times per week; olive oil as the principal source of fat; dairy products (principally cheese and yoghurt) consumed daily in low to moderate amounts; 0–4 eggs consumed weekly; and red meat consumed in low to moderate amounts. This diet is low in saturated fat (<8% of energy) and varies in total fat content from <25% to >35% of energy.

Fish

Regular consumption of the long chain omega-3 fatty acids, principally ecosapentaenoic acid and docosahexaenoic acid, typically found in fatty fish and fish oils, has been linked to the low levels of CHD seen in Inuits (Eskimos). The risk of fatal myocardial infarction in those with CVD has been shown to be reduced by consuming omega-3 fatty acids. Consumption of omega-3 fatty acids decrease triglyceride levels but have little effect on LDL-C or HDL-C. The proposed mechanisms is thought to involve the omega-3 fatty acids and their antiarrhythmic properties, ability to reduce blood pressure and heart rate, lower triglyceride levels, stimulate endothelial-derived nitric oxide, increase insulin sensitivity, decrease platelet aggregation and decrease proinflammatory eicosanoids. There would appear to be benefits in consuming at least two portions (portion = 140 g) of fish per week, including a portion of oily fish, particularly in those who have had a myocardial infarction. Pregnant women are advised to limit their intake of oily fish to two portions per week because of the potential accumulation of low level pollutants in the fish.

Trans fats

Trans fats are unsaturated fatty acids with at least one double bond in the trans configuration. They are formed when vegetable oils are hydrogenated to convert them into semisolid fats that can be incorporated into margarines or used in commercial manufacturing processes. Trans fats are typically found in deep fried fast foods, bakery products, packaged snack foods, margarines and crackers. When the calorific equivalent of saturated fats, cis unsaturated fats and trans fats are consumed, trans fats raise LDL-C, reduce HDL-C and increase the ratio of TC:HDL-C. In addition to these harmful effects, trans fats also increase the blood levels of triglycerides, increase levels of Lp(a) and reduce the particle size of LDL-C, all of which further increase the risk of CHD. It is, therefore, necessary to reduce the dietary intake of trans fatty acids to less than 0.5% of total energy intake and this has led to calls for a complete ban on trans fats in foods.

Stanol esters and plant sterols

The availability of margarines and other foods enriched with plant sterols or stanol esters appears to increase the likelihood that LDL-C can be reduced by dietary change. Both stanol esters and plant sterols at a maximum effective dose of 2 g/day inhibit cholesterol absorption from the gastro-intestinal tract and reduce LDL-C by an average of 10%. They compete with cholesterol for incorporation into mixed micelles, thereby impairing its absorption from the intestine. However, as with other dietary changes, the reduction seen varies between individuals and is probably dependent on the initial cholesterol level. There is currently no evidence that ingestion lowers the risk of cardiovascular events.

Antioxidants

Antioxidants occur naturally in fruit and vegetables and are important components of a healthy diet. Their consumption is thought to be beneficial in reducing the formation of atherogenic, oxidised LDL-C. Primary and secondary prevention trials with antioxidant vitamin supplements, however, have not been encouraging. Neither vitamin E nor beta-carotene supplements would appear to reduce the risk of CHD but likewise have not been shown to be harmful.

Salt

Dietary salt (sodium) has an adverse effect on blood pressure and, therefore, a potential impact on CHD and stroke. As part of dietary advice the average adult intake of sodium should be reduced from approximately 150 mmol (9 g)–100 mmol (6 g) of salt or even lower. This intake can be reduced by consuming fewer processed foods, avoiding many ready meals and not adding salt to food at the table.

Exercise

Moderate amounts of aerobic exercise (brisk walking, jogging, swimming, cycling) on a regular basis have a desirable effect on the lipid profile of an individual. These beneficial effects have been demonstrated within 2 months in middle-aged men exercising for 30 min, three times a week. Current advice for adults who are not routinely active is to undertake 30 min of moderate-intensity activity on at least 5 days of the week. This can be undertaken in bouts of 10 min. For active individuals, additional aerobic exercise of vigorous intensity is recommended for 20–30 min three times a week. Exercise per se probably has little effect on TC levels in the absence of a reduction in body weight, body fat or dietary fat. Perhaps the most important effect of regular exercise is to raise levels of HDL-C in a dose-dependent manner according to energy expenditure.

Overall, comprehensive dietary and lifestyle changes (stopping smoking, stress management training and moderate exercise) can bring about regression of coronary atherosclerosis. Unfortunately, many find it difficult to attain or sustain the necessary changes. In others, dietary and lifestyle changes alone will never be adequate or will not bring about the necessary improvement in lipid profile quickly enough. As a consequence, the use of lipid-lowering drugs is widespread.

Drugs

If an individual is found to be at risk of CVD (primary prevention) it may be appropriate to give a trial of dietary and lifestyle changes for 3–6 months. This rarely achieves the required effect on the lipid profile and drug therapy is required. This must not, however, negate a sustained effort by the individual to make appropriate dietary and lifestyle adjustments. In an individual requiring treatment for secondary prevention, a delay of several months in starting treatment is not appropriate and treatment will normally be commenced immediately with a lipid-lowering agent.

Primary prevention

In primary prevention, dyslipidaemia should not be treated in isolation and management must be embarked upon with clear goals. In addition to lifestyle advice, this will not only address management of dyslipidaemia but will also seek to optimise use of antihypertensive agents, other cardiovascular protective therapies and achieve tight blood glucose control as appropriate. In patients without evidence of arterial disease, treatment must be considered if the risk of CVD is >20% or more over 10 years. Although some dispute the benefit of statins in primary prevention (Kausik et al., 2010), treatment will normally include:

• a lipid-lowering agent such as simvastatin 40 mg/day (or alternative) but no treatment targets are set

• personalised information on modifiable risk factors including physical activity, diet, alcohol intake, weight and tight control of diabetes

• advice to stop smoking

• advice and treatment to achieve blood pressure below 140 mmHg systolic and 90 mmHg diastolic.

Some also consider an isolated raised TC:HDL ratio >6.5 warrants treatment regardless of the risk assessment outcome, but this approach has received little support in national treatment guidelines.

Secondary prevention

In individuals diagnosed with CVD or other occlusive arterial disease, treatment should include:

• a lipid-lowering agent to lower TC aiming towards a TC <4 mmol/L and LDL-C <2 mmol/L

• advice to stop smoking

• personalised information on modifiable risk factors including physical activity, diet, alcohol intake, weight and diabetes

• advice and treatment to achieve blood pressure at least below 140 mmHg systolic and 90 mmHg diastolic

• tight control of blood pressure and glucose in those with diabetes

• low-dose aspirin (75 mg daily)

• ACE inhibitors especially for those with left ventricular dysfunction, heart failure, diabetes, hypertension or nephropathy

• β-blocker for those who have had a myocardial infarction and in those with heart failure

• warfarin (or aspirin) for those with atrial fibrillation and additional stroke risk factors.

Lipid-lowering therapy

There are five main classes of lipid-lowering agents available:

• Statins

• Fibrates

• Bile acid binding agents

• Cholesterol absorption inhibitors

• Nicotinic acid and derivatives.

Agents such as soluble fibre and fish oils have also been used to reduce lipid levels. A number of new agents are also under investigation for their novel effect on different parts of the cholesterol biosynthesis pathway (Table 24.3).

Table 24.3 Mechanism of lipid-lowering agents under investigation

Drug group	Mechanism
Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors	ACAT esterifies excess intracellular cholesterol. Inhibition of ACAT prevents transport of cholesterol into the arterial wall and thereby prevents atheroma developing. Lowers VLDL-C and triglycerides
Bile acid sequestrants	Related to first-generation resins but improved patient tolerance. Sequester bile acids and prevent re-absorption. Reduce LDL-C while HDL-C and triglycerides increase or remain unchanged
Cholesteryl ester transfer protein (CETP) inhibitors	CETP is responsible for the transfer of cholesteryl ester from HDL-C to the atherogenic LDL-C and VLDL-C
Lipoprotein lipase (LPL) activity enhancers	LPL is responsible for VLDL-C catabolism with subsequent loss of triglycerides and increase in HDL-C. Protects against atherosclerosis
Microsomal triglyceride transfer protein (MTP) inhibitors	Inhibit absorption of lipid and reduce hepatic secretion of lipoproteins, thereby reducing atherosclerotic plaque formation
Peroxisome proliferator-activated receptor (PPAR) activators	PPAR-α and -γ regulate the expression of genes involved in lipid metabolism and inhibit atherosclerotic plaque rupture. They reduce entry of cholesterol into cells, lower LDL-C and triglycerides, and increase HDL-C
Squalene synthase inhibitors	Inhibit squalene synthase, upregulate LDL receptor activity and enhance removal of LDL-C

The choice of lipid-lowering agent depends on the underlying dyslipidaemia, the response required and patient acceptability. The various groups of drugs available have different mechanisms of action and variable efficacy depending on the lipid profile of an individual. Statins are currently the drugs of choice in the majority of patients with dyslipidaemia due to the overwhelming evidence that treatment with these agents reduces cardiovascular events.

Statins

The discovery of a class of drugs, the statins, which selectively inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) was a significant advance in the treatment of dyslipidaemia. Their primary site of action is the inhibition of HMG-CoA reductase in the liver and the subsequent inhibition of the formation of mevalonic acid, the rate-limiting step in the biosynthesis of cholesterol. This results in a reduction in intracellular levels of cholesterol, an increase in expression of hepatic LDL receptor, and enhanced receptor-mediated catabolism and clearance of LDL-C from serum. Production of VLDL-C, the precursor of LDL-C, is also reduced. The overall effect is a reduction in TC, LDL-C, VLDL-C and triglycerides with an increase in HDL-C. The reduction in LDL-C occurs in a dose-dependent manner, with a lesser and dose-independent effect on VLDL-C and triglycerides.

Simvastatin was the first member of the group to be marketed in the UK and it was followed by pravastatin, fluvastatin, atorvastatin, cerivastatin and rosuvastatin. Cerivastatin was withdrawn from the market in 2001 due to an observed increased risk of fatal rhabdomyolysis whilst rosuvastatin, the newest member of the group, was launched in March 2003. Lovastatin has been available in the USA for many years whilst pitavastatin, likewise, has been available in Japan since 2003 with little attempt, until recently, to market in the UK.

The efficacy of statins has been demonstrated in a number of landmark, randomised placebo-controlled trials. A greater absolute benefit was seen in those trials that involved established CVD, that is, secondary prevention studies, compared to those that involved individuals without established CVD, that is, primary prevention studies. Statins are currently the lipid-lowering agents of choice in both primary and secondary prevention of CVD.

There is much debate around the statin of choice. Simvastatin is currently the preferred agent because of its relatively low cost, safety profile and evidence of efficacy (see Table 24.4). Perhaps more important is the need to identify patients who need treatment, ensure they receive an appropriate, effective dose of a statin and adhere to treatment. Despite overwhelming evidence of benefit, effectiveness is frequently compromised by poor adherence with up to 50% of patients discontinuing treatment within 12 months and 75% within 3 years. Patient factors that influence this include perception of risk, side effects of medication, expected treatment duration and socio-demographic factors.

Table 24.4 Typical recommendations for use of lipid-lowering agents (UKMI, 2009) (LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; TC, total cholesterol)

Rosuvastatin is the most potent of the statins with evidence of impact on morbidity and mortality. It is normally reserved for those individuals that have had an inadequate response to their first-line statin. There remain concerns about its safety profile, and rhabdomyolysis in particular, when used at the higher dose of 40 mg/day. It is recommended that this dose should only be used in individuals with severe FH and at high cardiovascular risk under specialist supervision. In patients of Asian origin (Japanese, Chinese, Filipino, Vietnamese, Korean and Indian), the maximum dose should not exceed 20 mg/day because of their increased predisposition to myopathy and rhabdomyolysis.

All the statins require the presence of LDL receptors for their optimum clinical effect, and consequently they are less effective in patients with heterozygous FH because of the reduced number of LDL receptors. However, even in the homozygous patient where there are no LDL receptors they can bring about some reduction of serum cholesterol, although the mechanism is unclear.

Adverse effects

Many side effects appear mild and transient. The commonest include gastro-intestinal symptoms, altered liver function tests and muscle aches. Less common are elevation of liver transaminase levels in excess of three times the upper limit of normal, hepatitis, rash, headache, insomnia, nightmares, vivid dreams and difficulty concentrating.

Myopathy (unexplained muscle soreness or weakness) leading to myoglobulinuria secondary to rhabdomyolysis is also a rare but serious potential adverse effect of all the statins that can occur at any dose. The risk of myopathy is increased:

• when there are underlying muscle disorders, a family history of muscle disorders, renal impairment, untreated hypothyroidism, alcohol abuse, or the recipient is aged over 65 years or female

• where statins are co-prescribed with other lipid-lowering drugs, for example, fibrates, nicotinic acid

• when there is a past history of myopathy with another lipid-lowering drug or statin

• where there is co-prescription of simvastatin or atorvastatin with drugs that inhibit CYP3A4.

The statins are a heterogeneous group metabolised by different CYP450 isoenzymes. Simvastatin, atorvastatin and lovastatin are metabolised by CYP3A4, fluvastatin is metabolised by CYP 2C9, and pravastatin and rosuvastatin are eliminated by other metabolic routes and less subject to interactions with CYP450 isoenzymes than other members of the family. Nevertheless, caution is still required as a 5- to 23-fold increase in pravastatin bioavailability has been reported with ciclosporin. Simvastatin and atorvastatin do not alter the activity of CYP3A4 themselves, but their serum levels are increased by known inhibitors of CYP3A4 (Table 24.5). Advice has been published for the prescribing of simvastatin and atorvastatin with inhibitors of CYP3A4 (Table 24.6).

Table 24.5 Examples of drug interactions involving statins and the cytochrome P450 enzyme pathway

CYP 450 isoenzyme	Inducers	Inhibitors
CYP3A4
Atorvastin	Phenytoin	Ketoconazole
Lovastatin	Barbiturate	Itraconazole
Simvastatin	Rifampicin	Fluconazole
	Dexamethasone	Erythromycin
	Cyclophosphamide	Clarithromycin
	CarbamazepineOmeprazole	Tricyclic antidepressants
		Nefazodone
		Venlafaxine
		Fluoxetine
		Sertraline
		Ciclosporin
		Tacrolimus
		Diltiazem
		Verapamil
		Protease inhibitors
		Midazolam
		Corticosteroids
		Grapefruit juice
		Tamoxifen
		Amiodarone
CYP2C9
Fluvastatin	Rifampicin	Ketoconazole
	Phenobarbitone	Fluconazole
	Phenytoin	Sulfaphenazole

Table 24.6 Advice for prescribing simvastatin or atorvastatin with inhibitors of CYP3A4

Avoid simvastatin with potent inhibitors of CYP3A4:	HIV protease inhibitors, azole, antifungals, erythromycin, clarithromycin, telithromycin
Do not exceed the following doses:	Simvastatin 10 mg daily with ciclosporin, gemfibrozil or niacin (>1 g/day)
	Simvastatin 20 mg daily with verapamil or amiodarone
	Simvastatin 40 mg daily with diltiazem
Avoid grapefruit juice when taking simvastatin
Atorvastatin to be used cautiously with CYP3A4 inhibitors:	Additional care required at high doses of atorvastatin; avoid drinking large quantities of grapefruit juice

Pleiotropic properties

While the effect of statins on the lipid profile contributes to their beneficial outcome in reducing morbidity and mortality from CVD, other mechanisms, known as pleiotropic effects, may also play a part. These effects include plaque stabilisation, inhibition of thrombus formation, reduced serum viscosity and anti-inflammatory and antioxidant activity. These pleiotropic properties, that is, cholesterol-independent effects, are far reaching and reveal a clinical impact beyond a process of reducing TC. For example, lowering TC produces only modest reductions of a fixed, atherosclerotic, luminal stenosis but results in a qualitative change of the plaque and helps stabilise it. This protects the plaque from rupturing and triggering further coronary events.

Inflammation is thought to play a prominent part in the development of atherosclerosis and increased levels of C-reactive protein have been used to identify individuals at risk of plaque rupture and consequent myocardial infarction and stroke. Statins have been shown to reduce the levels of C-reactive protein in several trials.

An important aspect of vascular endothelium dysfunction is the impaired synthesis, release and activity of endothelial-derived nitric oxide, an important and early marker of atherosclerosis. After the administration of a statin, one of the earliest effects observed (within 3 days) is an increased endothelial nitric oxide release, thereby mediating an improvement in vasodilation of the endothelium.

For some while it has been thought that part of the beneficial effect of statins on CVD could be attributed to an effect on blood coagulation. It is now evident that statins, amongst their many actions, decrease platelet activation and activity, reduce prothrombin activation, factor Va generation, fibrinogen cleavage and factor XIII activation, and increase factor Va inactivation.

Over-the-counter sale

Low-dose (10 mg) simvastatin can be purchased from community pharmacies in the UK to treat individuals at moderate cardiovascular risk. Men aged 55–70 years with or without risk factors and men aged 45–54 years or women aged 55–70 years with at least one risk factor (smoker, obese, family history of premature CHD or of South Asian origin) are eligible for treatment. Simvastatin cannot be sold to individuals who have CVD, diabetes or familial dyslipidaemia or are taking lipid-lowering agents or medication that may interact with simvastatin. The rationale for over-the-counter sale is to reduce the risk of a first major coronary event in adults at moderate risk but sales have been low. Moreover, the evidence base to support the use of 10 mg simvastatin and achieve long-term cardiovascular benefit is limited.

Patient counselling

In patients receiving a statin, a once-daily regimen involving an evening dose is often preferred. Several of the statins (fluvastatin, pravastatin, simvastatin) are claimed to be more effective when given as a single dose in the evening compared to a similar dose administered in the morning. This has been attributed to the fact that cholesterol biosynthesis reaches peak activity at night. However, atorvastatin and rosuvastatin may be taken in the morning or evening with similar efficacy. A reduction in TC and LDL-C is usually seen with all statins within 2 weeks, with a maximum response occurring by week 4 and maintained thereafter during continued therapy.

Fibrates

Members of this group include bezafibrate, ciprofibrate, fenofibrate and gemfibrozil. They are thought to act by binding to peroxisome proliferator-activated receptor α (PPAR-α) on hepatocytes. This then leads to changes in the expression of genes involved in lipoprotein metabolism. Consequently, fibrates reduce triglyceride and, to a lesser extent, LDL-C levels while increasing HDL-C. Fibrates take 2–5 days to have a measurable effect on VLDL-C, with their optimum effect present after 4 weeks. In addition to their effects on serum lipids and lipoproteins, the fibrates may also have a beneficial effect on the fibrinolytic and clotting mechanisms. The fibrates also produce an improvement in glucose tolerance, although bezafibrate probably has the most marked effect.

In the patient with elevated triglycerides and gout, only fenofibrate has been reported to have a sustained uricosuric effect on chronic administration. Overall, there appears little to differentiate members of the group with regard to their effect on the lipid profile, with fenofibrate and ciprofibrate being the most potent members of the group.

In patients with diabetes, the typical picture of dyslipidaemia is one of raised triglycerides, reduced HDL-C and near normal LDL-C. Despite the effect of fibrates to reduce triglycerides and increase HDL-C, statins are first-line lipid-lowering agent in most guidelines because of a lack of clear evidence that fibrates prevent CVD in diabetes. It was hoped that a 5-year study of fenofibrate in individuals with type 2 diabetes (FIELD Investigators, 2005) would clarify the issue. However, in the final analysis the results provided little convincing evidence to change from recommending a statin, although they did confirm the safety of using a combination of a statin and fenofibrate. In contrast, gemfibrozil should not be used with a statin.

Overall, fibrates should not be used first line to reduce lipid levels in either primary or secondary prevention. Fibrates can be used first line in patients with isolated severe hypertriglyceridaemia. In individuals with mixed hyperlipidaemia, fibrates may be considered when a statin or other agent is contraindicated or not tolerated.

Adverse effects

Overall, the side effects of fibrates are mild and vary between members of the group. Their apparent propensity to increase the cholesterol saturation index of bile renders them unsuitable for patients with gallbladder disease. Gastro-intestinal symptoms such as nausea, diarrhoea and abdominal pain are common but transient, and often resolve after a few days of treatment. Myositis has been described, and is associated with muscle pain, unusual tiredness or weakness. The mechanism is unclear but it is thought fibrates may have a direct toxic action on muscle cells in susceptible individuals.

Fibrates have been implicated in a number of drug interactions (Table 24.7), of which two in particular are potentially serious. Fibrates are known to significantly increase the effect of anticoagulants, while concurrent use with a statin is associated with an increased risk of myositis and, rarely, rhabdomyolysis. Concurrent use of cerivastatin and gemfibrozil was noted to cause rhabdomyolysis and this contributed to the withdrawal of cerivastatin from clinical use in 2001.

Table 24.7 Typical drug interactions involving bile acid binding agents and fibrates ^a

Drug group	Interacting drug	Comment
Bile acid binding agents Colestyramine/colestipol		All medication should be taken 1 h before or at least 4 h after colestyramine/colestipol to reduce absorption caused by binding in the gut
	Acarbose	Hypoglycaemia enhanced by colestyramine
	Digoxin	Absorption reduced
	Diuretics	Absorption reduced
	Levothyroxine	Absorption reduced
	Mycophenolate mofetil	Absorption reduced
	Paracetamol	Absorption reduced
	Raloxifene	Absorption reduced
	Valproate	Absorption reduced
	Statins	Absorption reduced
	Vancomycin	Effect of oral vancomycin antagonised by colestyramine
	Warfarin	Increased anticoagulant effect due to depletion of vitamin K or reduced anticoagulant effect due to binding or warfarin in gut
Colesevelam		All medication should be taken at least 4 h before or 4 h after colesevelam to reduce absorption caused by binding in the gut
	Ciclosporin	Absorption reduced
	Digoxin	Absorption unchanged
	Glyburide	Absorption reduced
	Levothyroxine	Absorption reduced
	Oral contraceptive	Absorption reduced
	Statins	Absorption unchanged
	Valproate	Absorption unchanged
	Warfarin	Absorption unchanged. Increased anticoagulant possible due to depletion of vitamin K
Fibrates	Antidiabetic agents	Improvement in glucose tolerance
	Ciclosporin	Increased risk of renal impairment
	Colestyramine/colestipol	Reduced bioavailability of fibrate if taken concomitantly
	Statin	Increased risk of myopathy
	Warfarin	Increased anticoagulant effect

a Absorption studies involve concomitant administration.

Bile acid binding agents

The three members of this group in current use are colestyramine, colestipol and colesevelam. Both colestyramine and colestipol were formerly considered first-line agents in the management of patients with FH but now have limited use. Colesevalam is the most recent of the bile acid binding agents to receive marketing authorisation (in 2004) and consequently has never had a first-line indication. Each of the bile acid binding agents reduce TC and increase triglyceride levels.

Following oral administration, neither colestyramine, colestipol nor colesevelam are absorbed from the gut. They bind bile acids in the intestine, prevent re-absorption and produce an insoluble complex that is excreted in the faeces. The depletion of bile acids results in an increase in hepatic synthesis of bile acids from cholesterol. The depletion of hepatic cholesterol upregulates the hepatic enzyme 7-α-hydoxylase which increases the conversion of cholesterol to bile acids. This increases LDL receptor activity in the liver and removes LDL-C from the blood. Hepatic VLDL-C synthesis also increases and it is this which accounts for the raised serum triglycerides.

Colestyramine has a starting dose of one 4 g sachet twice a day. Over a 3- to 4-week period the dose should normally be built up to 12–24 g daily taken in water or a suitable liquid as a single dose, or up to four divided doses each day. Occasionally, 36 g a day may be required, although the benefits of increasing the dose above 16 g a day are offset by gastro-intestinal disturbances and poor patient adherence.

Colestipol is also available in a granular formulation and can be mixed with an appropriate liquid at a dose of 5 g once or twice daily. This dose can be increased every 1–2 months to a maximum of 30 g in a single- or twice-daily regimen.

Colesevalam is up to six times as potent as the other bile acid binding agents, probably because of a greater binding to glycocholic acid. Whether this translates into better clinical outcomes or more, or less, problems with drugs administered concurrently is unclear. Colesevalam is administered as a 625-mg tablet to a maximum dose of 4.375 g/day (7 tablets). There is limited evidence to suggest it may achieve a higher adherence than colestyramine or colestipol. It can be taken as a single- or twice-daily regimen.

Adverse effects

With all three agents, side effects are more likely to occur with high doses and in patients aged over 60 years. Bloating, flatulence, heartburn and constipation are common complaints. Constipation is the major subjective side effect, and although usually mild and transient, it may be severe.

Colestyramine, colestipol and colesevelam are known to interact with many drugs primarily by interfering with absorption (Table 24.7). Whether these absorption-type interactions are qualitatively and quantitatively similar between the different agents is unclear and the picture is confused when the absorption of a given drug is known to interact with one bile acid binding agent but has not been tested with other members of the group.

Long-term use of bile acid binding agents may also interfere with the absorption of fat soluble vitamins and supplementation with vitamins A, D and K is recommended.