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.