REDUCING CARDIOVASCULAR RISK

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CHAPTER 4 REDUCING CARDIOVASCULAR RISK

Understanding cardiovascular risk 86
Raised blood pressure 91
Dyslipidaemia 109
Obesity 121
Reducing platelet adhesiveness 125
Other risk factors 127
An “Alternative” view of targets 129

OVERVIEW

Since the origin of much diabetes-related morbidity and mortality is vascular, reducing cardiovascular risk is an important aim in the management of type 2 diabetes. Following a preliminary discussion of cardiovascular risk, each of the main treatable cardiovascular risk factors (rationale, assessment, targets and interventions) is reviewed.

There is strong evidence to support the efficacy of modifying cardiovascular risk factors to prevent or delay the onset and development of cardiovascular disease (CVD). Whilst careful attention needs to be paid to the assessment and modification of individual risk factors, for any “high-risk” individual (which includes all people with type 2 diabetes), the greatest benefit will come from attacking aggressively all relevant risk factors, irrespective of the baseline, and not from an excessive focus on one factor to the possible exclusion of others: in other words, a broadly based approach. This approach is followed in the most recent guidelines from the Joint British Societies (Wood et al 2005) and the American Diabetes Association (ADA 2007). Readers may also find it useful to refer to a 2006 review by Marshall and Flyvbjerg published in the BMJ (Marshall & Flyvbjerg 2006).

The section ends with a brief survey of the important non-treatable risk factors and an “alternative” view of targets.

UNDERSTANDING CARDIOVASCULAR RISK

The incidence of atheromatous disease is much greater in the diabetic than general population. It is the devastating effects of this atheromatous disease that require effective and aggressive interventions, aimed at minimising future mortality and morbidity. There is considerable evidence to support an approach that assumes, for type 2 diabetics, that prevention needs to be secondary (CVD is present) rather than primary (CVD is absent), even in those without any manifestation or evidence of vascular disease. To prevent future CVD, asymptomatic patients may have to undergo potentially unpleasant or even dangerous treatment. Such interventions are more likely to be appropriate and justifiable if both the concept of risk and the factors contributing to increased risk are understood.

DEFINITIONS

Risk can be defined as the probability or expected frequency of harmful effects (due to a biological agent) occurring over a defined period of time.

Although risk can be expressed in different ways, it is useful to understand the difference between absolute and relative risk:

• The absolute risk of a particular event occurring over a specified period of time is usually expressed either as a percentage (a %) or a ratio (b incidences per a defined population size).
• Relative risk is usually expressed as a particular event being c % or d times more or less likely to occur in a defined population than in a compared population over a specified period of time.

Where the absolute risks of two compared events or interventions are very low, small differences of risk may be relatively “large”. For example, if a treatment reduces the risk of an adverse event occurring from 2% to 1%, then the absolute risk reduction is an unimpressive 1%, but the relative risk reduction is a staggering 50%: this fact does not escape copywriters in advertising.

The results of a risk–benefit analysis of an intervention are often presented now as “number needed to treat” (NNT). NNT is the reciprocal of absolute risk reduction. If a treatment reduces absolute risk by 1 in 10 or 10%, then the NNT of that treatment is 10. NNT is a better, much less misleading, representation of a treatment’s effectiveness than relative risk reduction.

Although the term vascular can refer to the whole of the circulatory system, it is sometimes used to refer to a part of the system. In order to be precise, the term vascular should be qualified in such circumstances to indicate which part of the circulation is being described. When considering the long-term vascular complications of diabetes, it is useful to subdivide these according to vessel size into:

• Macrovascular – coronary heart disease, cerebrovascular disease and peripheral arterial disease

and

• Microvascular – retinopathy, nephropathy and neuropathy.

Discussions about vascular risk relate mostly to macrovascular disease, and the distinction needs to be made between:

• Coronary heart disease (CHD) risk, which refers to the probability of developing CHD

and

• CVD risk, which refers to the probability of developing all forms of macrovascular or cardiovascular disease: a combination of the risks for developing coronary heart disease, cerebrovascular disease and peripheral arterial disease.

These concepts are relevant when quantifying and describing risk.

WHAT FACTORS ARE ASSOCIATED WITH CARDIOVASCULARRISK IN PATIENTS WITH DIABETES?

Different parameters, characteristics or factors contribute, both individually and collectively, to the overall cardiovascular risk in any single individual, particularly one with diabetes. Not all factors affect cardiovascular risk equally, nor are all of them independent or susceptible to modification.

Cardiovascular risk factors can be divided into nonmodifiable and modifiable (see Table 4.1). Only modifiable factors can respond to intervention. However, some nonmodifiable risk factors are needed to calculate global cardiovascular risk and, if present, can serve as a prompt to help identify those individuals in whom this risk should be assessed and “tackled”, particularly in people normally considered to be at lower risk, such as those without diabetes.

TABLE 4.1 Cardiovascular risk factors and markers in people with diabetes mellitus

Nonmodifiable risk factors Modifiable risk factors
Age Smoking status
Gender Raised blood pressure
Ethnic group Dyslipidaemia
Family history Lack of physical activity
Poor diet
Obesity
Poor glycaemic control
Excess alcohol
Elevated fibrinogen
Cardiomyopathy
Raised inflammatory markers
Microalbuminuria
Hyperhomocysteinaemia

Of the modifiable risk factors for CVD, smoking, raised blood pressure and dylipidaemia are generally regarded as the most important, both for their contribution to overall cardiovascular risk and for the resultant reduction of that risk when “corrected”.

Although individual risk factors may have an independent effect upon the global cardiovascular risk, their overall effect upon cardiovascular risk is often more than additive, with different risk factors combining “at times … to become permissive for harm or create harm greater than that effected by simple addition” (Simmons 2002). In 1993 the MRFIT study demonstrated that the greater than additive adverse effect of a collection of risk factors is especially marked in diabetes, where the increase in risk attributed to any single or combination of risk factors is doubled when compared to a nondiabetic population (Stamler et al 1993). There are still gaps in the evidence base. Matters become more complicated when evaluating the efficacy of various interventions.

It is important to move away from focussing on a single risk factor to the exclusion of others. There are recognised situations or scenarios where risk factors are clustered, e.g. metabolic syndrome. Interventions that concentrate upon modifying a single risk factor may be much less effective in reducing cardiovascular risk than in adopting a multi-factorial approach.

SHOULD CARDIOVASCULAR RISK BE ESTIMATED IN PATIENTS WITH DIABETES?

The prediction of cardiovascular risk grew out of the need to identify a threshold beyond which interventions, in particular the modification of lipid profiles, could be “justified”. Risk prediction tools have been developed to guide treatment decisions (i.e. whether treatment should be initiated and monitoring method), since an intuitive estimate of cardiovascular risk is unlikely to be accurate and the combination of risk factors and their interdependent relationships makes it difficult to calculate the risk of a cardiovascular event occurring, either on an additive or on a piecemeal basis. By identifying those patients in whom absolute risk is greatest, clinicians (and managers) should be more confident that an appropriate absolute risk-lowering intervention will be both more clinically and more cost effective. Such information is extremely important in any health-care system where resources are finite and need to be used in those most likely to benefit from intervention.

However, if all diabetics are regarded as being at “high” risk of developing CVD, then it can be argued that the only benefit of risk prediction in these individuals is to monitor the effect of treatment, since the modification of all treatable cardiovascular risk factors can be justified in virtually every patient with diabetes.

CARDIOVASCULAR RISK MODELS

Cardiovascular risk models have used data from the observation of a population cohort over a period of time, based upon the recording of risk factors and of CVD events. The usefulness of a risk model depends upon whether the calculation takes account of all important contributory risk factors and whether the important demographics of the individual being assessed are adequately represented in the population used in the model.

Risk prediction tables have been used in the UK since the mid 1990s. Initially for primary prevention, the Department of Health recommended a threshold of annual risk for a CHD event of 3%, now reduced to 1.5%, above which the prescription of expensive drugs could be justified. The latest Joint British Societies’ guidelines, consistent with the aim of preventing CVD events, have a threshold of annual risk for a CVD event of 2% (Wood et al 2005).

Many risk models have derived their data from the Framingham Heart Study. These models predict risk for CVD, CHD or stroke, either over a period of 5 or 10 years or annualised. The calculations included age, gender, smoking status, blood pressure (some include only systolic blood pressure), lipid profile (total cholesterol and high-density lipoprotein), the presence or absence of diabetes, and the presence or absence of left ventricular hypertrophy. Several other geographical and time-based cohorts have been used to generate risk models. Ideally, the risk calculator should be incorporated into the software being used during the consultation. A current favourite risk model is the updated New Zealand Calculator (derived from Framingham), as it incorporates decision support and can be used to inform patients of the effectiveness of modifying risk factors (New Zealand Guidelines Group 2003).

All of these models have several flaws, listed in Table 4.2, and any calculation using models derived from Framingham data or other population cohorts should be applied with caution. The main limitations are:

1. If risk is “annualised”, i.e. expressed as a percentage likelihood of an adverse event occurring in one or a defined number of years, the estimation may be incorrect. The rate at which the incidence of CVD increases with age is incremental rather than linear, making it difficult to determine where exactly to place an individual within the timescale of a risk engine, particularly as the duration of exposure to a risk marker has to be assumed and may be inaccurate. In the Framingham calculation, there is little difference in the annualised age-corrected risk between years 1 and 10.
2. Since the Framingham cohort only recruited a relatively small number of diabetics, it is less valuable for evaluating risk in this population.

TABLE 4.2 Potential drawbacks of cardiovascular risk prediction tools

Applicable to both diabetic and nondiabetic populations Applicable to a diabetic population
The use of shorter fixed time spans, as opposed to long-term or lifetime Under-representation of diabetics in the study populations, leading to a smaller database upon which to base calculations of risk
Annualised risk does not reflect the incremental increased incidence of CVD with age While risk models regard diabetes as a categorical variable, they ignore the level of glycaemia, which is probably an important predictor of CVD and CHD in patients with type 2 diabetes (Turner et al 1998)
Failure to include all the relevant risk factors contributing to cardiovascular risk Failure to include important markers or factors associated with increased cardiovascular risk in diabetics, such as microalbuminuria and raised serum triglycerides
The lack of valid data for certain ethnic groups  
Failure to take into consideration the confounding effect of modern treatments  
Different risk engines will give different risk predictions with the same data  

The UKPDS database was used to produce a diabetes-specific risk engine (Stevens et al 2001 – also available online: http://www.dtu.ox.ac.uk) to predict annual CHD risk (defined as fatal or nonfatal MI or sudden death). The calculation incorporates HbA1c, systolic blood pressure, TC:HDL-C ratio, age, sex, ethnic group, smoking status and time elapsed since diabetes was diagnosed. The engine can also report the different levels of risk for CHD, PVD and cerebrovascular disease. Unlike other databases, the UKPDS database is based upon an interventional study.

However, the UKPDS database and risk engine do have the following drawbacks:

• The risk engine has only been validated in a type 2 diabetes population
• The calculation does not include microalbuminuria, family history, triglycerides or ECG findings
• The effect of aspirin, other anti-platelet agents and smoking cessation were not stated.

The UKPDS risk engine is a more “refined” tool to predict cardiovascular risk in diabetics without evident CVD. However, despite “imperfections”, using one of the models derived from the Framingham data is currently the best way to estimate cardiovascular risk in untreated Northern European patients, provided that caution is used when applying the actual results. To produce a more accurate figure in patients of South Asian ethnicity or with a first-degree relative who suffered a premature CVD event, clinicians should consider multiplying the result of a Framingham calculation by 1.5 (if both factors are present, the result could be doubled). Although crude, this manoeuvre may partly counteract two drawbacks of a Framingham-derived model.

NICE intends to advise on cardiovascular risk assessment, as part of its imminent guidance on lipids (to be issued in December 2007, at time of writing).

AN APPROACH TO MODIFYING CARDIOVASCULAR RISK

Having assessed the level of cardiovascular risk in an individual and then set targets for modifying the factors that contribute to this risk, it is now appropriate to consider which interventions are most likely to achieve this risk reduction. Before initiating any treatment, a careful balancing of the relative benefits and risks for the patient needs to be made. Ideally, the approach to reducing cardiovascular risk should be “multi-factorial”: the gain to the patient is minimised if any important modifiable factor is ignored. This approach can make interpreting research evidence more difficult, since most studies are designed to evaluate interventions that modify only one factor. The differences between two interventions addressing a risk factor may be less if other risk factors are being simultaneously treated.

The recently published Joint British Societies’ guidelines on the prevention of cardiovascular disease in practice provide a useful overview of assessment and management (Wood et al 2005).

RAISED BLOOD PRESSURE

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RATIONALE

The presence of both raised blood pressure and diabetes mellitus in the same individual is a synergistic and potentially deadly combination. There is strong evidence to demonstrate that raised arterial pressure is a significant, and potentially treatable, contributor to the development of major diabetes complications, both microvascular (nephropathy, retinopathy) and macrovascular (CHD, major stroke). Much of this evidence comes from several large trials involving type 2 diabetics, starting with the UKPDS (Stratton et al 2000). Lowering blood pressure in type 2 diabetics reduces the risk of deaths and complications related to diabetes (UKPDS 1998a).

Raised blood pressure is more prevalent in the type 2 diabetic population than in the general population (SIGN 1997). At a cellular level, hypertension is associated with increased sodium retention and increased pressor responsiveness in diabetics compared to nondiabetics (Dawson et al 1993). In adult diabetics, other atherogenic risk factors (dyslipidaemia, elevated fibrinogen and left ventricular hypertrophy) are also more prevalent.

TARGETS

Neither research evidence nor expert consensus has found a level of blood pressure below which treatment does not confer benefit. The target blood pressure levels currently recommended by several learned bodies, summarised in Table 4.3, do not concur, but the overall trend has been downwards over recent years. If target organ damage is present, interventions should aim to achieve and maintain even lower target blood pressure levels. However, less strict targets may be appropriate in elderly or seriously ill patients with limited life expectancy.

TABLE 4.3 Target blood pressure levels for diabetics recommended by different organisations

Blood pressure target (mmHg) Learned body/organisation Date published
145/85 New GP Contract 2003, reviewed 2006
140/90 NICE (North of England 2004) August 2004
140/90 NICE (NICE 2006a) June 2006
140/80 SIGN (SIGN 2001) November 2001
140/80 National Clinical Guidelines for Type 2 Diabetes (Hutchinson et al 2002) October 2002
140/80 UKPDS 36 (Adler et al 2000) 2000
130/80 (optimal) British Hypertension Society Guidelines 2004
140/80 (acceptable) BHS-IV (Williams 2004)  
130/80 American Diabetes Association (ADA 2007) January 2006
130/80 JBS 2 (Wood et al 2005) December 2005

Reaching such tight targets may not be possible in or acceptable to some type 2 diabetics, despite or because of the concurrent prescribing of several agents. However, small reductions of blood pressure, maintained over a few years, can significantly reduce cardiovascular risk in all diabetics: many studies achieved reductions of the order of 10 mmHg systolic and 5 mmHg diastolic. Rather than aiming always for a fixed endpoint, an individualised target based upon the starting level of blood pressure and an achievable reduction may be more realistic and appropriate for many patients. Professionals should bear in mind that, from the patient’s perspective, lowering blood pressure is less “meaningful” than reducing the risk of suffering a real event (such as MI, stroke or diabetic complication).

EVALUATION

Measurement of blood pressure

It is being increasingly recognised that the measurement of blood pressure need not be restricted to the encounter with a health-care professional:

1. Many sphygmomanometers are available for self use.
2. Ambulatory blood pressure devices can be purchased by and used in primary care.

However, routine use of automated ambulatory blood pressure monitoring or home monitoring devices in primary care is not currently recommended by NICE (NICE 2006a): further research is needed to determine their precise role.

A variety of automated sphygmomanometers are now available. Before purchasing any model, the buyer is advised to enquire whether the device has passed independent validation using the protocols of the British Hypertension Society (BHS) and the Association for the Advancement of Medical Instrumentation Standard (AAMI) (O’Brien et al 2001). Additional useful advice may be available from the local hospital’s medical physics department. Further independent evaluation of the available blood pressure measuring devices is being undertaken and may be published at some point in the future.

The use of mercury sphygmomanometers is still legal (the problems arise with safe disposal of mercury). When set up properly they can be as accurate as the best automated machine. Many aneroid sphygmomanometers lose accuracy when jolted.

Due to pressures of time and less than ideal ergonomics, many health professionals do not invariably measure a patient’s blood pressure correctly. Detailed authoritative guidance on how it should be done is given in Table 4.4, a counsel of perfection. To minimise inaccuracies, some key points to remember when measuring blood pressure include:

1. Use the correct-sized cuff.
2. Ensure the arm is supported, the patient is quiet and his legs are not crossed.
3. Arrhythmias render any blood pressure measurement less reliable.
4. Daytime ambulatory blood pressure values average 10/5 mmHg less than surgery measurements.
5. Readings can vary significantly between arms, time of day and different days.
6. Beware of the “white coat effect” (readings can be raised when taken by health-care professionals) (MHRA 2006).

TABLE 4.4 Guidelines for Blood Pressure Measurement

Blood pressure measurement: procedure
Measure sitting blood pressure routinely: standing blood pressure should be recorded at least once at the initial estimation
Try to standardise the procedure:

remove tight clothing
relaxed temperate setting, with the patient seated (ideally for at least 5 minutes prior to measurement)
position arm for measurement out-stretched, in line with mid-sternum, and supported at heart level
avoid talking during measurement
use a properly maintained, calibrated, and validated device

Correctly wrap a cuff containing an appropriately sized bladder around the upper arm and connect to a manometer. Cuffs should be marked to indicate the range of permissible arm circumferences; these marks should be easily seen when the cuff is being applied to an arm Palpate the brachial pulse in the antecubital fossa of that arm Rapidly inflate the cuff to 20 mmHg above the point where the brachial pulse disappears Deflate the cuff and note the pressure at which the pulse re-appears: the approximate systolic pressure Re-inflate the cuff to 20 mmHg above the point at which the brachial pulse disappears Using one hand, place the stethoscope over the brachial artery ensuring complete skin contact with no clothing in between
Slowly deflate the cuff at 2–3 mmHg per second listening for Korotkoff sounds. Read blood pressure to the nearest 2 mmHg:

Phase I: The first appearance of faint repetitive clear tapping sounds gradually increasing in intensity and lasting for at least two consecutive beats: note the systolic pressure
Phase II: A brief period may follow when the sounds soften or “swish”
Auscultatory gap: In some patients, the sounds may disappear altogether
Phase III: The return of sharper sounds becoming crisper for a short time
Phase IV: The distinct, abrupt muffling of sounds, becoming soft and blowing in quality
Phase V: The point at which all sounds disappear completely: note the diastolic pressure

When the sounds have disappeared, quickly deflate the cuff completely When possible, take readings at the beginning and end of consultations. Take the mean of at least two readings. More recordings are needed if marked differences between initial measurements are found

(from North of England 2004, O’Brien et al 2003, British Hypertension Society website)

Target organ damage

Any evidence of target organ damage should be sought. The “organs” to consider are the eyes (retinopathy), kidneys (proteinuria, renal impairment), heart (left ventricular hypertrophy) and feet (neuropathy, impaired circulation and/or foot ulcer).

Potential causes of hypertension

If there are any underlying causes of hypertension, is the lifestyle (diet, alcohol, smoking, lack of exercise) a contributory factor? Some types of medication can cause raised blood pressure, such as cold cures, hormone replacement therapy, oral corticosteroids, nonsteroidal anti-inflammatory drugs, and carbenoxolone. Examination occasionally reveals palpable kidneys (which could indicate polycystic kidneys or an adrenal mass), renal bruits (which may indicate renovascular disease) and delayed or absent femoral pulses (which occur in co-arctation of the aorta).

Family history

The family history should be checked for hypertension, vascular or renal disease, particularly in first-degree relatives (parents, siblings or children).

Investigations

In addition to routine diabetic investigations (eGFR, lipid profile, urinary albumin:creatinine ratio), requesting an ECG, an echocardiogram (if available) or a renal ultrasound may provide useful information. However, referral to a specialist may be indicated for further investigations to inform management, particularly when there are concerns or when treatment targets are not achieved.

INTERVENTIONS: OVERVIEW

The main aims here are to reduce the overall cardiovascular risk and prevent diabetes complications.

When is treatment indicated?

A single measurement is rarely sufficient to ascertain an individual’s “true” blood pressure level and, thus, to justify a decision on whether to treat. Repeated measurements need to be taken over a length of time (the 2006 NICE guidelines recommend at least two further separate readings). The duration of observation prior to a treatment decision depends upon how elevated the measurements are, and if target organ damage and/or any other vascular risk factors are present. If the measurements are elevated only slightly and there is no target organ damage in a “low-risk” individual, it is reasonable to observe over several months. If the measurements are elevated markedly or target organ damage is present in a “higher-risk” individual, a briefer duration of observation with earlier intervention is indicated.

If there is considerable variation between measurements or if there is the possibility of “white coat” hypertension, it may prove helpful to undertake 24-hour ambulatory blood-pressure monitoring, if available.

INTERVENTIONS: NONPHARMACOLOGICAL METHODS

Nonpharmacological methods of reducing blood pressure are worth undertaking. As for all diabetic patients, those with raised blood pressure should be urged to not smoke, restrict alcohol, reduce salt intake, take more exercise and eat healthily, aiming for weight loss if obese. Good glycaemic control reduces vascular risk.

INTERVENTIONS: PHARMACOLOGICAL METHODS

The huge range and quantity of blood-pressure-lowering drugs available mirrors that of blood glucose-lowering medication. Before discussing the individual drug classes, several key concepts need to be borne in mind:

• Apart from likely efficacy, a number of factors may influence which drug is chosen as first-line.
• In many patients, more than one drug will be required to gain and maintain adequate blood pressure control.
• The actual level of blood pressure achieved is as important as which class of drug is used.
• Blood pressure control should be achieved within the context of correcting all relevant modifiable cardiovascular risk factors.

In support of the Diabetes NSF, the National Clinical Guidelines for type 2 diabetes published its recommendations for the pharmacological management of raised blood pressure in 2002 (Hutchinson et al 2002). However, these have been superseded by the 2006 guidelines from NICE (NICE 2006a), and the 2005 JBS 2 guidance on the prevention of CVD. The Quality and Outcomes Framework of the GMS contract sets a unified threshold for intervention and target (see Appendix 3).

Blood pressure reviews

Blood pressure should be checked not only at the full periodic diabetes review, but also at the interim review (every 4–6 months). If there is an intervention, the interval between blood pressure reviews should be shorter, every 1–3 months, and any side effects monitored.

Referral

Referral is indicated if:

• An underlying cause of hypertension or if an abnormality on physical examination is found
• Blood pressure achieved with a suitable combination of drugs is still significantly above target
• Target organ damage (particularly kidneys) is present.

Drug classes for the treatment of raised blood pressure

Five classes of blood-pressure-lowering drugs have been shown to be effective in reducing cardiovascular mortality and morbidity in patients with type 2 diabetes and raised blood pressure:

1. Angiotensin converting enzyme (ACE) inhibitors
2. Angiotensin II receptor blockers (ARB)
3. Beta (β) blockers
4. Nondihydropyridine and long-acting dihydropyridine calcium channel blockers (CCB)
5. Thiazide and thiazide-like diuretics (Clinical Evidence online, ADA 2004).

Although some of the supporting evidence came from trials comparing treatments against placebo, more data are now available comparing different effective treatments or combinations. An overview of this evidence is found in Table 4.5. The trials cited below are referred to by their acronyms, with their full names given in Appendix 5. The indications, cautions and contraindications for the major classes of antihypertensive drugs are summarised in Table 4.6.

TABLE 4.5 Summary of studies of antihypertensive therapies in type 2 diabetes

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TABLE 4.6 Compelling and possible indications, contraindications and cautions for the major classes of antihypertensive drugs (Wood et al 2005)

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In addition, there are other drug classes of blood-pressure-lowering drugs that are sometimes used in patients with diabetes:

• alpha-1 adrenergic blockers
• potassium-retaining diuretics (spironolactone)
• other antihypertensive agents (the rest).

Further details of the names and dosages of different blood-pressure-lowering agents are given in Appendix 1 and in the BNF Section 2.

Angiotensin converting enzyme (ACE) inhibitors

This drug class blocks the conversion of angiotensin-I to angiotensin-II (a powerful vasoconstrictor and an indirect facilitator of the sympathetic nervous system) by inhibiting the angiotensin converting enzyme. This produces a reduction in angiotensin-II levels, leading to arteriolar and venous dilatation and a fall in blood pressure. The antihypertensive effect of ACE inhibitors is dose-related.

Angiotensin-II has other actions that are thought to be harmful to the cardiovascular system, contributing to the pathogenesis of large and small vessel structural changes in hypertension and other CVD (Luft 2001). ACE inhibitors also suppress aldosterone secretion, increase renal blood flow (producing natriuresis) and increase circulating levels of bradykinin, a vasodilating cytokine which can cause cough. ACE inhibitors have little effect upon heart rate or airways resistance. ACE inhibitors have no adverse effects upon lipid metabolism or glucose tolerance, but there have been reports that they may be less effective in Afro-Caribbean patients. Drugs in this class have generic names ending in “-pril”. They include captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, quinopril, ramipril and trandolapril.

Class side-effects include:

• Persistent cough in 10 to 20% of users (greater in East Asians)
• Angio-oedema in about 1% (threefold greater in Afro-Caribbeans)
• Taste disturbance
• Rash.

ACE inhibitors should not be prescribed to women who are likely to become pregnant, due to the teratogenic risk of foetal renal maldevelopment, nor to patients with bilateral renal artery disease, as this might precipitate deterioration in renal function leading to renal failure. Concurrent prescribing of ACE inhibitors with potassium supplements or potassium-sparing diuretics should be avoided, unless specifically required and with careful electrolyte monitoring.

Initiating an ACE inhibitor can produce a sharp fall in blood pressure in patients when the renin-angiotensin system is activated (e.g. when dehydration, heart failure, or accelerated hypertension are present), but this sudden drop is rarely seen in uncomplicated hypertension. Although renal artery stenosis may be detected by the presence of a renal artery bruit, it is often sub-clinical. As a precaution, serum eGFR or creatinine should be checked within 2 weeks of initiating an ACE inhibitor in order to detect any loss of renal function early enough to stop the drug and prevent significant irreversible deterioration. A change of less than 10% from the baseline value is not clinically significant.

The ABCD (Estacio et al 1998) and FACET (Tatti et al 1998) studies found ACE inhibitors to be superior to dihydropyridine calcium channel blockers in preventing cardiovascular events in type 2 diabetics. ACE inhibitors have been shown to improve cardiovascular outcomes in high cardiovascular risk patients with diabetes, independently of whether hypertension was present (HOPE 2000, PROGRESS 2001). In the ASCOT study, the treatment group, in which the ACE inhibitor perindopril was the add-in drug, achieved lower blood pressures, had fewer CVAs and total CVD events, and lower all-cause mortality (Dahlöf et al 2005). Some of these differences could be attributed to the lower blood pressure levels achieved and improvements in other cardiovascular risk factors in this group. ASCOT was stopped early due to differences in mortality between the two treatment groups: as a result, it lacked sufficient power to detect a statistically significant difference between the groups for the primary endpoint (nonfatal MI or CHD death).

Angiotensin II receptor blockers (ARB)

This drug class blocks type I angiotensin-II (AT1) receptors. These drugs are less likely than ACE inhibitors to cause cough or angio-oedema, due to their selectivity for the AT1 receptor and their lack of potentiation of bradykinin and possibly other vasopeptides. Therefore, ARBs may be suitable for patients in whom ACE inhibitors are not tolerated.

Drugs in this class have generic names ending in “-sartan”. Currently available are candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan. Cautions and contraindications are the same as for ACE inhibitors. Both ACE inhibitors and ARB conserve renal function in diabetic nephropathy and are beneficial in heart failure.

In the LIFE study, an ARB was superior to a β-blocker in improving CVD outcomes in a subset of patients with diabetes, hypertension and left ventricular hypertrophy (Dählof et al 2002, Lindholm et al 2002). In the CHARM study, candesartan improved cardiovascular outcomes against placebo (Pfeffer et al 2003). The candesartan and lisinopril microalbuminuria (CALM) study (Mogensen et al 2000) suggested that the combination of the ACE inhibitor lisinopril with the ARB candesartan may be more effective in reducing blood pressure and urinary albumin excretion than the individual drugs in type 2 diabetics (although the study dose of lisinopril was only half the maximal dose).

Beta (β) blockers

The antihypertensive effect of beta-blockers is not completely understood. β1-blockers competitively inhibit β-adrenoreceptors in the heart. β2-blockers inhibit β-adrenoreceptors in peripheral vasculature, bronchi, and elsewhere. β-blockers decrease heart rate (negative chronotropic effect), the force of cardiac muscle contraction and cardiac output (negative inotropic effect), and renin secretion. Some β-blockers may have direct CNS activity, although this is not necessarily responsible for their blood-pressure-lowering effect. In addition to their established role in treating hypertension and angina, some β-blockers are now used to treat heart failure. They are also used to relieve some symptoms of anxiety, in the prophylaxis of migraine, and topically in glaucoma.

The different β-blockers now available (generic names end in “-lol”) vary in:

1. Duration of action: shorter-acting β-blockers may need to be given two to three times daily. Modified-release formulations may be suitable as once daily in treating hypertension. Some β-blockers (e.g. atenolol, bisoprolol, carvedilol, celiprolol, and nadolol) have a longer duration of action, allowing a once-daily regimen.
2. Selectivity for β1-receptors (cardioselectivity): the first-generation β-blockers (e.g. propranolol and oxprenolol) are noncardioselective. The second-generation β-blockers (e.g. atenolol, bisoprolol and metoprolol) tend to be more cardioselective.
3. Lipid or water solubility: some are lipid soluble and some are water soluble. Atenolol, celiprolol, nadolol, and sotalol are the most water-soluble; they are less likely to enter the brain and cause CNS disturbances (e.g. lethargy, impaired concentration and memory, vivid dreams). Since water-soluble β-blockers are excreted renally, dosage reduction may be necessary in renal impairment to prevent accumulation.
4. Partial agonist activity (also known as intrinsic sympathomimetic activity or ISA): β-blockers with ISA (e.g. acebutolol, oxprenolol and pindolol), similarly to the more cardioselective β-blockers, are less likely to cause peripheral vasoconstriction and have lesser negative chronotropic and ionotropic effects.
5. Effects on metabolism: first-generation β-blockers can exacerbate metabolic abnormalities (increased triglyceride and reduced HDL-C levels, and reduced hepatic glucose mobility, especially when combined with thiazide diuretics). The second-generation β-blockers have a less (but still demonstrable) adverse effect upon serum triglyceride and HDL-cholesterol levels. The third-generation β-blockers (e.g. celiprolol and nebivolol) are not thought to have an adverse effect upon plasma lipids.

These differences may influence choice in treating particular diseases or individual patients, although they are not invariably or equally relevant clinically.

The third-generation β-blockers (e.g. celiprolol and nebivolol) have a peripheral vasodilating effect. The cardiac remodelling effects of sympathetic nervous system dysfunction in the heart may be prevented or minimised by the use of β-blockers, especially third-generation agents such as carvedilol. This action may be responsible for the reduction in morbidity and mortality in patients with diabetes reported in heart failure trials. Combined receptor antagonists (e.g. carvedilol and labetalol) act on both α- and β-receptors. The α-blocking activity offsets peripheral vasoconstriction and the adverse effect on plasma lipids produced by β-blockade.

All β-blockers should be avoided in patients with obstructive airways disease (asthma or bronchospasm) and used with caution in diabetes treated by insulin (risk of masking the symptoms of imminent hypoglycaemia). β-blockers can also cause erectile dysfunction.

Recently, doubts have been cast on whether the β-blocker atenolol does reduce cardiovascular mortality and stroke in hypertensive patients, despite its proven blood-pressure-lowering effect (Carlberg et al 2004). Because atenolol has been used as a reference drug in many studies, it is unclear whether these reservations apply to atenolol alone or to other β-blockers as well. β-blockers are not recommended as first-line drugs for “routine treatment” in the 2006 NICE guidelines.

However, the following need to be borne in mind:

• The actual reduction of blood pressure per se is important.
• Drug combinations including β-blockers are frequently required to achieve target blood pressure levels.
• β-blockers are important in treating angina and heart failure, frequently present in diabetics.
• β-blockers are safe and recommended in women who are fertile and could become pregnant.
• β-blockers have important benefits in secondary prevention post-myocardial infarction.

Other currently available β-blockers not mentioned above are esmolol, nadolol, and timolol.

Calcium channel blockers (CCB)

This drug class blocks voltage-dependent calcium channels on the surface of cell membranes, preventing the influx of calcium ions into the cell and reducing the availability of intracellular calcium for muscle contraction; leading to reduced vascular tone and decreased peripheral vascular resistance; and a fall in blood pressure. The most important of the six known types of calcium channel in the cardiovascular system is the long-lasting (L-type) channel, found in all excitable cells, including the vasculature, myocardium and cardiac conducting tissue.

L-type CCBs can be subdivided into three different classes:

• Class I, phenylalkylamines (e.g. verapamil). They depress cardiac conduction and may precipitate heart failure if there is AV or SA node dysfunction or if prescribed concurrently with β-blockers. Verapamil has an additional anti-arrhythmic action.
• Class II, dihydropyridines, abbreviated as DCCB (e.g. amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine and nisoldipine). They are relatively selective for the blocking L-type channels in smooth muscle cells, thus inducing vascular relaxation with a fall in vascular resistance and arterial pressure. They do not depress conduction or contractility; thus, they are much less likely to precipitate heart failure. They may be used safely in combination with β-blockers. The main side effects of DCCBs are vasodilator: dose-dependent peripheral oedema (resulting from transudation of fluid from vascular compartments into the dependent tissues due to pre-capillary arteriolar dilatation), headache, flushing, palpitations and gum hypertrophy. These side effects can sometimes be offset by dose titration or by the use of slow-release or long-acting drugs such as amlodipine, lacidipine or lercanidipine.
• Class III, benzothiazepines (e.g. diltiazem). This class has a slightly negative or negligible ionotropic effect.

Both class I and III CCBs are sometimes referred to as nondihydropyridine CCBs. All three CCB classes do not affect plasma lipids or glucose metabolism, and are effective in elderly and black patients.

Bioavailability is an important factor to consider when prescribing sustained-release preparations of CCBs. Different preparations containing the same quantity of a given drug are unlikely to have identical pharmacokinetic profiles. It is recommended that such preparations are prescribed by their proprietary name and that patients are not transferred to another preparation without assessment and titration.

A prospective randomised, blinded trial suggested that ACE inhibitors were more effective than CCBs at preventing myocardial infarction in hypertensive patients with diabetes and concerns were raised over the safety of CCBs (Estacio et al 1998). At the European Society of Cardiology meeting in 2000, Furberg and his colleagues presented their meta-analysis of several trials, finding no difference in the blood pressure levels achieved by CCBs and other drug classes, but suggested that patients receiving CCBs were at increased risk from certain major cardiovascular events (a question of safety or of efficacy?). The National Clinical Guidelines for Type 2 Diabetes in 2002, recommended prescribing long-acting (avoid short-acting) CCBs only as second-line treatment or as part of combination therapy (Hutchinson et al 2002). The INVEST study found that patients with CHD and hypertension (even in the diabetic subgroup) had a similar reduction in CVD mortality if treated with either verapamil or atenolol (Pepine et al 2003). ASCOT reported DCCBs to be safe and effective (Dahlöf et al 2005). The British Hypertension Society did not express concerns about the safety or efficacy of CCBs in their 1999 (Ramsay et al 1999) and 2004 (Williams 2004): DCCBs are one of the three drug class options recommended as first line by NICE in its 2006 guidelines.

Thiazide/thiazide-like diuretics

These lower blood pressure by complex mechanisms. Their antihypertensive effect is thought to be mediated by arteriolar vasodilatation. This is partly due to the urinary loss of sodium that results from a blockade of renal tubular reabsorption of sodium. Reflex vasoconstrictor activation (including the renin-angiotensin-aldosterone system) may accompany the early loss in blood volume induced by thiazides, resulting in a temporary increase in peripheral resistance. However, following initiation of a thiazide, further blood pressure lowering will occur over a period of days as peripheral resistance gradually decreases. The antihypertensive dose-response to thiazides is flat and they should be prescribed at the lowest effective dose. The duration of diuresis differs from the duration of antihypertensive effect.

Thiazide diuretics include bendroflumethiazide, chlorthiazide, cyclopenthiazide, hydrochlorothiazide, hydroflumethiazide and polythiazide (generic drug names end in “-thiazide”). They may differ from thiazide-like diuretics (these include chlortalidone and indapamide) in their duration of action, ion calcium-blocking activity, and carbonic anhydrase inhibitory activity. The significance of these differences is uncertain.

Although thiazide and thiazide-like diuretics are generally well tolerated and can enhance the blood-pressure-lowering effect of other drug classes, they can be associated with several unwanted metabolic effects, including:

• hypokalaemia (drug and dose dependent)
• worsening glucose tolerance (particularly when prescribed in combination with a β-blocker)
• slight worsening of serum lipid profile (rises in LDL-C and triglycerides)
• small rise in serum urate levels (avoid in gout)
• hypercalcaemia.

Thiazide or thiazide-like diuretics can also cause erectile dysfunction. They interact with nonsteroidal anti-inflammatory drugs (less effect on blood pressure lowering) and lithium (increased risk of lithium toxicity). The BNF states that the thiazide-related diuretic indapamide is “claimed to produce less metabolic disturbance”, particularly less hyperglycaemia, although hypokalaemia is still possible.

In the large ALLHAT trial (ALLHAT 2002), the thiazide chlorthalidone was found to be as effective as as amlodipine (a DCCB) and lisinopril (an ACE inhibitor) as an initial blood-pressure-lowering therapy for reducing cardiovascular events; also, chlorthalidone reduced heart failure when compared with amlodipine. The INSIGHT trial found no significant difference in the overall onset of cardiovascular events between co-amilozide and the CCB nifedipine (Mancia et al 2003). However, in ALLHAT increased rates of hypokalaemia and increased cholesterol and fasting glucose levels occurred on chlorthalidone, significantly when compared to lisinopril, but of minimal clinical significance when compared to amlodipine. In the ASCOT study, the group in which bendroflumethiazide was used as an add-in drug had a poorer cardiovascular outcome (Dahlöf et al 2006), but how much was this due to the effect of the first-line drug atenolol, the levels of blood pressure achieved or the effects on other cardiovascular risk factors? Nonetheless, thiazide diuretics remain recommended as first line in the 2006 NICE and ADA guidelines.

Loop diuretics are often better than thiazides at augmenting the blood-pressure-lowering effect of ACE inhibitors/ARBs.

Alpha (α)-1 adrenergic blockers

This drug class can be subdivided into selective (e.g. doxazosin, indoramin, prazosin and terazosin) and nonselective (phentolamine). These drugs block the activation of post-synaptic α-1 adrenoreceptors in the vasculature, resulting in arteriolar and venous vasodilatation. The selective α-1 blockers do not affect glucose tolerance, uric acid and potassium levels; furthermore, they appear to improve lipid profiles by reducing total cholesterol and triglycerides, while increasing HDL-C.

The major side effects of α-1 blockers are first-dose syncope and orthostatic hypotension. These effects can be minimised or prevented by prescribing a low initial dose and by avoiding concomitant prescribing of diuretics. Alpha-1 blockers should be used with caution in the elderly, since their side effects increase the risk of falls. The short-acting prazosin, one of the earlier members of this class, is more likely to cause postural hypotension than the longer-acting doxazosin or terazosin. Other side-effects of α-1 blockers include fatigue, weakness, stuffy nose and headache.

The α-blocker arm of the ALLHAT study used doxazosin and was terminated after an interim analysis showed that doxazosin was significantly less effective than diuretic therapy (chlortalidone) in preventing cardiovascular events (ALLHAT 2000).

These drugs may alleviate the symptoms of benign prostatic hypertrophy in men, particularly if there is detrusor hyperactivity, but can exacerbate stress incontinence in women.

Spironolactone

This potassium-retaining diuretic acts by blocking sodium/potassium exchange in the renal distal tubules. It has two main roles in blood pressure lowering:

1. It may limit potassium loss in patients treated with thiazide or thiazide-like diuretics.
2. Hyperaldosteronism is more common in “resistant” hypertension than previously recognised. Spironolactone can be very effective as a fourth-line drug in patients whose blood pressure levels may be dependent on hyperaldosteronism (Hood et al 2002).

The NICE 2006 guidelines recommend spironolactone as a possible add-in drug in difficult-to-treat hypertension when combinations of the three standard first-line agents have not lowered blood pressure sufficiently. Potassium-retaining diuretics need to be monitored carefully in patients with impaired renal function due to the risk of developing hyperkalaemia, particularly if combined with either an ACE inhibitor or ARB. Spironolactone can commonly cause gynaecomastia due to its anti-androgen effect. A recent population-based, case-control study claimed to find an association between spironolactone and upper gastrointestinal bleeding and ulcers (Verhamme et al 2006), although there may be confounding factors and causality was not proven.

Centrally acting, older and other antihypertensive agents

Once a mainstay in blood-pressure-lowering treatment, centrally acting, older and other antihypertensive drugs are currently reserved for patients whose raised blood pressure is not controlled by, or who have contraindications to, the other drug classes. These agents are less favoured than other drug groups because side effects can be more frequent, and may be unpleasant or potentially dangerous.

These drugs include:

1. Sympatholytic agents, which can be subdivided into:

• the imidazoline (I1) agonist, moxonidine, which binds highly selectively to imidazoline receptors in the brain’s venterolateral medulla, causing reduced peripheral sympathetic activity. This leads to falls in peripheral resistance and blood pressure. Moxonidine has little effect on α-2 receptors, which cause dry mouth and sedation.
• the central α-agonists, methyldopa and clonidine, reduce sympathetic vasoconstriction and total peripheral vascular resistance. The major side effects of these drugs are dose-related: sedation and drowsiness.

2. The vasodilators, hydralazine, diazoxide and minoxidil, act by relaxing vascular smooth muscle, producing decreased peripheral vascular resistance. Their major side effects include gastrointestinal upset and fluid retention. Minoxidil may cause hirsutism, an effect exploited by its topical use in balding men.

Which drugs should be chosen?

When reviewing evidence, it is crucial to distinguish between “surrogate” endpoints of levels of blood pressure achieved and the “real” endpoints of mortality or morbidity. The characteristics and treatments of subjects recruited into drug trials may not resemble those of patients frequently encountered in primary care.

Which drug should be the initial therapy?

As stated above, five drug classes (ACE inhibitors, ARBs, β-blockers, CCBs and diuretics) have been shown to reduce cardiovascular events in individuals with both diabetes and hypertension (ADA 2004, Clinical Evidence online). Which of these drug classes should be the first-line therapy in patients with type 2 diabetes and raised blood pressure? There is no simple answer.

The most recent JBS guidelines concluded that “in general the various drug classes are about as effective as each other at reducing cardiovascular mortality and morbidity per unit fall in blood pressure” … with the caveat that there is “heterogeneity in response to different drug classes, optimal drug combinations, and specific categories of hypertension” (Wood et al 2005). The ADA recommends initial drug therapy with an agent from one of the five drug classes listed above (ADA 2004). For routine treatment, the 2006 NICE guidelines recommend choosing from ACE inhibitors, ARBs, DCCBs and diuretics, but not β-blockers, except in pregnant women or in patients with CHD and/or heart failure (NICE 2006a).

In the 2006 NICE treatment template (see Table 4.7), the reasoning behind drug selection is that hypertension can be classified as “high renin” and “low renin” and, as such, it is best treated initially with drugs that either inhibit the renin-angiotensin system (ACE inhibitor or ARB, known as A drugs) or those that do not inhibit the renin-angiotensin system (CCB or a thiazide diuretic – known as C or D drugs). “Younger” people (aged 55 years or less) tend to have higher renin levels in comparison to older people and blacks of all ages. Thus, the recommended initial therapy in the former group is a drug from the A group, and in the latter group a drug from the C or D group. This is a change from earlier (2004) NICE guidance which stated that there was “no compelling evidence” to support the opinion that different classes of drug are more effective in lowering the risk of developing CVD in either older or younger age patients (North of England Hypertension Guideline Development Group 2004).

TABLE 4.7 The NICE 2006 recommendations for combining blood-pressure-lowering drugs (NICE Clinical Guideline 2006a)

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In patients with diabetes and incipient or established heart failure, blockade of the renin-angiotensin and of the cardiac sympathetic nervous systems with ACE inhibitors and β-blockers, respectively, improves outcomes. The cardioprotective effects of these drug classes should be taken into consideration when selecting a blood-pressure-lowering agent.

Nevertheless, the reader should bear in mind the findings of three studies:

1. The UKPDS showed that a blood pressure reduction of 10/5 mmHg reduced the incidence of diabetes complications. However, the trial was underpowered to compare the main agents used, captopril and atenolol (UKPDS 1998a).
2. The ALLHAT (antihypertensive and lipid lowering to prevent heart attack trial) study found no large differences between initial therapy with either chlortalidone, lisinopril or amlodipine in reducing blood pressure and cardiovascular events (ALLHAT 2002), notwithstanding certain concerns about the trial’s design and conclusions. A further analysis of the ALLHAT results found “no evidence of superiority for treatment with CCB or ACE inhibitors compared with a thiazide-type diuretic during first-step antihypertensive therapy in diabetes mellitus, IFG, or normoglycaemia” (Whelton et al 2005).
3. The Blood Pressure Lowering Treatment Trialists’ Collaboration conducted a meta-analysis of 29 trials that involved 162 341 participants with over 700 000 years of follow-up and found that “the main driver from BP-lowering therapy is BP lowering per se” (Blood Pressure Lowering Treatment Trialists’ Collaboration 2003).

There has been a debate as to whether ethnicity contributes to different outcomes in drug treatments; nevertheless, there is strong evidence that blood-pressure-lowering therapy reduces cardiovascular risk irrespective of ethnicity (ALLHAT 2000). Blood pressure in blacks often responds well to dietary salt restriction and there are theoretical reasons why thiazides and CCBs may be more effective in lowering blood pressure than β-blockers, ACE or ARB. However, a review by the University of York in 2004 (University of York 2004) concluded that “there is insufficient evidence that any antihypertensive drug or drug combination is superior in reducing morbidity and mortality outcomes in hypertensive black people.” There is also no evidence currently available to show that South Asians respond differently than white Europeans to blood-pressure-lowering medication. A recent meta-analysis suggested that adverse reactions to cardiovascular drugs, including ACE inhibitors and thrombolytic therapy, may be different between some ethnic groups: a factor that may influence clinical decisions about drug choices and doses (McDowell et al 2006).

Considering all of the above, the following approach seems sensible:

• The first-line agent should be from a drug class that has been shown to reduce CVD events in diabetics.
• Contraindications, potential side-effects, likely tolerability, potential drug interactions and the logistics of monitoring all need to be taken into account when making a choice.
• When heart failure is either incipient or established, blockade of the renin-angiotensin and of the cardiac sympathetic nervous systems with ACE inhibitors and β-blockers, respectively, is desirable.
• When diabetic nephropathy is incipient, established or worsening, ACE inhibitors/ARBs should be considered first.
• Most patients will need combination therapy (see Table 4.7).
• The importance of modifying other cardiovascular risk factors must not be ignored.

The most important message, however, is that:

The extent of blood pressure lowering is probably more important than the choice of agent(s). Even a small reduction in blood pressure will improve outcome.

Combining drug groups rationally

In many patients, more than one blood-pressure-lowering drug needs to be prescribed concurrently to achieve target or produce a substantial reduction in blood pressure. Several factors may influence the selection of the second or third (or even fourth) drug in the combination. These include tolerability, potential drug interactions, and contraindications.

The BHS 2004 Guidelines introduced a treatment template to assist practitioners to combine different drug classes in a rational and effective way. This was modified in the 2006 NICE guidelines, shown in Table 4.7. Ultimately, the aim should be to achieve the best possible blood pressure control, with minimal and tolerable side-effects.

DYSLIPIDAEMIA

RATIONALE

QOF image

DM16

DM17

An abnormal lipid profile (also called dyslipidaemia) is a major independent risk factor in the development of CHD. Cholesterol and triglycerides do not circulate freely in solution in plasma, but are bound to proteins and are transported as macromolecular complexes, known as lipoproteins; these are classified according to their density, ranging from very-low-density lipoproteins (VLDL) through low-density lipoproteins (LDL), then intermediate-density lipoproteins (IDL) to high-density lipoproteins (HDL). Quantitatively, TG is the “major” lipid group transported in the blood, with 70 to 150 g entering and leaving plasma daily, compared with 1 to 2 g of cholesterol. About 70% of the total cholesterol (TC) in plasma is carried in the LDL fraction and 25% is carried in the HDL fraction.

The combination of elevated levels of LDL with reduced levels of HDL predisposes an individual to the development of arteriosclerosis, regardless of whether diabetes is present. There is a direct and continuous association between total and LDL cholesterol levels in the serum and CVD risk, while serum HDL levels have an inverse correlation with CHD risk (Betteridge 1997). The “hallmark” of obesity is the over-production by the liver of VLDL, which is then converted to LDL and is often associated with elevated levels of triglycerides. LDL levels may also be raised due to defective clearance, which has many causes, including reduced numbers or activity of LDL-receptors. Elevated levels of TG have a major adverse effect upon CHD risk. In contrast, HDL has several anti-atherogenic actions. Low HDL-C increases vulnerablity to the dynamic features of atherogenesis (often mediated by raised LDL-C): these include cholesterol accumulation, inflammation, pro-thrombotic activity, matrix fragilisation and oxidative stress. Cholesterol levels can be affected by both genetic (e.g. familial hyperlipoproteinaemias) and environmental factors, and by the presence of other conditions, such as hypothyroidism and obstructive liver disease. Individuals who migrate from a country with a lower prevalence of CVD to a country with a higher prevalence often alter their eating habits and other behaviours accordingly, resulting in a CVD risk closer to that of their new country’s endogenous population.

The lipid profile is frequently “adverse” in patients with impaired glucose tolerance or type 2 diabetes: total cholesterol, LDL-C and triglycerides may be elevated, while HDL-C levels are often lower. Also, HDL-C is often “dysfunctional” or less active in patients with diabetes. This abnormal profile often precedes the onset of intermediate hyperglycaemia or diabetes by several years, so that atherogenesis may occur prior to the development of hyperglycaemia.

There is now strong evidence that improving the lipid profile, particularly in lowering LDL-C, does reduce significantly the incidence of CHD mortality and morbidity in individuals at higher risk (Baigent et al 2005).

TARGETS

The aim of lipid modification should be to both improve and maintain lipid levels beyond the threshold at which there is no increased CHD risk. However, there is now evidence that lowering total and LDL-C in high-risk patients (including diabetics), irrespective of the baseline, improves outcomes. For these individuals, the consensus is now moving away from the target being a fixed endpoint to a percentage reduction. This is consistent with the latest guidance from both the Joint British Societies and the ADA, which recommend targets that are either a fixed end point or a minimum percentage reduction, whichever is lower.

The range of targets recommended by these and other authoritative bodies is summarised in Table 4.8. The current national policy (NICE and NSF) for lipid targets (whichever results in a lower absolute level) is a total cholesterol less than 5.0 mmol/l (or reduced by 20–25%), and a LDL-C less than 3.0 mmol/l (or reduced by 30%), instead of JBS2’s lower recommended optimal levels. However, these targets may be revised when NICE issues its guidance on lipid modification (at writing, due December 2007). As with other risk factors, it is sensible to set less strict targets in some older patients with a limited life expectancy.

TABLE 4.8 Target lipid levels recommended by different learned bodies or organisations

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The latest JBS2 guidelines do not give targets for either triglyceride or HDL-C, due to a lack of evidence from interventional studies.

The ADA’s recommended targets do not include total cholesterol, only lipoprotein functions. In addition to LDL-C, the ADA targets, in diabetics with overt CVD, include:

• Triglyceride levels less than 1.7 mmol/l
• HDL-C levels greater than 1.15 mmol/l in men and 1.44 mmol/l in women (ADA 2007).

The new GMS contract QOF’s only current lipid target is a total cholesterol of less than 5.0 mmol/l, although this could change in the future. Looking at the most recent evidence, simply achieving this target may not correct an atherogenic lipid profile sufficiently, especially in high-risk patients. Primary care teams should consider setting a target for LDL-C, and possibly HDL-C and triglycerides, in high-risk patients.

Future recommendations are likely to demand an even more “aggressive” approach to lipid regulation, where there would be no lower limit for intervention in or for the target of LDL-C in high-risk patients.

EVALUATION

Serum lipid estimation is best done after an overnight fast, because chylomicrons from the last meal can affect triglyceride levels. The practice should request that the local chemical pathology laboratory provides total cholesterol, lipoprotein fractions, and triglyceride levels in its report. Most laboratories will give LDL-C and HDL-C values.

INTERVENTIONS: OVERVIEW

The management of dyslipidaemia can be divided into pharmacological and nonpharmacological methods. Irrespective of the baseline levels, improving the lipid profile will reduce cardiovascular risk in all type 2 diabetics.

INTERVENTIONS: NONPHARMACOLOGICAL

Nonpharmacological management should not be overlooked. Weight loss, reduced alcohol intake and increased levels of physical activity can lead to decreased TG and LDL cholesterol, and increased HDL levels (behavioural change is currently the most effective way of raising HDL-C levels). Improved glycaemic control will lower TG levels. “Maximal” dietary modification can reduce LDL cholesterol by up to 0.65 mmol/l.

Unless the patient is at high risk requiring immediate drug treatment, a trial period of from 3 to 6 months is useful to ascertain the success of a dietary and/or exercise regimen.

INTERVENTIONS: PHARMACOLOGICAL MANAGEMENT

There are several classes of lipid-regulating drugs currently available. The statins are the mainstay of lipid-regulating pharmacotherapy, but it is both important and useful to know about the other classes of lipid-regulating drugs.

In support of the Diabetes NSF, the National Clinical Guidelines for Type 2 Diabetes published its recommendations in 2002 for the management of “abnormal” serum lipids (McIntosh et al 2002). Following the findings of several important studies, this guidance has now been superseded by the JBS 2 guidelines published in December 2005:

1. All diabetics should be regarded as being high risk of developing a CVD event.
2. Treatment with a statin is now recommended for all diabetics, with the exception of those under 40 whose most recent HbA1c is not greater than 9.0%, whose total cholesterol is below 6.0 mmol/l, and are without any target organ damage or significant cardiovascular risk factors (these exclusions are likely to disappear, as it is clear that all diabetics benefit from LDL-C lowering). Statin treatment is indicated in all those aged under 40 with existing CVD, irrespective of whether diabetes co-exists.
3. Other classes of lipid-regulating drugs should be considered in addition to a statin if the total and LDL cholesterol targets are not achieved, or if levels of HDL-C and/or triglycerides need to be modified.

The American Diabetes Association’s 2006 recommendations are quite similar to JBS 2:

1. All those with overt CVD should be treated with a statin to achieve an LDL-C reduction of 30 to 40%.
2. In those without overt CVD:

a. Treat all those aged 40 years or more with a statin, regardless of baseline LDL-C, to same target
b. Treat those under the age of 40 years, but at increased risk due to other cardiovascular risk factors, and not achieving lipid goals with nonpharmacological interventions.

Once started on treatment, patients require earlier review to monitor the response to and the safety of their treatment. A combination of lipid-regulating drugs may be required in high-risk individuals who require aggressive correction of their dyslipidaemia. There are little data available on the reduction in cardiovascular events in patients on combinations of a statin and either a fibrate or nicotinic acid.

A meta-analysis of 12 RCTs (including ALLHAT, ASCOT, MRC/HPS, 4S, LIPID, CARE) comparing the efficacy of lipid-lowering treatment for diabetic and nondiabetic patients, concluded that:

1. Treatment, particularly with statins significantly reduced cardiovascular risk in both diabetic and nondiabetic patients
2. Diabetic patients benefit more than nondiabetic patients from treatment in both primary and secondary prevention, when the results are adjusted for baseline risk (Costa et al 2006).

Although this meta-analysis has some limitations (varying definitions of diabetes, three studies combined results for coronary events and stroke, two studies used gemfibrozil, effects of dose were not explored), it was published after JBS2 and may have important implications for clinical practice: probably “all” patients with type 2 diabetes should receive statin treatment if their LDL-C is equal to or greater than 2.0 mmol/l (Reckless 2006), going beyond the JBS 2 guidelines discussed above.

Statins

Hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors are commonly known as statins and have been available for at least 15 years. By competitive inhibition of the rate-limiting enzyme responsible for the hepatic synthesis of cholesterol, statins block the endogenous synthesis of cholesterol, causing the hepatocyte’s cholesterol requirements to be met by the uptake of circulating cholesterol via a catabolic LDL receptor on the cell surface; the number of these receptors is thought to be increased by statins. Statins can reduce plasma LDL-C by up to 40%. These drugs also have a moderate effect on increasing HDL-C and lowering plasma TG levels, although this is less than their effect on LDL-C.

Although statins are usually well tolerated, they should be used with caution in patients with a history of liver disease or with a high alcohol intake. As with fibrates, rhabdomyolysis and reversible myositis are rare but significant side effects of statins, particularly in patients with renal impairment and hypothyroidism or taking concurrent fibrates or ciclosporin. Patients taking statins should have liver function tests (LFTs) and creatine kinase (CK) estimations two to three months after starting treatment, after a further increase in dose, or if symptoms of myositis occur at any time on therapy. They should also be advised to report promptly unexplained muscle pain, tenderness or weakness.

Five statins are currently available in the UK: atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin. Another statin, cerivastatin, was withdrawn due to the risk of rhabdomyolysis when it was used in combination with gemfibrozil (a fibrate).

Several well-publicised trials demonstrated that pravastatin (CARE [Goldberg et al 1998], LIPID 1998, PROSPER [Shepherd et al 2002], WOSCOPS 1998) and simvastatin (Scandinavian Simvastatin Survival Study and MRC/BHF) reduced both total and LDL cholesterol levels and were effective in the primary and secondary prevention of CHD, although the cholesterol levels achieved in many patients in these studies fell short of the JBS 2 targets. In elderly individuals at high risk of developing vascular disease, pravastatin reduced the risk of CHD after 3 years (Shepherd et al 2002). Three recent studies have provided the strongest evidence base for the benefits of lipid lowering using statins in type 2 diabetics:

1. MRC/BHF Heart Protection Study reported that a lowering of LDL-C by 30% (using simvastatin) significantly reduced the risk of a major CHD event at 4.8 years (relative risk reduction 22%, number needed to treat 20), independent of the diabetic patient’s baseline LDL-cholesterol (Heart Protection Study Collaborative Group 2003).
2. In 2004 the Collaborative AtoRvastatin Diabetes Study (CARDS) recruited 2838 type 2 diabetics. It reported that, compared with placebo, treatment with atorvastatin 10 mg significantly reduced cardiovascular events at 3.9 years (absolute risk reduction 3.2%, RRR 35.6%, NNT 32). Acute coronary events were reduced by 36%, coronary revascularisation by 31% and stroke by 48% in the atorvastatin group. Baseline lipids, sex and age did not affect the results (Colhoun et al 2004).
3. The ASCOT primary prevention trial of high-risk, uncontrolled hypertensive patients recruited 2532 patients with diabetes. In the lipid-lowering arm, subjects had a baseline nonfasting TC below 6.5 mmol/l. The primary endpoint of nonfatal MI plus fatal CHD was reduced by over one-third more in patients treated with atorvastatin 10 mg compared to placebo, even with equivalent blood pressure reduction (Sever et al 2003).

Furthermore, a meta-analysis of 14 RCTs concluded that an absolute reduction in LDL-C, independently of the baseline level, reduces CVD risk (relative risk reduction of 21% in CVD events per mmol/l reduction in LDL-C). This effect appears to apply equally to subgroups in which there had been previous uncertainty, such as people with diabetes and no pre-existing vascular disease and people aged more than 75 years (Baigent et al 2005).

Although, in its 2006 technology appraisal of statins, NICE accepted that statin therapy is “cost-effective” in type 2 diabetics, it concluded “that the decision whether to initiate statin therapy in diabetics should be made where a clinical assessment has estimated the CVD risk to be likely to be equivalent to at least 20% over 10 years.” Since NICE noted that there were “no data on clinical events to suggest the superiority of any one statin over all the others in reducing cardiovascular events”, it recommended initial statin therapy using “a drug with low acquisition cost” (NICE 2006b).

Some of NICE’s conclusions may seem a little surprising as:

1. By introducing an assessment of CVD risk for this population (despite noting the “limitations of assessing risk in diabetics using standard risk calculators”!), NICE infers that not all patients with diabetes are at high risk, a standpoint not supported by a wide range of evidence.
2. NICE contradicts the most recent authoritative guidance given by both the Joint British Societies and the ADA.
3. Cardiovascular risk is reduced in all diabetics on statin therapy that lowers total cholesterol and LDL-C levels, irrespective of baseline lipid profile.

A “new generation” synthetic statin, rosuvastatin, is more potent than other statins in lowering LDL-C levels (achieving up to 45–50% reduction). In the ASTEROID study patients with existing atheroma were all prescribed maximal dose (40 mg) rosuvastatin for 2 years. Not only did a significantly better lipid profile (lower LDL-C and higher HDL-C) result, but a “significant” median reduction in fatty deposits occurred, suggesting that the treatment produced a regression in the build up of fatty deposits in the coronary arteries (Nissen et al 2006). Due to lack of controls on a lower dose of rosuvastatin or on a high dose of another statin, and the relatively short duration of this study, further research is needed to answer the following important questions:

• Do these changes lead to improved clinical outcomes?
• Are these changes dose-related?
• Would other statins have produced a similar effect?

ASTEROID reported “infrequent” side-effects, despite previous reports of increased risk of serious muscle toxicity associated with rosuvastatin, particularly in certain subpopulations (renal impairment, hypothyroidism, Japanese and Chinese origin, alcohol abuse, concomitant use of fibrates) to the US Food and Drug Administration (FDA) and other regulatory bodies. These led to revised guidance being issued in 2004 for prescribing rosuvastatin, advising that mainly the lower doses of 5–10 mg should be prescribed in primary care, with the maximum dose of 40 mg to be prescribed only under close (i.e. specialist) supervision and with greater caution. NICE indicated that, particularly with insufficient data on clinical events currently available for rosuvastatin, there is “significant uncertainty” over rosuvastatin’s cost-effectiveness (NICE 2006b). Currently, rosuvastatin is a second-line drug, but it may be increasingly used when “older” statins fail to achieve the progressively “tighter” targets set by authoritative bodies.

A note of caution should be introduced at this point. Statins do not produce significant increases in low HDL-C levels. Women and non-Caucasians were not always well represented in lipid-lowering interventional studies and currently there are no published studies reporting the effect of lipid-lowering therapy on “hard” cardiovascular outcomes in any population originating from the Indian subcontinent (Winocour and Fisher 2003). Being a female and/or nonwhite diabetic does increase an individual’s susceptibility to the adverse effects of many cardiovascular risk factors. However, it is reasonable, until further evidence is published, not to allow the patient’s gender or ethnicity to influence decisions about the type of therapy to reduce cardiovascular risk.

“At the end of the day” while there may be some subgroups of type 2 diabetics in whom the evidence for the benefits of statin therapy may be considered less robust than in others (Drugs and Therapeutics Bulletin 2006), there is a clear consensus in the guidance from JBS2 and the ADA: all type 2 diabetics aged over 40 (and many aged under 40) are at increased CVD risk, regardless of baseline levels, and should be on a statin.

Anion-exchange resins (bile acid sequestrants)

The two available agents in this drug class are cholestyramine and colestipol. They act by binding bile acids in the gut, preventing their reabsorption. This promotes conversion of cholesterol into bile acids by the liver, resulting in increased LDL-receptor activity of hepatic cells which increases LDL-cholesterol clearance. Also, since bile acids are required for the intestinal absorption of sterols, use of these agents results in increased faecal loss of dietary cholesterol. Although these drugs reduce LDL-cholesterol by up to 25% more than by dietary modification alone, they can aggravate hypertriglyceridaemia.

Anion-exchange resins are not especially palatable. They are not absorbed and can cause gastrointestinal side-effects (constipation more than diarrhoea, nausea, vomiting and discomfort) and can interfere with the absorption of fat-soluble vitamins (A, D and K – supplementation may be necessary on long-term therapy).

Currently there are no systematic reviews or RCTs in people with diabetes and higher risk for macrovascular complications comparing anion exchange resins (colestyramine, colestipol) versus placebo or comparisons of different anion exchange resins, or different doses for CVD outcomes.

Fibrates

Fibrates are broad-spectrum, lipid-modulating agents. Their use can lead to:

• Decreased serum TG levels
• A reduction of LDL-C by up to 18%
• Increased HDL-C levels
• Decreased VLDL levels.

The currently available fibrates are bezafibrate, ciprofibrate, fenofibrate and gemfibrozil.

All fibrates can cause rhabdomyolysis or other muscle toxicities. These usually present as muscle pain, associated with elevated serum creatine phosphokinase (CPK), particularly in patients with impaired renal function or hypothyroidism. The risk of muscle toxicity is increased if a fibrate is taken concurrently with a statin or ciclosporin. There is also a risk of a rise in serum creatinine, particularly with fenofibrate.

Bezafibrate suppresses endogenous synthesis of cholesterol and triglycerides. It also “causes the expression” of an increased number of specific LDL receptors, increasing the catabolism of LDL-C. Triglyceride catabolism is stimulated through systemic lipoprotein lipase and hepatic lipase. Ciprofibrate and fenofibrate lower plasma LDL, VLDL and TG levels and raise serum HDL levels without increasing the risk of developing gall stones. Gemfibrozil reduces raised levels of TG, TC, LDL-C and VLDL and raises low levels of HDL-C. Its lowering of plasma TG levels is likely to be achieved by reducing the hepatic synthesis of VLDL and increasing VLDL clearance.

Five randomised controlled trials (RCTs) found that fibrates, compared to placebo, have a “beneficial effect” upon cardiovascular mortality and morbidity and improve triglyceride levels (Clinical Evidence online). However, questions over safety were raised in two primary prevention studies (Koskinen et al 1992), while two secondary prevention studies suggested that fibrates were quite safe (Heinonen 1994, Rubins et al 1999).

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, comparing treatment with fenofibrate against placebo, provided mixed results. Fenofibrate did not significantly reduce the risk of the primary trial outcome of major coronary events. However, in the group treated with fenofibrate, there were fewer total cardiovascular disease events and a significant reduction in microvascular-associated complications. Fenobrate appeared also to be generally well tolerated in type 2 diabetics (Keech et al 2005).

Since statins are less effective in raising low HDL-C, alternative drug classes (such as fibrates and nicotinic acid group) need to be considered in lipid management. Despite the problems associated with combining gemfibrozil and the withdrawn statin cerivastatin, the need to raise HDL-C levels, along with lowering LDL-C and TG levels, may prompt the clinician to consider prescribing a statin–fibrate combination. Compared with fluvastatin plus placebo, fluvastatin plus fenofibrate significantly improved lipid profile in people with type 2 diabetes, dyslipidaemia, and history of CHD (Derosa et al 2004). It appears that this combination is relatively well tolerated, provided that renal, hepatic and thyroid function remains normal with CPK levels being monitored and that any muscle pains are promptly reported.

Cholesterol absorption inhibitors

This drug group selectively inhibits cholesterol transport across the wall of the small intestine, thus reducing the delivery of intestinal cholesterol to the liver. Ezetimibe is the first available product in this class. It is metabolised in the liver and small intestine to its active glucuronide form, which undergoes enterohepatic recycling, prolonging its action. Ezetimibe is not a bile acid sequestrant. It does not interfere with the absorption of TG, fatty acids or fat-soluble vitamins. Headache, abdominal pain and diarrhoea are common side effects of ezetimibe.

Ezetimibe’s licenses include:

• Adjunctive therapy to dietary modification in patients with hypercholesterolaemia, either in combination with a statin (acting synergistically to lower LDL-C levels) or as monotherapy (if a statin is inappropriate or contraindicated).
• Treatment of homozygous familial hypercholesterolaemia in combination with dietary modification and a statin.

There are no systematic reviews or RCTs in people with diabetes and higher risk for macrovascular complications comparing ezetimibe versus placebo, or comparisons of different doses for CVD outcomes (Clinical Evidence online). However, compared with statin plus placebo, statin plus ezetimibe significantly improved the lipid profile in type 2 diabetics over 8 weeks (Simons et al 2004). Adding ezetimibe to a statin is much more expensive than maximising the dosage of the statin. When aggressive LDL-C lowering is required, ezetimibe may have a role: either in combination with a statin beyond a maximal statin dose or as an alternative if statins are contraindicated or not tolerated. At the time of writing, NICE plans to issue a technology appraisal of ezetimibe in 2007.

Nicotinic acid group

The nicotinic acid group (nicotinic acid and acipimox are the currently available drugs in the UK) of drugs improve both serum cholesterol and triglyceride levels.

They appear to act in several ways, including partial inhibition of free fatty acid release from adipose tissue, increased lipoprotein lipase activity and decreased hepatic synthesis of LDL-C; thus producing lower LDL-C and triglyceride levels. Nicotinic acid was reported to increase HDL-C levels significantly in one RCT. However, a large proportion of this study’s subjects were also taking a statin (Grundy et al 2002). Nicotinic acid’s side effects, especially vasodilatation, can be troublesome. It also worsens glucose tolerance (it may precipitate diabetes).

Nicotinic acid is now available also in an extended-release formulation (Niaspan). Patients started on niaspan may experience transient facial flushing. This drug has been associated with hepatic toxicity; thus, liver function should be monitored prior and during prescribing. Niaspan should be used with caution in patients with a history of liver disease or who consume large quantities of alcohol.

In 2004 the Scottish Medicines Consortium advised that Niaspan was not recommended for the treatment of hypercholesterolaemia and mixed hyperlipidaemia, due to the lack of suitable studies (available at the time) comparing it with other lipid-regulating drugs. However, as with fibrates, the need for aggressive lipid regulation (especially if seeking to raise HDL-C levels and lower TG levels, as well as lowering LDL-C levels) may prompt clinicians to consider prescribing nicotinic acid, particularly in combination with a statin, subject to the cautions stated above.

Acipimox has fewer side effects than nicotinic acid, but may be less effective.

Fish oils

Fish oils reduce serum triglycerides. There are two preparations currently available:

1. Omega-3-acid ethyl esters (Omacor).
2. Omega-3 marine triglycerides (Maxepa). This can sometimes aggravate hypercholesterolaemia.

Increased consumption of fish oils has been recommended for some time, as this was said to be linked with a number of positive health outcomes, including protection from cardiovascular disease (Brunner 2006). However, a recent systematic review concluded that “long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer” (Hooper et al 2006).

Selection of drug therapy

Five classes of lipid-modifying drugs (but not all drugs within each class) have been shown in clinical trials to reduce myocardial infarction and coronary death: statins, fibrates, anion exchange resins, nicotinic acid and its derivatives, and fish oils. However, the largest and most convincing body of clinical trial data is for the use of a statin in reducing CVD and total mortality.

Table 4.9 summarises the indications, cautions and contraindications relating to the different classes of lipid-modifying drugs.

TABLE 4.9 Compelling and possible indications, contraindications and cautions for the major classes of lipid-modifying drugs (Wood et al 2005)

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If target lipid levels are not achieved with the first-line drug, then the following need to be considered:

1. Switching to more potent drugs (usually a second-generation statin)
2. Adding in ezetimibe or fibrate
3. Consider and correct, where appropriate, secondary causes, e.g. hypothyroidism, abnormal liver function
4. Improve glycaemic control (lowers serum TG and raises serum HDL-C)
5. Referral to either a lipid clinic or a diabetic clinic if all else fails or if the medication used causes problems.

Future possible approaches to lipid regulation

With the availability and proven effectiveness of LDL-C-lowering therapies, the future emphasis of drug development and of trials will undoubtedly move towards HDL-C-raising interventions.

OBESITY

DEFINITIONS AND TERMINOLOGY

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The World Health Organization (WHO) defines obesity as “a disease state in which excess fat has accumulated to an extent that health may be adversely affected.” The WHO categorises body weight into: normal weight, overweight, obesity and severe obesity, using the body mass index (BMI), expressed as kg/m2. NICE defines “morbid” obesity as greater than 40 kg/m2 or between 35 and 40 kg/m2 with other significant disease (e.g. diabetes, hypertension) (NICE 2002).

RATIONALE

Obesity with an abdominal distribution (also known as central obesity), rather with gluteal fat accumulation, is associated with metabolic syndrome, insulin resistance and a higher cardiovascular risk (particularly through dyslipidaemia), although it has not yet been demonstrated that obesity is an independent cardiovascular risk factor in diabetes.

Excess weight is almost always due to an imbalance between physical activity and dietary calorific intake: too little of the former in relation to too much of the latter. Any intervention to produce weight loss must correct this imbalance.

From a public health perspective, obesity is becoming an “epidemic”, contributing to the relentlessly rising prevalence of metabolic syndrome and diabetes. In England 66% of men and 55% of women are classified as either overweight or obese (Department of Health 2004). The Department of Health has issued guidance available on its website (DoH 2006).

TARGETS

Achieving and maintaining an ideal body weight does not invariably equate with abolishing obesity. Depending upon the definition of obesity, the suggested targets are:

• The ideal BMI is greater than 20 kg/m2 and less than 25 kg/m2 in whites (23 kg/m2 in Indo-Asians).
• The ideal waist circumference is less than 102 cm in white men, 88 cm in white women, 90 cm in Asian-Pacific men and 80 cm in Asian-Pacific women.

Substantial and sustained weight loss is not easy to achieve. It is both practical and humane, particularly as the loss has to result mainly from behavioural change, to set a target whose end point takes into account the starting point and that does not require an excessive rate of loss (no more than 1 to 2 kg per month). As patients get older, weight loss becomes progressively more difficult. A realistic target in some individuals may be simply to avoid further weight gain.

EVALUATION

To calculate body mass index (BMI), the height and weight of the patient need to be measured. The calculation, usually done automatically when the data are entered onto a software system, is:

BMI = weight (in kilograms) divided by the square of height (in metres).

BMI is a measure of body weight and not of body fat or its distribution, whereas obesity indicates the presence of excessive fat, but not necessarily of excessive body weight: BMI and weight are not measures of the same thing. Some diabetics have increased intra-abdominal fat, but a normal range BMI. The BMI ranges used in most risk tables are characteristic of a white population.

Measuring skin-fold thickness can underestimate body fat in individuals with mainly central obesity instead of gluteal fat accumulation. Although the waist–hip ratio (WHR) can be calculated, it may underestimate intra-abdominal obesity if gluteal obesity is also present.

The waist circumference is measured half way between the lowest point of the rib cage and the iliac crest (Despres & Lemieur 2001). It is an essential criterion for the diagnosis of metabolic syndrome, and a better predictor than BMI of cardiovascular and metabolic risk. In 2003 Diabetes UK produced a stratification of co-morbidity risk, correlated with BMI and waist circumference in adults, summarised in Table 4.10.

TABLE 4.10 Co-morbidity risks associated with different levels of BMI and waist circumference

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INTERVENTIONS

As with other risk factors, the most important component in the management of obesity is changing the patient’s behaviour. The imbalance between an excessive dietary calorific intake and an inadequate level of physical activity needs to be reversed. The target weight and rate of loss should be negotiated. When weight loss is an important on-going activity for the patient, more frequent reviews may be needed to monitor progress and to encourage the patient. Specialist help should be sought if the patient is very obese or fails to respond to medical interventions.

Anti-obesity drugs

Anti-obesity agents may help diabetics to lose weight when prescribed in combination with a restricted energy diet and, ideally, increased physical activity. There are three agents in current use, which act by different mechanisms. Orlistat and sibutramine have been shown to produce clinically significant weight loss in type 2 diabetics, including those treated with sulphonylureas. All three drugs are expensive.

1. Orlistat (proprietary name Xenical) acts within the stomach and small intestine as a long-acting inhibitor of pancreatic lipases. Its mode of action is to prevent the hydrolysis and subsequent absorption of ingested dietary fat (about 30%). The current prescribing licence for orlistat allows it to be prescribed to diabetics aged 18 to 75 years with a BMI of 28 kg/m2 or more, who can adhere to a hypocaloric diet. Treatment with orlistat can be continued up to 12 months (occasionally up to 24 months), provided that a further 5% of body weight is lost by the end of 3 months’ treatment. The decision to continue orlistat for longer than 12 months (usually for weight maintenance) should be made after considering the potential benefits and limitations with the patient (NICE 2006c).
2. Sibutramine (proprietary name Reductil) is an anorectic agent that acts centrally by inhibiting serotonin and norepinephrine reuptake, resulting in enhanced satiety. Patients will feel satisfied with smaller food portions. Sibutramine has several important contraindications (important macro- and microvascular disease, uncontrolled hypertension, severe renal impairment, glaucoma, benign prostatic hypertrophy with urinary retention) and it interacts with a number of other drugs, including antidepressants, drugs affecting CYP3A4 or serotonin levels. Sibutramine can be prescribed to diabetics aged 18 to 65 years with a BMI of 27 kg/m2 or more. Continuation beyond the first 4 weeks requires a weight loss of 2 kg; while continuation beyond 3 months requires a loss of 5% of the initial weight at the start of treatment. The maximum duration of treatment in the licence is 12 months (NICE 2006c).
3. Rimonabant (proprietary name Acomplia) received its European Union licence in June 2006; it is the first in a new class of drugs that selectively inhibits the endocannabinoid system, which plays an important role in the control of appetite, as well as regulating pleasure, relaxation and pain tolerance. Rimonabant is indicated as an adjunct to diet and exercise in obese patients with a BMI equal to or greater than 30 kg/m2 or in overweight patients with a BMI greater than 27 kg/m2 and associated risk factors such as type 2 diabetes or dyslipidaemia. Reports from phase 3 trials show that the use of the drug resulted in improvements in several cardiovascular risk factors (weight loss, reduction in waist circumference, reduced triglycerides and increased HDL-C), as well as reductions in fasting plasma glucose (Van Gaal et al 2005, Pi-Sunyer et al 2006). However, one in eight study subjects at the higher 20 mg dose discontinued medication, most commonly due to gastrointestinal side effects or depression; other adverse effects include upper respiratory tract infections, headache and dizziness. Rimonabant’s efficacy and safety has not been evaluated beyond two years. Based upon the relevant studies excluding subjects with psychiatric disorders and reporting an increased number of adverse psychiatric events, rimonabant is not recommended for patients with significant psychiatric disease or an antidepressant medication. Prescription is best initiated only under specialist supervision. Although rimonabant also shows promise in assisting smoking cessation, further data are required before it gains approval for this indication. The drug’s long-term effects, particularly on the endocannabinoid system (with its widespread receptors) also need further evaluation.

Gastric reduction (bariatric) surgery

The use of surgery to limit food intake and produce long-term weight loss is a radical and costly approach to reduce obesity. Several surgical techniques are now available. These include jejuno-ileal bypass, vertical banded gastroplasty and gastric bypass, all of which can result in significant weight loss. The more invasive the surgery, the greater the associated mortality and morbidity, but continuing or worsening severe obesity also carries significant risk to the patient of medical complications.

In the NICE 2006 guidance, “bariatric surgery is recommended as a treatment option for adults with obesity if all of the following criteria are fulfilled:

• they have a BMI of 40 kg/m2 or more, or between 35 kg/m2 and 40 kg/m2 and other significant disease (for example, type 2 diabetes or high blood pressure) that could be improved if they lost weight
• all appropriate non-surgical measures have been tried but have failed to achieve or maintain adequate, clinically beneficial weight loss for at least 6 months
• the person has been receiving or will receive intensive management in a specialist obesity service
• the person is generally fit for anaesthesia and surgery
• the person commits to the need for long-term follow-up.”

In addition, NICE recommended bariatric surgery “as a first-line option (instead of lifestyle interventions or drug treatment) for adults with a BMI of more than 50 kg/m2 in whom surgical intervention is considered appropriate” (Ref NICE 2006c).

NICE did not recommend any particular type of surgery to aid weight loss. The choice of surgical treatment should be made jointly by the individual and the doctor, taking into account individual factors (NICE 2002). Regional centres are now carrying out surgery on a regular basis.

Gastric reduction can be performed laparoscopically (using an adjustable LAP-BAND) in which the functional capacity of the stomach is permanently reduced by partitioning off of a small segment of the body of the stomach. This results in a reduced food intake, producing substantial and sustained weight loss in patients with a BMI greater than 35 kg/m2. It does appear to improve some of the major cardiovascular risk factors (Campbell & Rössner 2001), but there are no current data to compare the long-term benefits and risks of surgery with medical management in diabetics. In a severely obese nondiabetic population, the Swedish Obese Subjects Study reported improvements in lifestyle (lower energy intake and increased physical activity), hypertension and some biochemical variables (lower triglycerides and uric acid, but not hypercholesterolaemia) in those who underwent gastric surgery, compared to those who received conventional medical treatment (Sjöström et al 2004). Technically, this procedure may be difficult or impossible in patients whose BMI is very large (such as greater than 55 kg/m2), where gastric bypass is preferable.

The older surgical techniques bypass the stomach surgically; thus, restricting the stomach’s capacity as well as producing malabsorption. Post-operatively, patients undergoing this type of surgery require permanent vitamin and nutrient supplementation.

REDUCING PLATELET ADHESIVENESS

RATIONALE

Platelets are involved in the development of atherosclerosis and vascular thrombosis. In vitro evidence suggests that diabetics are often more sensitive to platelet-aggregating agents. Thromboxane is a potent vasoconstrictor and platelet aggregator. In patients with type 2 diabetes and cardiovascular disease, thromboxane production is increased. Aspirin blocks thromboxane synthesis by acetylating platelet cyclo-oxygenase.

There is considerable evidence from trials and meta-analyses that low-dose aspirin (75–162 mg/day, as effective as and possibly less risky than higher doses) should be prescribed, unless contraindicated, for secondary prevention of cardiovascular events in patients without or with diabetes mellitus. Despite the fact that diabetics with no previous cardiovascular disease run a similarly raised cardiovascular risk to nondiabetics with previous cardiovascular disease, aspirin is under-prescribed in diabetics (ADA Aspirin 2004); however, no studies have been yet published looking at primary prevention of CVD in diabetics using aspirin.

The major risks of aspirin therapy are damage to the gastric mucosa and gastrointestinal haemorrhage, even at relatively low doses. There is also an increased risk of minor bleeding episodes, such as epistaxis and bruising, but not retinal or vitreous haemorrhage. Enteric-coated preparations do not appear to reduce this risk. The contraindications to prescribing aspirin are allergy, bleeding tendency, concurrent anticoagulation treatment, recent gastrointestinal haemorrhage, history of asthma triggered by asthma, uncontrolled hypertension, and clinically active hepatic disease.

Clopidogrel (75 mg) may be considered as an alternative to aspirin in patients allergic to aspirin. It is also rather more expensive. There are limited data in diabetics, but one large study found clopidogrel to be slightly more effective than 325 mg aspirin in reducing the combined risk of stroke, myocardial infarction, or vascular death in a nondiabetic and diabetic study population (ADA – Aspirin Therapy 2004). Aspirin and clopidogrel are sometimes combined.

A recent systemic review found that relative risk of intracranial haemorrhage in patients treated with thrombolytic therapy was about 50% greater in Afro-Caribbean patients when compared to nonblack patients (McDowell et al 2006).

RECOMMENDATIONS

There is a clear consensus between the recommendations produced by JBS 2 (Wood et al 2005), the ADA (ADA 2007) and Diabetes UK that, unless contraindicated, aspirin should be prescribed in the dose range 75 to 150 mg to all patients with type 2 diabetes and existing CVD. Diabetes UK qualifies this with a lower age limit of 30 years (Diabetes UK 2001). Although all of these bodies recommend that, unless contraindicated, aspirin should be prescribed to most type 2 diabetics without evidence of CVD, the criteria vary:

For JBS 2, the criteria for prescribing a recommended dose of 75 mg are:

• All aged 50 years or more
• Under age 50 years with one of the following:

• duration of disease more than 10 years
• already receiving treatment for raised blood pressure
• evidence of target organ damage (retinopathy and/or nephropathy) whose blood pressure is controlled to below 150/90.

For the ADA, the criteria for prescribing a recommended dose of 75 to 162 mg are:

• All aged over 40 years with the presence of an additional cardiovascular risk factor (such as family history of CVD, hypertension, smoking, dyslipidaemia and albuminuria).
• “Consider” aspirin therapy, unless contraindicated, in people aged 30 to 40 years with the presence of an additional cardiovascular risk factor.

For Diabetes UK, the criteria for prescribing a recommended dose of 75 mg are:

• All aged over 30 years with one or more additional cardiovascular risk factors, as above, but also a BMI greater than 25 kg/m2 or more, South Asian ethnicity, or the presence of diabetic retinopathy.

In a 2006 clinical review, Marshall and Flyvberg go further than the above and recommend that low-dose “aspirin should be prescribed for patients aged over 40” (Marshall & Flyvberg 2006). Bearing in mind that type 2 diabetics require an approach based upon secondary prevention interventions (even in the absence of CVD) and that aspirin is under-prescribed, this recommendation has considerable merit.

In order to minimise the risk of the patient having a cerebrovascular event, it is recommended that aspirin is started only when blood pressure is controlled to less than 150/90. Aspirin should not be prescribed to individuals under the age of 21 years, because of the increased risk of Reye’s syndrome associated with aspirin use in young people.

OTHER RISK FACTORS

AGE

Cardiovascular disease risk and the prevalence of type 2 diabetes both increase with age: this may be due, in a large part, to the greater prevalence of adverse cardiovascular risk factors with increasing age. The increased incidence of CVD with age is incremental rather than linear. It is more worrying (but not surprising) that the onset of CVD occurs at a younger average age in the diabetic population.

GENDER

If the profile of other risk factors is otherwise similar, then healthy pre-menopausal females should be at less risk of developing CVD than their male contemporaries. However, in diabetic pre-menopausal females, this normally protective cardiovascular effect is lost (Barrett-Connor et al 1991). There is evidence that the presence of a cardiovascular risk factor sometimes has a greater adverse effect upon women than upon men when diabetes is present: for example, women appear to be more susceptible to the adverse effects of both active and passive smoking upon cardiovascular risk.

A meta-analysis of prospective cohort studies concluded that the excess risk for fatal CHD mortality associated with diabetes is greater in women (3.5 odds ratio) than in men (2.06 odds ratio) and the “adjusted pool” ratio of relative risks in women compared to men was 1.46. However, the analysis could not adjust for menopausal status (and hormone replace therapy) and duration of diabetes, which may be potential confounding factors (Huxley et al 2006).

The authors went on to postulate about the reasons for why this adverse effect was greater in women than in men:

• Women with diabetes not only had significantly higher blood pressure and lipid levels than men with diabetes, but also the differences among people with and without diabetes were greater in women than in men.
• Since men with diabetes or CVD are more likely to be taking aspirin, statins or antihypertensive drugs than women, there may be a treatment bias that favours men.

ETHNICITY

Due to complex and not entirely understood reasons, type 2 diabetes and CHD are commoner in certain ethnic groups, particularly in Indo-Asians, Afro-Caribbeans, Hispanic-Americans, Native Americans, Fijians and many other nonwhite populations. This increased prevalence appears to be due to a combination of greater prevalence of other cardiovascular risk factors (which also produces greater insulin resistance), and an increased vulnerability to the effects of these risk factors. However, the presence of diabetes increases the prevalence of underlying CVD in all populations, irrespective of the level of original risk.

Another aspect of ethnicity in respect to CVD that needs to borne in mind is that the risk of adverse reactions occurring to some cardiovascular drugs may vary between ethnic groups. Although sound clinical judgement must be the basis of any treatment decisions and considerably more research is needed, clinicians should be aware of potentially variable outcomes to drug treatment within the context of a risk assessment for that intervention (Eliasson 2006).

POSITIVE FAMILY HISTORY

Patients with a family history of premature arteriosclerosis are at greater risk of developing CVD, particularly in a first-degree relative, i.e. parent, sibling or child. This may be due largely to the increased prevalence (genetically mediated) of other adverse cardiovascular risk factors and an increased vulnerability to their effects. However, some families may also be exposed to one or more common adverse environmental components.

AN “ALTERNATIVE” VIEW OF TARGETS

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Two papers (Winocour 2002, Law & Wald 2002), published in the same issue of the British Medical Journal in 2002, analysed the benefits and problems associated with striving to achieve the targets advised by the various expert bodies and performance contracts.

Two problems of striving to reach a fixed target set for all patients, irrespective of their baseline prior to intervention, are:

1. The current targets set started as a mean and were achieved only by 50 to 70% of subjects in research studies.
2. Attaining these targets required polypharmacy, with the drawbacks of potentially reduced concordance and increased likelihood of drug interactions.

Given the typical cardiovascular risk profile of many type 2 diabetics and the tight recommended targets that need to be achieved, professionals could be prescribing simultaneously eight drugs:

• two hypoglycaemic agents
• three antihypertensive agents
• two lipid-modifying agents

and

• aspirin

in addition to prescribing for other medical problems!

Many patients would find such a regimen unacceptable or difficult. The factors that influence concordance are complex and vary between individual patients. Both once- and twice-daily regimens are associated with better concordance than three or more daily doses. Once-daily dosing has the advantage over twice-daily of reducing the tablet “load”. However, in patients known to miss medication, twice-daily dosing may result in shorter periods of sub-therapeutic medication levels (Wright 1993). Medication regimens may be simplified by combining more than one active drug in a single agent. There is evidence to suggest that fixed-dose combination pills and unit-of-use packaging are likely to improve adherence, although this has not been quantified (Connor et al 2004). Providing patients with a pocket-sized tablet dispenser holding one day’s tablets in up to three doses has been shown to improve adherence and glycaemic control (Maier et al 2006).

Winacour proposed alternative targets for glycaemic and blood pressure control (see Table 4.11). It may be preferable to set pragmatic individualised targets, in full collaboration with the patient and aiming to improve the adverse measurement of each component, rather than to pursue inflexibly several simultaneous “tough” targets.

TABLE 4.11 Targets for certain measurable components of diabetes care (Winocour & Fisher 2003)

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Law and Wald argue that variables, such as blood pressure, serum cholesterol, and body mass index, have a dose–response relationship with the diseases that they “cause”. They also argue “that a given change in the variables reduces the risk of disease by a constant proportion of the existing risk irrespective of the starting level of the variable or existing risk”, concluding that a patient’s overall absolute level of risk, not the level of individual risk factors, should determine the threshold for intervention. If a patient is at high risk, then appropriate intervention targets should require substantial changes in all reversible risk factors simultaneously. This is supported by the findings from the MRC/BHF Heart Protection Study that high-risk patients benefited from statin treatment, irrespective of pre-treatment cholesterol levels (Collins et al 2002). Greater risk reduction results from a significant change that falls short of reaching a fixed endpoint than from minimal change that does reach that endpoint.

Whatever targets are set and whatever interventions are undertaken, it is important what is measured accurately reflects what is and should be done. It is easier, but not necessarily preferable, to collect data about whether fixed end points have been reached (usually one measurement) than to measure how much change has occurred (which requires an additional measurement and calculation). Robert McNamara, the American Secretary of Defense in the 1960s, advised to avoid, “making what is measurable important, and find ways of making the important measurable”.

Perhaps, the important messages are that:

1. Targets should be set at a realistic and achievable level for the individual patient.
2. All treatable cardiovascular risk factors should be tackled in patients identified as “high risk”.
3. Any improvement in a risk factor is likely to produce some benefit, whatever the starting point.

KEY POINTS

• All patients with type 2 diabetes are at increased cardiovascular risk (when compared to the nondiabetic population).
• The most important modifiable cardiovascular risk factors are smoking, raised blood pressure, dyslipidaemia, increased waist circumference, physical inactivity and increased platelet adhesiveness.
• Treating all of these has been shown to reduce cardiovascular risk in diabetics.
• The greatest benefit will come from attacking aggressively all relevant risk factors, irrespective of the baseline, and not from an excessive focus on one factor to the possible exclusion of others.
• Pharmacotherapy for lowering blood pressure often requires combinations of drugs. The extent of lowering is probably more important than which drug(s) is (are) used.
• Lowering both total and LDL cholesterol with a statin is the mainstay of lipid modification, but other approaches may be required, particularly if the aim is to raise HDL cholesterol.
• Waist circumference is a better indicator of obesity than BMI. Anti-obesity drugs are often effective, but surgery is being increasingly used in the most extreme cases.
• Low-dose aspirin is indicated in many people with type 2 diabetes.
• The targets set for each risk factor need to be both realistic and individual for the patient.

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