Strategy for Arterial Risk Management in Type 2 (Non-insulin-dependent) Diabetes Mellitus

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CONTENTS AND STRUCTURE

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EUROPEAN ARTERIAL RISK POLICY GROUP

Correspondence

Correspondence to: Professor Philip Home, Department of Medicine, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
telephone : +44 191 222 7019
fax : +44 191 222 0723
e-mail : philip.home@ncl.ac.uk

CONTACTS AND POLICY GROUP

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SUMMARY

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VASCULAR DISEASE IN DIABETES

Impact on health and quality of life

• Over 1 in 10 people in northern Europe will develop Type 2 diabetes in their lifetime. The known prevalence of diabetes has tripled since the mid-1980s, and is expected to double again by the year 2010 [1].

• Cardiovascular disease causes around 65% of deaths in people with Type 2 diabetes mellitus, while hyperglycaemic emergencies, nephropathy and other aspects of diabetes account for a very small proportion of deaths in this group [2]. Accordingly, around 1 in 15 of the population will die from vascular disease in relation to diabetes

• Cardiovascular disease resulting from Type 2 diabetes is, therefore, becoming epidemic, particularly in newly industrializing countries

• While the mortality statistics are disturbing, disability and suffering due to cardiovascular disease resulting from diabetes is also of concern. Up to 20% of Type 2 diabetes patients in many populations have angina [3], and the risk of myocardial infarction (MI) is as high as in non-diabetic people who have already had an MI [4]. Ischaemic heart disease in people with diabetes is, however, often manifested as cardiac failure, rather than MI, although the latter is the more usual end point in population studies. The prevalence of intermittent claudication is equally high and the distal nature of the underlying peripheral vascular disease makes patients much less amenable to bypass procedures. This makes peripheral vascular disease a major contributor to amputation in diabetic patients. Stroke and other manifestations of cerebrovascular disease may also cause considerable disability.

An inappropriate emphasis

• Emphasis in the management of diabetes has remained focused on blood glucose control. Diagnosis is still based on blood glucose levels, and guidelines on the management of Type 2 diabetes are biased towards treatment of glucose levels [5]. Despite a lack of direct evidence linking the effects of blood glucose levels with cardiovascular outcome, management generally concentrates on achieving blood glucose targets. However, epidemiological evidence has recently indicated the level of hyperglycaemia as a significant risk factor for arterial disease [6,7]

• Reviews of the economic costs associated with diabetes have, historically, focused on peripheral vascular disease (amputation), ketoacidosis and nephropathy. Cardiovascular disease, recently confirmed as a major economic cost of diabetes [8], has been relatively ignored.

• The emphasis on glucose control has, to some extent, reflected the belief that the dyslipidaemia of diabetes reflects the hyperglycaemic state, and would resolve with its control. It is now clear that even patients with good glucose control (glycated haemoglobin levels in the normal range) have higher triglyceride and lower HDL cholesterol levels than the non-diabetic population and that the lipoprotein profile is more atherogenic [9].

Towards more modern management

• Management of people with diabetes should include reduction of arterial risk factors, encompassing more than blood glucose control

• Some progress along these lines has already been made, for example in the choice and definition of data-fields in the data-sets recommended for the management of diabetes [10]

• In line with the general approach to diabetes care, people with diabetes need to be involved with their own management, and a treatment plan worked out by agreement. This necessitates education on the relevance of blood lipid and blood pressure results, and the impact of lifestyle on total health risk

• With the aim of shifting the emphasis in this direction, a consensus meeting was held under the auspices of the International Diabetes Federation (European Region) on behalf of the St Vincent Declaration Action Programme. Participants with an active interest in the area were invited to review the relevant evidence and develop guidelines for assessment and management of arterial risk factors in Type 2 diabetic patients.

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BACKGROUND

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FACTORS CONSIDERED AND SELECTED

1.   Blood lipids

• Raised serum total cholesterol is a recognized risk factor for arterial disease in the general population [11] There is evidence that this is also the case in people with diabetes [3,12,13]

  In the Multiple Risk Factor Intervention Trial (MRFIT) which included over 5000 people with diabetes [11], a direct relationship between cardiovascular mortality and total serum cholesterol levels was seen in the diabetic group. For any given serum cholesterol level, the mortality risk was higher for people with diabetes than in non-diabetic people [3].

  Some 200 Type 2 diabetic subjects were included in the Scandinavian Simvastatin Survival Study (4S). The results of people with diabetes were the same as those of the whole group in this post-infarct study, the simvastatin treatment group showing significantly decreased mortality [12]. The diabetic subjects in the West of Scotland Study appeared to benefit from pravastatin therapy to the same extent as higher risk non-diabetic subjects [13]. The CARE study also showed benefit from pravastatin in a trial containing a large number of people with diabetes [14].

• Serum total cholesterol concentrations, however, are often of similar concentrations in diabetic and non-diabetic populations, do not give an indication of the relative levels of LDL, HDL and VLDL cholesterol, and fail to reflect lipoprotein profiles and properties known to be atherogenic.

  Examples of such abnormalities which might be particularly important in people with Type 2 diabetes are small dense LDL particles, and oxidized LDL. The presence of these abnormalities is, however, related to the dyslipidaemia frequently observed in patients with Type 2 diabetes, mostly manifested by low HDL cholesterol and raised serum triglyceride concentrations.

• Several studies suggest the importance of serum triglyceride levels in people with diabetes [15-17]. Triglyceride levels tend to be raised in diabetic patients and levels of triglycerides appear to be further related to the degree of blood glucose control.

  The pattern of moderately raised triglycerides and low HDL cholesterol appears to be associated with the atherogenic small, dense LDL and oxidized LDL profile [18].

  Epidemiological studies are inconsistent when addressing whether serum triglycerides or HDL cholesterol is the more important in prediction of arterial disease in people with diabetes. This is because the high correlation between serum triglyceride and HDL cholesterol concentrations means that it is not possible to assess them independently. However, triglycerides do predict cardiovascular disease independently of HDL cholesterol in the general population [19].

• Common measurements are total serum cholesterol, serum HDL cholesterol and serum triglycerides. From these, serum LDL cholesterol can usually be derived by simple calculation.

• Triglyceride measurement may be more accessible than HDL cholesterol, though both measures have a high inter- and intra-individual variability.

• Where assessment of HDL cholesterol is available (and triglycerides <4.5 mmol/l, or <400 mg/dl), serum LDL cholesterol can be calculated as:
  LDL cholesterol = Total cholesterol - (HDL cholesterol + Triglycerides/2.2)
  (use Triglycerides/5 if working in mg/dl). This measurement can then be used in preference to total cholesterol measurement for the assessment of arterial risk [20].

Arterial risk from serum lipid concentrations

The risk levels are defined in Table 1 and follow those used in earlier diabetes and non-diabetes guidelines.

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LIPIDS

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2. Blood pressure

• Raised blood pressure is a recognized population risk factor for cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and diabetes itself [21].The latter is presumably through its association with insulin insensitivity [22].

• The evidence for raised blood pressure as a factor for overall arterial risk [3,16] is inconsistent in epidemiological studies of people with diabetes. This presumably occurs as a result of the association of Type 2 diabetes with an abnormal lipid profile, abdominal adiposity and insulin insensitivity.

• However, the direct evidence demonstrating the benefits of lowering blood pressure with respect to cerebrovascular disease (stroke) in non-diabetic populations [23] and the efficacy of blood pressure control in diabetic nephropathy [24,25] together with the results of cardiac hypertrophy studies [26] make blood pressure control an important, modifiable, risk factor

• Blood pressure rises with age in developed populations, but not in hunter-gatherer populations with active lifestyles and diets typical of those experienced during earlier human evolution. This makes a nonsense of the assertion that 'normal' blood pressure levels increase with age.

• Epidemiological studies show that, in developed populations, the risk of stroke rises as blood pressure increases (130 mmHg systolic upwards) [27]

• Intervention to reduce blood pressure in people with Type 2 diabetes is, therefore, to be recommended in its own right.

• In people at lower risk of diabetic nephropathy (those without microalbuminuria, and those with pre-existing ischaemic heart disease or other reason for lowered life expectancy), intervention levels and targets can be similar to those for the non-diabetic population.

• Younger middle-aged patients (and others with long life expectancy) with microalbuminuria should be managed according to previously published guidelines for patients with a risk of diabetic nephropathy [28]

Interpreting blood pressure measurements

Arterial risk levels from blood pressure measurements are defined in Table 2.

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BLOOD PRESSURE

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3. Blood glucose concentration

Significance of hyperglycaemia

• Vascular risk increases with all levels of glucose intolerance, even in those people without diabetes [29,30].

• Epidemiological studies of diabetic populations show a rising risk with degree of hyperglycaemia across all studied plasma glucose concentrations [6,7,31].

• Many of the putative mechanisms for arterial damage, such as endothelial abnormalities, vascular permeability, lipoprotein profile, oxidative stress, platelet aggregation factors, coagulation factors and insulin insensitivity, are affected by higher blood glucose levels [4,32].

• Thus, while direct evidence of the benefits of controlling hyperglycaemia on vascular risk is still not available, the indirect evidence is compelling.

• Risk associated with hyperglycaemia will be compounded by other risk factors, notably age.

• The strongest data relating glucose control to arterial risk in people with diabetes involve HbA1c measurement [6,7]

• While the risk may be linear or curvilinear, in contrast to that of microvascular disease, some categorization of risk is possible (see box) based on levels typically found in this type of patient, and recommendations taken, for convenience, from risk levels for microvascular disease [5,33]

• Arterial risk levels from blood glucose concentrations are defined in Table 3.

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BLOOD GLUCOSE

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4. Body Mass Index

• Body weight higher than the calculated norm is a statistical risk factor for ischaemic heart disease in the general population and in people with Type 2 diabetes [34,35].

• However, obesity is associated with insulin insensitivity and abnormal blood lipid levels [36]. Its independence from associated risk factors has been questioned.

• Distribution of fat appears to be of greater importance than body weight itself, with visceral fat (the most metabolically active of the adipose tissues) most associated with changes in glucose and lipid metabolism [37].

• Epidemiological studies have demonstrated the importance of the waist:hip ratio [38] but this measure suffers from considerable operator variability.

• Accordingly, body mass index (BMI, weight/height² as kg/m²) is the most practicable clinical measurement for assessment of risk.

• However, for management purposes (response to intervention and lifestyle change) body weight alone is entirely satisfactory and easily understood.

• Arterial risk levels from body mass index estimation are defined in Table 4.