Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: full text,
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The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD)
Authors/Task Force Members,
gorzata Bartnik
Sweden
Germany
Poland
Belgium
UK
The Netherlands
Italy
Sweden
Finland
Sweden
Italy
Sweden
Finland
Iceland
Other Contributors,
Belgium
Italy
Sweden
Finland
ESC Committee for Practice Guidelines (CPG),
Italy
France
Poland
UK
France
The Netherlands
Norway
Greece
France
Italy
Portugal
Germany
Spain
Spain
Document Reviewers,
The Netherla
France
France
Germany
Italy
Denmark
Germany
Spain
Ireland
Portugal
Germany
Finland
Israel
Austria
Italy
UK
* Corresponding authors: Lars Rydén, Department of Cardiology, Karolinska University Hospital, Solna SE-171, 76 Stockholm, Sweden. Tel: +46 8 5177 2171; fax: +46 8 31 10 44; Eberhard Standl Department of Endocrinology, Munich Schwabing Hospital, D-80804 Munich, Germany. Tel: +49 89 3068 2523; fax: +49 89 3068 3906. E-mail address: lars.ryden{at}ki.se; eberhard.standl{at}lrz.uni-muenchen.de
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Preamble |
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 Top Preamble IntroductionDefinition, classification, and...Epidemiology of diabetes, IGH,...IntroductionIdentification of subjects at...PathophysiologyTreatment to reduce...Management of CVDHeart failure and diabetesArrhythmias: AF and sudden...Peripheral and cerebrovascular...Intensive careHealth economics and diabetesAppendixReferences |
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Guidelines and Expert Consensus documents aim to present management and recommendations based on all of the relevant evidence on a particular subject in order to help physicians to select the best possible management strategies for the individual patient, suffering from a specific condition, taking into account not only the impact on outcome, but also the risk–benefit ratio of a particular diagnostic or therapeutic procedure. Numerous studies have demonstrated that patient outcomes improve when evidence-based guideline recommendations are applied in clinical practice.
A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and also by other organizations or related societies. The profusion of documents can question the authority and credibility of guidelines, particularly if discrepancies appear between different documents on the same issue leading to confusion for practising physicians. In order to avoid these pitfalls, the ESC and other organizations have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents. The ESC recommendations for guidelines production can be found on the ESC website. It is beyond the scope of this preamble to recall all, but the basic rules.
In brief, the ESC appoints experts in the field to carry out a comprehensive review of the literature, with a view to making a critical evaluation of the use of diagnostic and therapeutic procedures, and assessing the risk–benefit ratio of the therapies recommended for management and/or prevention of a given condition. Estimates of expected health outcomes are included, where data exists. The strength of evidence for or against particular procedures or treatments is weighed, according to predefined scales for grading recommendations and levels of evidence, as outlined below.
The Task Force members of the writing panels, as well as the document reviewers, are asked to provide disclosure statements of all relationships they may have, which might be perceived as real or potential conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC and can be made available by written request to the ESC President. Any changes in conflict of interest that arise during the writing period must be notified to the ESC.
Guidelines and recommendations are presented in formats that are easy to interpret. They should help physicians to make clinical decisions in their daily routine practice, by describing the range of generally acceptable approaches to diagnosis and treatment. However, the ultimate judgement regarding the care of an individual patient must be made by the physician-in-charge of his/her care.
The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups or consensus panels. The Committee is also responsible for the endorsement of these Guidelines and Expert Consensus Documents or statements.
Once the document has been finalized and approved by all the experts involved in the Task Force, it is submitted to outside specialists for review. In some cases, the document can be presented to a panel of key opinion leaders in Europe on the relevant condition, for discussion and critical review. If necessary, the document is revised once more and finally approved by the CPG and selected members of the Board of the ESC and subsequently published.
After publication, dissemination of the message is of paramount importance. Publication of executive summaries and the production of pocket-sized and PDA-downloadable versions of the recommendations are helpful. However, surveys have shown that the intended end-users are often not aware of the existence of guidelines, or simply do not put them into practice. Implementation programmes are thus necessary and form an important component of the dissemination of knowledge. Meetings are organized by the ESC, and directed towards its member National Societies and key opinion leaders in Europe. Implementation meetings can also be undertaken at a national level, once the guidelines have been endorsed by the ESC member societies, and translated into the local language, when necessary.
All in all, the task of writing Guidelines or Expert Consensus Documents covers not only the integration of the most recent research, but also the creation of educational tools, and implementation programmes for the recommendations. The loop between clinical research, writing of guidelines, and implementing them into clinical practice can then only be completed if surveys and registries are organized to verify that actual clinical practice is in keeping with what is recommended in the guidelines. Such surveys and registries also make it possible to check the impact of strict implementation of the guidelines on patient outcome.
Classes of Recommendations:
Levels of Evidence:
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Introduction |
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TopPreambleIntroductionDefinition, classification, and...Epidemiology of diabetes, IGH,...IntroductionIdentification of subjects at...PathophysiologyTreatment to reduce...Management of CVDHeart failure and diabetesArrhythmias: AF and sudden...Peripheral and cerebrovascular...Intensive careHealth economics and diabetesAppendixReferences |
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Diabetes and cardiovascular diseases (CVD) often appear as the two sides of a coin: on one side, diabetes mellitus (DM) has been rated as an equivalent of coronary heart disease (CHD), and conversely, many patients with established CHD suffer from diabetes or its pre-states. Thus, it is high time that diabetologists and cardiologists join forces together to improve the quality management in diagnosis and care for the millions of patients who have both cardiovascular and metabolic diseases in common in one and the same person. The cardio-diabetologic approach not only is of utmost importance for the sake of those patients, but also instrumental for further progress in the fields of cardiology and diabetology.
The European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) have accepted this challenge and decided to develop joint, evidence-based guidelines for ‘Diabetes and Cardiovascular Diseases’. Experts from both sides were asked to form a Task Force and to write state-of-the-art chapters. Although individual authors have been assigned to draft the manuscripts according to their specific area of expertise, the guidelines were then extracted and harmonized as a true team effort by the whole group. Hence, the names of all authors appear only on the cover of these guidelines as members of the writing group. Some of the members of the Task Force were helped in the literature search and writing process by members of their respective teams and these contributors are also named on the cover as contributors. The guidelines were then reviewed by independent referees appointed by the two scientific organizations whose identity were disclosed, once all criticisms and suggestions had been incorporated into the text to achieve the broadest possible expertise and consensus. The referees are also acknowledged with their names on the cover and are an important, integral part of this scientific guideline exercise.
It may seem that these guidelines are rather extensive. They were, however, written for two ‘worlds’, diabetology and cardiology. Thus, information that may seem obvious, including pathophysiology, for one part may need a more extensive description for the other. A decision was therefore taken, to keep the main document as complete as possible, making an executive summary and pocket guidelines for those, who are searching short, practical information. These guidelines do not aim to provide detailed information on daily blood glucose management in patients because therapies are tailored to individual patient requirements, particularly in patients with type 2 diabetes. Achieving the agreed glucose level targets is more important than the therapy and regimen. For those requiring additional information on blood glucose management the Global Guideline for Type 2 Diabetes of the International Diabetes Federation (www.idf.org) is recommended.
The core approach of the group is depicted in Figure 1. An algorithm has been developed to help discover the alternate CVD in patients with diabetes, and vice versa, the metabolic diseases in patients with CHD, setting the basis for appropriate joint therapy. This algorithm has also been endorsed by the expert working group of the Declaration of Vienna on February 15, 2006 under the auspices of the Austrian Presidency of the European Union. The purpose of these guidelines is to improve the management of:
- Patients with overt diabetes.
- Patients at risk of developing diabetes, as demonstrated by impaired glucose tolerance.
- Cardiovascular diseases in these patient populations.
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It is a great privilege for the two co-chairmen of this task force of having been able to work with the finest and best reputed experts and scientists in the field at the European level and to give these guidelines now to the community of cardiologists and diabetologists. On this occasion, we wish to thank all members of the task force who so generously shared their knowledge, as well as the referees for their tremendous input. Special thanks go to Professor Carl Erik Mogensen for his advice on the diabetic renal disease and microalbuminuria sections. We would also like to thank the ESC and the EASD for making these guidelines possible. Finally, we want to express our appreciation of the guideline team at the Heart House, especially Veronica Dean, for their extremely helpful support.
Stockholm and Munich, September 2006
Professor Lars Ryden, Past-President ESC
Professor Eberhard Standl, Vice-President EASD
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Definition, classification, and screening of diabetes and pre-diabetic glucose abnormalities |
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TopPreambleIntroductionDefinition, classification, and...Epidemiology of diabetes, IGH,...IntroductionIdentification of subjects at...PathophysiologyTreatment to reduce...Management of CVDHeart failure and diabetesArrhythmias: AF and sudden...Peripheral and cerebrovascular...Intensive careHealth economics and diabetesAppendixReferences |
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Table of Recommendations:
Introduction
DM is a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects of insulin secretion, insulin action, or a combination of both.1 In type 1 diabetes, it is due to a virtually complete lack of endogenous pancreatic insulin production, whereas in type 2 diabetes, the rising blood glucose results from a combination of genetic predisposition, unhealthy diet, physical inactivity, and increasing weight with a central distribution resulting in complex pathophysiological processes. Traditionally, diagnosis of diabetes was based on symptoms due to hyperglycaemia, but during the last decades much emphasis has been placed on the need to identify diabetes and other forms of glucose abnormalities in asymptomatic subjects. DM is associated with development of specific long-term organ damage (diabetes complications) including retinopathy with potential blindness, nephropathy with a risk of progression to renal failure, neuropathy with risk for foot ulcers, amputation, and Charcot joints and autonomic dysfunction such as sexual impairment. Patients with diabetes are at a particularly high risk for cardiovascular, cerebrovascular, and peripheral artery disease.
Definition and classification of diabetes
Since the first unified classification of diabetes by the National Diabetes Data Group in 19792 and the World Health Organisation (WHO) in 1980,3 a few modifications have been introduced by the WHO4,5 and the American Diabetes Association (ADA),6,7 (Table 1).
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Impaired glucose tolerance (IGT) can be recognized by the results of OGTT only: 2-h post-load plasma glucose (2hPG)
7.8 and < 11.1 mmol/L (140 and < 200 mg/dL). A standardized OGTT test performed in the morning, after an overnight fast (8–14 h); one blood sample should be taken before and one 120 min after intake of 75 g glucose dissolved in 250–300 mL water in a course of 5 min (note: timing of the test is from the beginning of the drink).
Classification of diabetes includes both aetiological types and different clinical stages of hyperglycaemia as suggested by Kuzuya and Matsuda.8 Four main aetiological categories of diabetes have been identified as diabetes type 1, type 2, other specific types, and gestational diabetes, as detailed in the WHO document4 (Tables 2 and 3, Figure 2).
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Type 1 diabetes characterized by deficiency of insulin due to destructive lesions of pancreatic ß-cells; usually progresses to the stage of absolute insulin deficiency. Typically, it occurs in young subjects with acute-onset with typical symptoms of diabetes together with weight loss and propensity to ketosis, but type 1 diabetes may occur at any age,9 sometimes with slow progression. People who have antibodies to pancreatic ß-cells such as glutamic-acid-decarboxylase (GAD), are likely to develop either typical acute-onset or slow-progressive insulin-dependent diabetes.10,11 Today antibodies to pancreatic ß-cells are considered as a marker of type 1 diabetes, although such antibodies are not detectable in all patients.
Type 2 diabetes is caused by a combination of decreased insulin secretion and decreased insulin sensitivity. Typically, the early stage of type 2 diabetes is characterized by insulin resistance and decreased ability for insulin secretion causing excessive post-prandial hyperglycaemia. This is followed by a gradually deteriorating first-phase insulin response to increased blood glucose concentrations.12 Type 2 diabetes, comprising over 90% of adults with diabetes, typically develops after middle age. The patients are often obese or have been obese in the past and have typically been physically inactive. Ketoacidosis is uncommon, but may occur in the presence of severe infection or severe stress.
Gestational diabetes constitutes any glucose perturbation that develops during pregnancy and disappears after delivery. Long-term follow-up studies, recently reviewed by Kim et al.,13 reveal that most, but not all, women with gestational diabetes do progress to diabetes after pregnancy. Long-term studies that have been conducted over a period of more than 10 years reveal a stable long-term risk of 
70%.13 In some cases, type 1 diabetes may be detected during pregnancy.
Other types include: (i) diabetes related to specific single genetic mutations that may lead to rare forms of diabetes, as for instance MODY; (ii) diabetes secondary to other pathological conditions or diseases (as a result of pancreatitis, trauma, or surgery of pancreas); (iii) drug or chemically induced diabetes.
The clinical classification also comprises different stages of hyperglycaemia, reflecting the natural history of absolute or relative insulin deficiency progressing from normoglycaemia to diabetes. It is not uncommon that a non-diabetic individual may move from one category to another in either direction. Usually, a progression towards a more severe glucose abnormality takes place with increasing age. This is reflected by the increase in the 2-hPG level with age.14
The currently valid clinical classification criteria have been issued by WHO4 and ADA.7 These are currently under review by WHO and updated criteria will be introduced soon. The WHO recommendations for glucometabolic classification are based on measuring both fasting and 2-hPG concentrations and recommend that a standardized 75 g OGTT should be performed in the absence of overt hyperglycaemia.4 The thresholds for diabetes on fasting and 2-hPG values were primarily determined by the values where the prevalence of diabetic retinopathy, which is a specific complication of hyperglycaemia, starts to increase. Even though macrovascular diseases such as CHD and stroke are major causes of death in type 2 diabetic patients and people with IGT, macrovascular disease has not been considered in the classification. This sounds illogical and may give an impression that macrovascular diseases are less important than microvascular consequences of diabetes. Classification according to the ADA criteria strongly encourages the single use of fasting glycaemia only without an OGTT.6,7
The currently recommended categories of glucose metabolism according to WHO and the ADA are presented in Table 1 (for adults). The National Diabetes Data Group2 and WHO3 coined the term IGT, an intermediate category between normal glucose tolerance and diabetes. The ADA6 and the WHO Consultation4 proposed some changes to the diagnostic criteria for diabetes and introduced a new category called impaired fasting glucose/glycaemia (IFG). The ADA recently decreased the lower threshold for IFG from 6.1 to 5.6 mmol/L,7 but this has been criticized and has not yet been adopted by the WHO expert group that recommends to keep the previous cut-points as shown in the WHO consultation report in 1999. These criteria were reviewed by a new WHO expert group in 2005.
In order to standardize glucose determinations, plasma has been recommended as the primary specimen. Since many equipment use either whole blood or venous or capillary blood, thresholds for these vehicles have also been given. The non-plasma recommendations for threshold are based on approximate estimates rather than on validated conversion factors. A recent analysis based on the direct pair-wise comparison of various types of specimens suggest that the factors presented in Table 4 should be used to convert values measured in whole blood, capillary blood, and serum to plasma, respectively.15
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The glucometabolic category in which an individual is placed depends on whether only fasting plasma glucose (FPG) is measured or if it is combined with a 2-hPG value. For example, an individual falling into the IFG category in the fasting state may have IGT or diabetes disclosed by a post-load glucose.
The metabolic determinants and physiological bases of FPG and 2-hPG differ to some extent.1,16,17 This means the categorization of an individual on a FPG value may differ from that based on a 2-hPG. Having a normal FPG requires the ability to maintain an adequate basal insulin secretion and an appropriate hepatic insulin sensitivity to control hepatic glucose output. Abnormalities of these functions characterize IFG. During an OGTT, the normal response to the absorption of the glucose load is both to suppress hepatic glucose output and to enhance hepatic and skeletal muscle glucose uptake. To keep a post-load glucose level within the normal range requires appropriate dynamics of the ß-cell secretory response, amount and timing, in combination with adequate hepatic and muscular insulin sensitivity.
Recommendation
The definition and diagnostic classification of diabetes and its pre-states should be based on the level of the subsequent risk of cardiovascular complications. Class I, Level of Evidence B.
Glycated haemoglobin
Glycated haemoglobin (HbA1c), a useful measure of metabolic control and the efficacy of glucose-lowering treatment, is an integrated summary of circadian blood glucose during the preceding 6–8 weeks, equivalent to the lifespan of erythrocytes.18 It provides a mean value but does not reveal any information on the extent and frequency of blood glucose excursions. HbA1c has never been recommended as a diagnostic test for diabetes.4,7 A primary reason is the lack of a standardized analytical method and therefore lack of a uniform, non-diabetic reference level between various laboratories. A high HbA1c may only identify a fraction of asymptomatic people with diabetes. HbA1c is insensitive in the low range and a normal HbA1c cannot exclude the presence of diabetes or IGT.
Markers of glucometabolic perturbations
An inherent difficulty in the diagnosis of diabetes is the present lack of an identified, unique biological marker that would separate people with IFG, IGT, or diabetes from people with normal glucose metabolism. The use of diabetic retinopathy has been discussed, but the obvious limitation is that this condition in a majority of the patients only becomes evident after several years of hyperglycaemic exposure.1,5–10 On the other hand, diabetic retinopathy is diagnosed in 1% of the non-diabetic population. Thus far, total mortality and CVD have not been considered for defining those glucose categories that carry a significant risk. Nevertheless, the vast majority of people with diabetes die from CVD and asymptomatic glucometabolic perturbations more than double mortality and the risk for myocardial infarction (MI) and stroke. Since the majority of type 2 diabetic patients develop CVD, which is a more severe (often even fatal) and costly complication of diabetes than retinopathy, CVD should be considered when defining cut-points for glucose.
Comparisons between FPG and 2-hPG
The diagnostic levels of FPG and 2-hPG are largely based on their association with the risk of having or to develop retinopathy. As outlined in the 1997 report by the ADA,6 the incidence of retinopathy increases already above a FPG of 7.0 mmol/L, and not above the higher threshold level of 7.8 mmol/L as previously used for the diagnosis of diabetes. The DECODE Study (Figure 3) has shown that any mortality risk in people with elevated FPG is actually related to a concomitantly elevated 2-hPG glucose.15,19,20 Thus, the current cut-off point for diabetes based on a 2-hPG 11.1 mmol/L may be too high. Lowering the threshold, although not yet formally challenged.
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It has been noted that, although an FPG
7.0 mmol/L and a 2-hPG of 11.1 mmol/L sometimes identifies the same individuals, often they may not coincide. In the DECODE Study,21 recruiting patients with diabetes by either criterion alone or by their combination, only 28% met both, and 40% met the fasting and 31% the 2-hPG criterion only (Figure 4). Among those who met the 2-hPG criterion, 52% did not meet the fasting criterion, and 59% of those who met the fasting criterion did not meet the 2-hPG criterion. In the U.S. NHANES III Study of previously undiagnosed diabetic adults aged 40–74 years, 44% met both the FPG and the 2-hPG criteria, whereas 14% met the FPG criterion only and 41% the 2-hPG criterion only.22
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Screening for undiagnosed diabetes
Recent estimates suggest that 195 million people throughout the world have diabetes and that this number will increase to 330, maybe even to 500 million, by 2030.23,24 Many patients, up to 50% in most investigations, with type 2 diabetes are undiagnosed21,22,34 since they remain asymptomatic and therefore are undetected for many years. Detecting people with undiagnosed type 2 diabetes is important for both public health and every day clinical practice. Mass screening for asymptomatic diabetes has not been recommended in the general population pending evidence that the prognosis of such patients will improve by early detection and treatment.25,26 Importantly, lack of evidence relates to lack of studies testing the hypothesis that early screening would indeed be advantageous. One such study (ADDITION) is ongoing in Denmark, the Netherlands, and the UK. Indirect evidence suggests that screening might be beneficial as it improves the possibility of early detection of diabetes and thereby improved prevention of cardiovascular complications. In addition, there is an increasing interest in identifying people with IGT, who might benefit from life style or pharmacological intervention to reduce or delay the progression to diabetes.27
Extensive data from epidemiological studies have challenged the practice not to utilize the 2-hPG showing that a substantial number of people, who do not meet the FPG criteria for abnormal glucose tolerance, will satisfy the criteria when exposed to an OGTT.14,21,22,28 Thus, the risk of a false negative diagnosis is substantial when measuring FPG alone. The argument for FPG over 2-hPG is primarily related to the matter of feasibility. An OGTT has been considered a less well-suited tool at a population level, mainly because the test takes somewhat more than 2 h to conduct. However, 2-hPG is the only way to detect IGT. Many subjects with IGT will develop CVD before progressing to diabetes.28
Recommendation
Early stages of hyperglycaemia and asymptomatic type 2 diabetes are best diagnosed by an OGTT that gives both fasting and 2-hPG values. Class I, Level of Evidence B.
Detection of people at high-risk for diabetes
Persons at high-risk for developing diabetes and those with asymptomatic diabetes by definition have no symptoms of diabetes and typically are not aware of their high-risk status. Although much attention has been directed at detecting undiagnosed type 2 diabetes in the past decades, only recently attention has turned to those with lesser degrees of glucometabolic abnormalities, which tend to share the same risk factors with type 2 diabetes.
Three general approaches for early detection exist: (i) measuring blood glucose to explicitly determine prevalent impaired glucose homeostasis (IGH), a strategy that will detect undiagnosed diabetes as well; (ii) using demographic and clinical characteristics and previous laboratory tests to determine the likelihood of future incident diabetes, a strategy that leaves current glycaemic state ambiguous; (iii) collecting questionnaire-based information on factors that provide information about the presence and extent of a number of aetiological factors for type 2 diabetes, a strategy that also leaves the current glycaemic state ambiguous.
The two latter approaches can serve as primary and cost-efficient screening tools, identifying a subgroup of the population in whom glycaemic testing may be targeted with a particular yield. The second option is particularly suited for certain groups, including those with pre-existing CVD and women who have had gestational diabetes, whereas the third option is better suited for the general population (Figure 5). Glycaemic testing is necessary as a secondary step in all three approaches to accurately define IGH, as the initial screening step is not diagnostic.
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There will be a trade-off between sensitivity and specificity among the strategies. The final choice will depend on the goal and on relative health liabilities such as false positive vs. false negative. If the burden, as imposed by confirmatory testing, is not great and treatment is relatively harmless and inexpensive, one may accept a higher false positive rate. On the other hand, if the consequences of not treating in a timely manner are minor, a higher false negative rate may be acceptable. In algorithms that use multiple tests, the sequence will depend on the various steps leading to the confirmatory test, including costs, feasibility, and compliance. False labelling may be a problem in the first approach only, as the two other deals with elevated risk factors that are less sensitive to misclassification and by their own right already should lead to life style advise.25 Including more glycaemic tests will contribute with more explicit information on the glycaemic status, whereas fewer tests result in more uncertainty. If a strategy does not incorporate an OGTT at any stage, individual glucose tolerance cannot be determined. Fasting glucose and HbA1c will not reveal information about glucose excursions after meals or a glucose load.
It is necessary to separate three different scenarios: (i) general population; (ii) subjects with assumed metabolic abnormalities, including those who are obese, hypertensive, or who have a family history of diabetes; and (iii) patients with prevalent CVD. When patients with prevalent CVD have glucometabolic abnormalities, in most cases it is the 2-hPG value which is elevated, whereas fasting glucose is often normal.30 Thus, the measurement of fasting glucose alone should be avoided in such patients. Since patients with CVD by definition can be considered at high-risk, there is no need to carry out a separate diabetes risk assessment, but an OGTT should be carried out in them. In the general population, the appropriate strategy is to start with risk assessment as the primary screening tool combined with subsequent glucose testing of individuals identified to be at a high risk.31 This tool predicts the 10-year risk of type 2 diabetes with 85% accuracy, and in addition it detects current asymptomatic diabetes and abnormal glucose tolerance.32,33
Recommendation
Primary screening for the potential type 2 diabetes can be done most efficiently using a non-invasive risk score, subsequently combined with a diagnostic oral glucose tolerance testing in people with high score values. Class I, Level of Evidence A.
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Epidemiology of diabetes, IGH, and cardiovascular risk |
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TopPreambleIntroductionDefinition, classification, and...Epidemiology of diabetes, IGH,...IntroductionIdentification of subjects at...PathophysiologyTreatment to reduce...Management of CVDHeart failure and diabetesArrhythmias: AF and sudden...Peripheral and cerebrovascular...Intensive careHealth economics and diabetesAppendixReferences |
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Table of Recommendations:
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Introduction |
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TopPreambleIntroductionDefinition, classification, and...Epidemiology of diabetes, IGH,...IntroductionIdentification of subjects at...PathophysiologyTreatment to reduce...Management of CVDHeart failure and diabetesArrhythmias: AF and sudden...Peripheral and cerebrovascular...Intensive careHealth economics and diabetesAppendixReferences |
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The prevalence of type 2 diabetes increases with age especially in Europe.14 Post-load hyperglycaemia reflects the acute increase in blood glucose after a glucose load, whereas fasting blood glucose shows the glucose concentration after an overnight fast and reflects mostly hepatic glucose production. They represent physiologically different aspects of glucose metabolism and may be differently influenced by the ageing process; post-prandial glucose excursions increase with age. The impact of gender on different abnormalities in glucose regulation is another unsolved issue.23,35,36 Recently, the DECODE Study reported data on the age- and gender-specific prevalence of diabetes and IGH, as well as the age- and gender-specific prevalence of isolated fasting or 2-h post-load hyperglycaemia in European populations.38
Prevalence of diabetes and IGH
Plasma glucose concentrations, age and gender
The mean 2-h plasma glucose concentration rises with age in European populations, particularly after the age of 50 (Figure 6). Women have significantly higher mean 2-h plasma glucose concentrations than men, and this gender difference becomes more pronounced after the age of 70, probably because of survival disadvantage in men compared with women. Mean FPG concentration increases only slightly with age, in men up to 69 years and in women across all ages. Mean FPG concentration is higher in men than in women during the age period 30–69 years and becomes higher in women after 70 years.
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Prevalence of diabetes and IGH
The age-specific prevalence of diabetes rises with age up to the seventh and eighth decades in both men and women (Figure 7).14 The prevalence is less than 10% in subjects below the age of 60, 10–20% between 60–69 years, whereas 15–20% in the oldest age groups have previously known diabetes and a similar proportion have screen-detected asymptomatic diabetes. This suggests that the lifetime risk of diabetes in European people is 30–40%.
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The prevalence of IGT increases linearly by age, but the prevalence of impaired fasting glycaemia does not (Figure 8). In middle-aged people, the prevalence of IGH is about 15%, whereas in the elderly 35–40% of European people have IGH. The prevalence of diabetes and IGT defined by isolated post-load hyperglycaemia is higher in women than in men, but the prevalence of diabetes and impaired fasting glucose (IFG) diagnosed by isolated fasting hyperglycaemia is higher in men than in women.14
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Diabetes and coronary artery disease
The most common cause of death in European adults with diabetes is coronary artery disease (CAD). Several studies have demonstrated they have a risk that is two to three times higher than that among people without diabetes.39 There are wide differences in the prevalence of CAD in patients with type 140 or 2 diabetes and also between different populations. The follow-up study of 10 centres of the WHO Multinational Study of Vascular disease in diabetes41,42 including about 4700 type 1 and 2 patients, revealed that Japanese patients had a notably lower incidence of CAD than subjects from other parts of the world. Furthermore, their CAD incidence rates were lower than those in many non-diabetic western populations. CVD was the most common cause of mortality accounting for 44% of all deaths among patients with type 1 and 52% in patients with type 2 diabetes.42 In the EURODIAB IDDM Complication Study, involving 3250 type 1 diabetic patients from 16 European countries, the prevalence of CVD (a past history and electrocardiographic abnormality) was 9% in men and 10% in women.43 The prevalence increased by age, from 6% in the age group 15–29 years to 25% in the age group 45–59 years, and with the duration of diabetes. In type 1 diabetic patients, the risk of CAD increases dramatically with the onset of diabetic nephropathy. Up to 29% of patients with childhood-onset type 1 diabetes and nephropathy will, after 20 years with diabetes, have CAD compared to only 2–3% in similar patients without nephropathy.44 In this context, besides hyperglycaemia, other CVD risk factors, such as hypertension, smoking, and dyslipidaemia, seem to be important contributing factors for CAD.45,46
Several studies compared the magnitude of risk for CAD associated with the history of type 2 diabetes or the presence of previous CAD. In a 7-year follow-up of a Finnish Study47 and a 20-year follow-up of the Nurse's Health Study48 patients with type 2 diabetes without any previous acute coronary events had a similarly high number of fatal CAD events as non-diabetic patients with a previous MI. The combination of type 2 diabetes and previous CAD identifies a group of patients with particularly high risk for coronary deaths. Moreover, the Nurse's Health Study indicated a strong relation between the duration of known diabetes and CAD mortality. Recently, data were reported from 51 735 Finnish men and women, aged 25–74 years and followed for an average of 17 years, during which time 9201 deaths occurred.49 Among men with diabetes only, with MI only and with both diseases, combined hazard ratios (HR) for coronary mortality, adjusted for other risk factors, were 2.1, 4.0, and 6.4, respectively, compared to men without either disease. The corresponding HRs for women were 4.9, 2.5, and 9.4. HRs for total mortality were 1.8, 2.3, and 3.7 in men and 3.2, 1.7, and 4.4 in women. Diabetic men and women had comparable mortality rates, whereas coronary mortality among men was markedly higher. Thus, a history of diabetes and MI markedly increased CVD and all-cause mortality. The relative effect of diabetes was larger in women, whereas the relative effect of the history of MI was more substantial among men. The increased risk of CAD in subjects with diabetes was only partly explained by concomitant risk factors including hypertension, obesity, dyslipidaemia, and smoking. Thus, the diabetic state or hyperglycaemia itself and its consequences are very important for the increased risk for CAD and related mortality. Further support to the important relation between diabetes and MI was obtained from the Interheart Case Control Study.160 Diabetes increased the risk by more than two times in men and women independent of ethnicity.
Asymptomatic hyperglycaemia and CAD
In 1979, a series of papers from the International Collaborative Group50 did not find any consistent evidence for either a threshold or a graded association between asymptomatic hyperglycaemia and CAD. There were, however, several methodological concerns with these early studies. Many of them used fasting glucose only; moreover, differences in glucose assays, glucose load, sample time after loading, follow-up time, and the population studied may have contributed to the inconsistent observations. After the introduction of standard criteria, in 1980, several studies revealed an association between 2-h plasma glucose and CAD in the general population.51–63 Some studies also showed an association with fasting glucose. A meta-analysis of 20 epidemiological studies found a progressive relationship between plasma glucose, fasting and post-load, and the incidence of cardiovascular events among people without diabetes. However, the results were not adjusted for other potential confounding factors.64
Recommendation
The relationship between hyperglycaemia and CVD is to be seen as a continuum. For each 1% increase of HbA1c, there is a defined increased risk for CVD. Class I, Level of Evidence A.
The risk of CVD for people with overt diabetes is increased by two to three times for men and three to five times for women compared to people without diabetes. Class I, Level A.
IGH and CAD
Cardiovascular risk and post-prandial hyperglycaemia
The major disagreement in the classification of glucose homeostasis between the criteria issued by WHO and ADA focuses on whether diabetes should be diagnosed by means of a fasting or a 2-hPG. While different people are identified as diabetic and particularly as having IGH, when testing for fasting glucose than for a post-load glucose, it is clinically important to know how these two entities relate to mortality and the risk for CVD. Three early cohort studies, the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study, assessed the relationship between 2-hPG and the risk for CAD in European men.56,57,65 With known diabetes excluded, CVD mortality in individuals with a high 2-hPG (>95th centile in the Whitehall Study and >80th centile in the Paris and Helsinki studies) was twice that in subjects with normal glucose levels. In the Japanese Funagata Diabetes Study, survival analysis concluded that IGT, but not IFG was a risk factor for CVD.63 In a recent Finnish Study, IGT at baseline was an independent risk predictor of incident CVD and premature all-cause and cardiovascular mortality, a finding not confounded by the development of clinically diagnosed diabetes during follow-up.29
The 23-year follow-up of the Honolulu Heart Programme suggested a dose–response relationship between 1 h glucose after a 50 g load and CAD mortality.59 The Chicago Heart Study of 12 000 men without a history of diabetes showed that white men with asymptomatic hyperglycaemia [1 h glucose 11.1 mmol/L (200 mg/dL)] had an increased risk of CVD mortality compared with men having a low post-load glucose < 8.9 mmol/L (160 mg/dL).58 The Rancho Bernardo Study indicated that elderly Californian women (but not men) with isolated post-challenge hyperglycaemia [2-hPG 11.1 mmol/L (200 mg/dL) and FPG < 7.0 mmol/L (126 mg/dL)] had a significantly increased risk of CVD.51
Several studies assessed the association of CVD with fasting and 2-hPG. Based on longitudinal studies in Mauritius, Fiji, and Nauru, Shaw et al.62 reported that people with isolated post-challenge hyperglycaemia doubled their CVD mortality compared with non-diabetic persons, whereas there was no significant increase in mortality related to isolated fasting hyperglycaemia [FPG 7.0 mmol/L (126 mg/dL) and 2-hPG < 11.1 mmol/L (200 mg/dL)]. In the Cardiovascular Health Study, including 4515 subjects above the age of 65 years, the relative risk for incident CAD was higher in individuals with abnormal glucose homeostasis (comprising IGT, IFG, and newly diagnosed diabetes, detected by both fasting and 2-hPG) than in those with normal glucose levels. However, criteria based on FPG alone were less sensitive than the WHO 1999 criteria based on fasting and 2-hPG for predicting CAD.52 A recent analysis of the US Second National Health and Nutrition Survey data, including 3092 adults aged 30–74 years, found a graded increase in mortality associated with abnormal glucose tolerance ranging from a 40% greater risk in adults with IGT to an 80% greater risk in adults with newly diagnosed diabetes.67
The most convincing evidence for a relation between abnormal glucose tolerance and an increased CAD risk has been provided by the DECODE Study, jointly analysing data from more than 10 prospective European cohort studies including more than 22 000 subjects.68,69 Death rates from all-causes, CVD, and CAD were higher in diabetic subjects diagnosed by 2-hPG than in those not meeting this criterion. Significantly increased mortality was also observed in subjects with IGT, whereas there was no difference in mortality between subjects with impaired and normal fasting glucose. Multivariate analyses showed that high 2-hPG predicted mortality from all-causes, CVD, and CAD, after adjustment for other major cardiovascular risk factors, but high fasting glucose alone did not. High 2-hPG was a predictor for death, independent of FPG, whereas increased mortality in people with elevated FPG largely related to the simultaneous elevation of the 2-hPG. On the other hand, FPG did not add any predictive information once 2-hPG was entered into the model. All-cause and CVD mortality were increased in subjects with an FPG 7.0 mmol/L (126 mg/dL), but even among them it was a simultaneous elevation of 2-hPG that explained the increased mortality.15,19 The largest absolute number of excess CVD mortality was observed in subjects with IGT, especially those with normal FPG. The relation of 2-hPG with mortality was linear, but such a relation was not seen with FPG.
Recommendation
Information on post-prandial (post-load) glucose provides better information about the future risk for CVD than fasting glucose, and elevated post-prandial glucose also predicts the cardiovascular risk in subjects with normal fasting glucose levels. Class I, Level of Evidence A.
Glycaemic control and cardiovascular risk
Although several prospective studies have unequivocally confirmed that post-load hyperglycaemia increases CVD morbidity and mortality and is a better predictor for subsequent events than a high FPG, it still remains to be demonstrated that lowering a high 2-hPG will reduce this risk in well designed, randomized controlled trials (RCT). Such studies are underway, but thus far data are scarce. A secondary endpoint analysis of the STOP-NIDDM (Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus) revealed statistically significant reductions in CVD event rates in IGT subjects receiving acarbose compared with placebo.70 Since acarbose specifically reduces post-prandial glucose excursions, this is the first demonstration that lowering post-prandial glucose may lead to a reduction in CVD events. It should, however, be noted that the power in this analysis is low due a very small number of events.
The largest trial in type 2 diabetic patients so far, the United Kingdom Prospective Diabetes Study,71 was not powered to test the hypothesis that lowering blood glucose by intensive treatment can reduce the risk of MI, although there was a 16% (marginally significant) reduction in intensively compared with conventionally treated patients. In this study, post-load glucose excursions were not measured and over the 10 years of follow-up, the difference in the HbA1c concentrations between the intensive and conventional groups was only 0.9% (7.0 vs. 7.9%). Moreover, the drugs used for intensive treatment, sulphonylureas, long-acting insulin and metformin, mainly influence FPG, but not post-prandial glucose excursions. The German Diabetes Intervention Study, recruiting newly diagnosed type 2 diabetic patients, is so far the only intervention study that has demonstrated that controlling post-prandial hyperglycaemia (blood glucose measured 1 h after breakfast) had a greater impact on CVD and all-cause mortality than controlling fasting blood glucose.72 During the 11-year follow-up, poor control of fasting glycaemia did not significantly increase the risk of MI or mortality, whereas poor vs. good control of post-prandial glucose was associated with a significantly higher mortality. Additional support is obtained from a meta-analysis of seven long-term studies using acarbose in type 2 diabetic patients. The risk for MI was significantly lower in patients receiving acarbose compared with those on placebo.73
Recommendation
Improved control of post-prandial glycaemia may lower cardiovascular risk and mortality. Class IIb, Level of Evidence C.
Gender difference in CAD related to diabetes
In the middle-aged general population, men have a two to five times higher risk for CAD than women.74,75 The Framingham Study was the first to underline that women with diabetes seem to lose their relative protection against CAD compared with men.76 The reason for the higher relative risk of CAD in diabetic women than diabetic men is still unclear.
The 14-year follow-up of the Rancho Bernardo Study showed that the multivariate-adjusted relative hazards of death from CAD in diabetic, compared with non-diabetic subjects, was 3.3 in women and 1.9 in men.77 In a 13-year follow-up study of a Finnish cohort, free from CVD at baseline and with or without type 2 diabetes, the diabetes-related adjusted HR for a major coronary event was 2.8 (95%CI 2.0–3.7) for men and 9.5 (95%CI 5.5–16.9) for women.78 In a Scottish 12-year long follow-up, asymptomatic hyperglycaemia (casual blood glucose >7.0 mmol/L) was a significant risk factor for CVD in both genders, however, it was a stronger risk factor in women than in men.79 A review about the impact of gender on the occurrence of CAD mortality reported that the overall relative risk (the ratio of men to women) for CAD mortality was 1.46 (95%CI 1.21–1.95) in diabetic and 2.29 (2.05–2.55) in non-diabetic subjects. This suggests that the gender differential is reduced in diabetes.35 The result from the DECODE Study, including 8172 men and 9407 women without known diabetes, showed that newly diagnosed diabetic women had a higher relative risk for cardiovascular mortality than newly diagnosed diabetic men.68 This association was independent of age, body mass index (BMI), systolic blood pressure, total cholesterol, and smoking. Recent data related to hormonal replacement therapy show that, particularly in diabetic women, the risk of CVD increases significantly.80
A meta-analysis of 37 prospective cohort studies, including 447 064 diabetic patients estimated the diabetes-associated, gender-related risk of fatal CAD.81 CAD mortality was higher in patients with diabetes than in those without (5.4 vs. 1.6%). The overall relative risk among people with and without diabetes was significantly greater among women with diabetes 3.50 (95%CI 2.70–4.53) than among men with diabetes 2.06 (95%CI 1.81–2.34).
Recommendation
Glucometabolic perturbations carry a particularly high risk for cardiovascular morbidity and mortality in women, who in this respect need special medical attention. Class IIa, Level of Evidence B.
Glucose homeostasis and cerebrovascular disease
Diabetes and stroke
The risk for cerebrovascular morbidity and mortality (stroke, cerebrovascular accidents), which causes substantial costs for society, is magnified by diabetes.82–89 Indeed, CVD is the predominant long-term cause of morbidity and mortality in patients with both type 1 and type 2 diabetes. Since the first observations, presented by the Framingham investigators, several large population-based studies have verified an increased frequency of stroke in the diabetic population.85,88 Diabetes was the strongest single risk factor for stroke (relative risk for men 3.4 and for women 4.9) in a prospective study from Finland with a follow-up of 15 years.82 Diabetes is a prominent risk factor for ischaemic stroke, but data on haemorrhagic stroke have been controversial,90–93 although a recent report from the Framingham Study suggested an increased risk of haemorrhagic stroke in type 2 diabetes.88
In Europe, ischaemic CVD accounts for about 80% of all strokes,94 but the female:male mortality ratio differs for stroke subtypes, ethnicity, and age.93,94 DM may also cause microatheromas in small vessels, such as the lenticulostriate arteries, leading to lacunar stroke, one of the most common subtypes of ischaemic stroke. Lacunar stroke is a unique subtype and requires specific clinical and imaging features for diagnosis. The presence of DM was associated with symptomatic cerebral infarcts, but not with silent infarcts,95 which are five times as prevalent as symptomatic brain infarcts in the general population.96
An inverse correlation has been reported between diabetes and aneurysmal subarachnoid haemorrhage, but two studies claim that diabetes is closely associated with subarachnoid haemorrhage.97,98 Stroke patients with diabetes, or with hyperglycaemia in the acute stage of stroke, have a higher mortality, worse neurological outcome, and more severe disability than those without.82,90–101
There is much less information concerning the risk of stroke in type 1 than in type 2 diabetes. Deckert et al.102 who followed type 1 diabetic patients for more than 40 years, reported a 10% cumulative incidence of stroke and 7% mortality from stroke. The World Health Organization Multinational Study of Vascular Disease in Diabetes indicated increased cerebrovascular mortality in type 1 diabetic patients, however, with considerable variations between countries.103 Patients, generally, are much younger in type 1 than in type 2 diabetes, and stroke is known as a disease of elderly people with two-thirds of all strokes occurring above the age of 65 years. Thus, the true risk of stroke in type 1 diabetic patients may still be less well-established. The data from the nationwide cohort of more than 5000 Finnish childhood-onset type 1 diabetic patients showed that, by the age of 50 years (i.e. after 20–40 years with diabetes), the risk for an acute stroke was equal to that of an acute coronary event without any gender-related difference.44 Presence of diabetic nephropathy was the strongest predictor of stroke, causing a 10-fold increase of risk.
IGT and stroke
Considerably less is known about the frequency of asymptomatic diabetes and IGT in patients with stroke. In a recent Austrian study104 involving 238 patients, 20% had previously known diabetes, 16% newly diagnosed diabetes, 23% IGT, but only 0.8% had IFG. Thus, as few as 20% had a normal glucose homeostasis. Another 20% of the patients had hyperglycaemic values, which could not be fully classified due to missing data in the OGTT. Patients with diabetes had more severe strokes at admission, a more serious outcome at discharge, and a higher rate of infectious complications. In an Italian study, 106 patients were recruited with acute ischaemic stroke and without any history of diabetes, 81 patients (84%) had abnormal glucose metabolism at discharge and 62 (66%) after 3 months (39% IGT and 27% newly detected diabetes). Post-load hyperglycaemia at discharge was a predictor of diabetes after 3 months.105
Recommendation
People with diabetes and IGT have an increased risk for stroke. Class I, Level of Evidence A.
In stroke patients, unrecognized hyperglycaemia is mostly high post-load glucose seen in the OGTT, whereas the measurement of fasting glucose is insensitive in detecting unrecognized hyperglycaemia. Class I, Level of Evidence B.
Prevention of CVD in people with IGH
Although overall trends in CVD mortality have shown a significant downward trend in developed countries during the last decades, it has been suggested that the decline has been smaller or not existent at all in diabetic subjects.106 A more recent study reports on a 50% reduction in the rate of incident CVD events among adults with diabetes. The absolute risk of CVD was, however, two-fold greater than among persons without.161 More data are needed to judge this issue in European populations.
Accumulating evidence has shown that deterioration of IGT in type 2 diabetes can be effectively prevented by life style intervention.22,109 Whether this also leads to the prevention of CVD needs to be seen in the follow-up of these trial populations.
An imminent issue is to prove that prevention and control of post-prandial hyperglycaemia will cause a reduction in mortality, CVD, and other late complications of type 2 diabetes. There is also a need to reconsider the thresholds used to diagnose hyperglycaemia.20 The majority of premature deaths related to IGH occur in people with IGT15,19 obviating the need for increased attention to people with a high 2-hPG. A first step would be to detect such people through systematic screening of high-risk groups (see the following section).31,41 The best way to prevent the negative health consequences of hyperglycaemia may be to prevent the development of type 2 diabetes. Controlled clinical outcome trials among asymptomatic subjects with hyperglycaemia are underway, but results will only be available after some years. Meanwhile, the only way to make clinical treatment decisions in such subjects is to make inferences from the observational epidemiological data and pathophysiological studies.
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Identification of subjects at high risk for CVD or diabetes |
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