19.2 Dysglycaemia: definition, classification, and diagnosis

Diabetes mellitus (DM) is defined as a high glucose concentration in the circulating blood. The main types of DM are classified as type 1 DM (T1DM) and type 2 DM (T2DM). DM comprises heterogeneous groups of diseases in which underlying aetiology, clinical presentation, and disease progression may vary considerably. Classification of DM is important for determining therapy, but some individuals cannot be clearly classified as having T1DM or T2DM at the time of diagnosis. Dysglycaemia is defined as either DM or elevated blood glucose that does not reach the threshold of DM (also called prediabetes). People with dysglycaemia are at high risk for multiple co-morbidities, in particular cardiovascular disease (CVD). Genetic predisposition is important for both T1DM and T2DM, but these cannot be diagnosed by genetic testing. Diagnosis of DM and dysglycaemia can be made using blood glucose determination. A glycated haemoglobin (HbA1c) level greater than 6.5% has also been recommended as a diagnostic test for DM, but it has a low sensitivity to detect DM that may be detected by blood glucose measurement. The classification of DM and dysglycaemia and diagnostic criteria are based on recommendations from the World Health Organization and the American Diabetes Association. Population screening of blood glucose is not recommended due to the poor sensitivity of random blood glucose and HbA1c to correctly identify people with T2DM and/or correctly exclude people without DM. However, patients with CVD should be evaluated with an oral glucose tolerance test. For population screening, simple non-laboratory diabetes risk scores for DM have been developed. Randomized controlled trials have demonstrated that lifestyle modification, based on modest weight loss, healthy diet and increased physical activity, prevents or delays progression to T2DM in high-risk individuals.

Diabetes mellitus (DM) is defined as a high glucose concentration in the circulating blood. The main types of DM are classified as type 1 DM (T1DM) and type 2 DM (T2DM); T1DM has typically a rapid onset, while T2DM is a progressive disorder characterized by a state of long-standing and gradually increasing hyperglycaemia. T1DM and T2DM are heterogeneous groups of diseases in which underlying aetiology, clinical presentation, and disease progression may vary considerably. Classification of DM is important for determining therapy, but some individuals cannot be clearly classified as having T1DM or T2DM at the time of diagnosis.¹ The traditional paradigms of T2DM occurring only in adults and T1DM only in children are no longer accurate, as both types of disease occur in all ages. Although difficulties in distinguishing diabetes type at onset, the true diagnosis becomes more obvious over time. Both types of DM result from a complex interplay between lifestyle, environmental factors, and genetic factors, but these factors are different for T1DM and T2DM.

Dysglycaemia is defined as either DM or elevated blood glucose that does not reach the threshold of DM (also called prediabetes). Once hyperglycaemia occurs, people with any type of DM are at high risk for multiple co-morbidities affecting most organs of the body, in particular cardiovascular disease (CVD) that affect the heart, brain, peripheral vessels, and also microcirculation in many organs. CVD associated with DM is common; the majority of people with DM have CVD.² DM magnifies the risk of CVD morbidity and mortality.^3,4 Globally, approximately 5 million people die from DM each year.

Although the initial events resulting in DM are not well understood, the data on the major risk factors for T2DM are well known. Also, once dysglycaemia has initiated, many pathophysiological processes in the natural history of the progression to T2DM are also known, thanks to several prospective studies. These include deficient insulin secretion, often combined with insulin resistance in peripheral tissues that utilize glucose. In contrast, the natural history of T1DM, that is, the rapid development of pancreatic beta-cell failure, is currently not understood. The persistent presence of specific antibodies is a strong predictor of T1DM, especially in European populations, but the rate of progression to frank diabetes is variable.

There are many issues that still remain open concerning the temporal relation between dysglycaemia and CVD, the role of hyperglycaemia and other glycaemia-specific factors, and the contribution of other conventional CVD risk factors. As in people without diabetes, the major CVD risk factors such as elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, hypertension, smoking, and other unhealthy lifestyles (diet, physical inactivity; see Section 18) remain important determinants of CVD in people with DM and dysglycaemia (see Chapter 18.2). In addition, emerging risk factors such as kidney and liver function, prothrombotic factors, and enhanced inflammatory activation that further affect the CVD risk are more common in people with people with dysglycaemia than in normoglycaemic people. The increased clustering of multiple atherogenic risk factors often referred to as the metabolic syndrome links DM to high CVD risk.

This chapter will consider the definition, classification, and diagnosis of DM and dysglycaemia. Early detection and intervention are important for the management of dysglycaemia and associated atherogenic metabolic abnormalities that often precede development of DM. Nowadays, since dysglycaemia is common, physicians caring for patients with CVD must understand the effects of DM and other forms of dysglycaemia and their detrimental accumulation on CVD risk.

While the evidence is unequivocal that the progression to T2DM can be prevented in high-risk people with impaired glucose tolerance,^5,6,7 we do not currently have methods to prevent T1DM. Once DM has been diagnosed, a high priority should be given to the management of both hyperglycaemia and other major risk factors for CVD. Increasing evidence indicates that controlling CVD risk factors in people with DM will reduce the risk of CVD in people with DM.^3,8

The European Society of Cardiology in collaboration with the European Association for the Study of Diabetes have prepared guidelines on diabetes, pre-diabetes, and cardiovascular diseases.² The emphasis in these guidelines has been ‘to provide information on the current state of the art in how to prevent and manage the diverse problems associated with the effects of DM on the heart and vasculature in a holistic manner. In describing the mechanisms of disease, we hope to provide an educational tool, and, in describing the latest management approaches, an algorithm for achieving the best care for patients in an individualized setting’.²

The American Diabetes Association (ADA) has developed and disseminated diabetes care standards, guidelines, and related documents during the last 25 years. The latest, ‘Standards of Medical Care in Diabetes—2017’, was published in January 2017 as a Supplement in Diabetes Care.⁹ This includes chapters on ‘Classification and Diagnosis of Diabetes’¹⁰ and ‘Cardiovascular Disease and Risk Management’.¹¹

The prevalence of DM has increased dramatically worldwide during the last several decades, and it has been estimated that approximately 415 million people had diabetes in 2015, of whom more than 95% have had T2DM.¹² This number is estimated to increase to 642 million by 2040 and it is thought that almost half of these are unaware of their condition. In addition, it was estimated that another 318 million individuals have impaired glucose tolerance, and are therefore at high risk to progress to T2DM during the coming years; of these, half will develop DM within 10 years.¹³ In Europe, the current number of people with DM is 60 million, and the estimate for 2040 is 71 million.

The occurrence of DM varies markedly among populations. The risk of T1DM is the highest in European populations, especially in northern Europe, and low in East Asian populations.^14,15 The incidence of childhood-onset T1DM has increased globally during the last decades, by approximately 3% per year.^14,15 The prevalence of T2DM is highest in many Pacific Island populations, native Americans and Australians, and several Middle East countries.¹² It is important to note that the prevalence of T2DM is age dependent, rising with age. There have been several population surveys on DM and dysglycaemia, but the actual survey data are missing for most countries. The DECODE study (Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Europe) has carried out a collaborative analysis of European prevalence data in a standardized manner.¹⁶ The prevalence of DM rises with age in both sexes and can be summarized as follows: less than 10% of people aged less than 60 years, 10–20% aged 60–69 years, and 15–20% aged 70 years or older have previously diagnosed DM, and in addition similar proportions have previously undiagnosed, asymptomatic DM. This means that the lifetime risk for DM is 30–40% in European populations. The prevalence of impaired glucose tolerance also increases linearly from about 15% in middle-aged Europeans to 35–40% in elderly Europeans. The latest nationwide diabetes survey using recommended standard methodology, carried out in Turkey, showed a dramatic increase in prevalence from 1997–1998 to 2010: indeed, the rate of increase for DM was 90% and for impaired glucose tolerance 106%.¹⁷ Overall, in Europe men have a higher incidence of T1DM and also a higher prevalence of T2DM before age of 70 years compared with women.

Genetic predisposition is important for both T1DM and T2DM. In T1DM, most of the genetic susceptibility is conferred by the human leucocyte antigen region of chromosome 6,¹⁸ and more than 50 other known susceptibility loci only explain a small additional proportion of the risk (see also Section 15).¹⁹ Human leucocyte antigen genotyping can be used for the identification of people at high risk, but only about one-third of such people develop the disease, as shown in twin studies.²⁰ For T2DM, over 120 genetic markers have been found to be associated with the disease risk, but they only explain a small part of the genetic risk and no major susceptibility loci have been found.²¹ At present, genetic testing cannot be used in clinical practice to screen for DM or risk for DM.

The majority of new cases of T2DM in Europe occur in the context of ‘Westernized’ unhealthy lifestyles, that is, an unhealthy diet and low physical activity resulting in increasing levels of obesity. Since dysglycaemia is not associated with any specific symptoms, it has been estimated that, at the time of clinical diagnosis of DM, the disease has often existed for more than 10 years. Therefore, without active case-finding a large number of cases of DM remain unrecognized for a long time. The delay in diagnosis and subsequent lack of effective management will eventually lead to an increased risk of complications and mortality.

The classification of DM and dysglycaemia is based on recommendations from the World Health Organization (WHO)^22,23 and the ADA.^24,25 Since the original definition of DM is elevated glucose concentration in circulating blood, a diagnosis of DM and dysglycaemia can be made using blood glucose determination. HbA1c has also been recommended as a diagnostic test for DM,^10,26,27 but it has a low sensitivity to predict DM,²⁸ and HbA1c values below 6.5% do not exclude DM that may be detected by blood glucose measurement.^10,27,28 Four main aetiological categories of DM have been identified: T1DM, T2DM, ‘other specific types’ of DM, and ‘gestational DM’ (Table 19.2.1).²³ In this chapter, issues related to T1DM and T2DM will mainly be discussed.

Type 1 diabetes. T1DM is characterized by deficiency of insulin due to destruction of pancreatic beta-cells, progressing towards absolute insulin deficiency. Typically, T1DM occurs in young people. Children with T1DM commonly present with the hallmark symptoms of polyuria and polydipsia, and approximately one-third present with diabetic ketoacidosis.^29,30 It is recommended that blood glucose rather than HbA1c is used to diagnose T1DM with acute symptoms. The onset of T1DM may be more variable in adults, and they may not present with the classic symptoms seen in children. Diabetic ketoacidosis most frequently occurs in those who already have diabetes, but it may also be the first presentation in someone who had not previously been known to be diabetic. There is often a particular underlying problem that has led to a diabetic ketoacidosis episode; this may be intercurrent illness (e.g. pneumonia, influenza, gastroenteritis, or urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction, or stroke. Young people with recurrent episodes of diabetic ketoacidosis may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain. Some patients with T2DM also may present with diabetic ketoacidosis.²⁹ Diabetic ketoacidosis occurs because of a lack of insulin in the body. The lack of insulin and corresponding elevation of glucagon leads to increased release of glucose by the liver (a process that is normally suppressed by insulin) from glycogen via glycogenolysis and also through gluconeogenesis. High glucose levels spill over into the urine, taking water and solutes (such as sodium and potassium) along with it in a process known as osmotic diuresis.^31,32 The absence of insulin also leads to the release of free fatty acids from adipose tissue (lipolysis), which are converted into ketone bodies (acetoacetate and beta-hydroxybutyrate) through beta oxidation in the liver. Beta-hydroxybutyrate can serve as an energy source in the absence of insulin-mediated glucose delivery. In ketoacidosis due to diabetes, blood glucose is usually very high, over 13 mmol/L.³² Ketoacidosis due to diabetes may be diagnosed when the combination of hyperglycaemia (high blood sugars), ketones in the blood or on urinalysis, and acidosis is demonstrated. In about 10% of cases the blood sugar is not significantly elevated (‘euglycaemic ketoacidosis due to diabetes’).²⁹

T1DM may occur at any age, sometimes with a slow progression.³³ In the latter condition, latent autoimmune DM in adults (the so-called LADA), insulin dependence develops over a few years. People who have autoantibodies to pancreatic beta-cell proteins such as glutamic acid decarboxylase, protein tyrosine phosphatase, insulin, or zinc transporter protein are likely to develop either acute-onset or slowly progressive insulin dependence.^34,35 Autoantibodies targeting pancreatic beta-cells are a marker of T1DM, although they are not detectable in all patients and decrease with age. Compared with other ethnicities and geographic regions, T1DM is more common in Europid individuals, and also autoantibodies in European T1DM patients are more common, probably due to specific genetic reasons.

Type 2 diabetes. T2DM is characterized by beta-cell dysfunction usually combined with insulin resistance in peripheral tissues in association with obesity (particularly abdominal adiposity), unhealthy diet, and sedentary lifestyle (see Chapter 18.3)—major risk factors for T2DM. The early stage of T2DM is characterized by impaired first-phase insulin secretion causing post-prandial hyperglycaemia. This is followed by a deteriorating second-phase insulin response and persistent hyperglycaemia in the fasting state.^37,38 T2DM typically develops after middle age and comprises over 90% of diabetes in adults. However, there is a trend towards a decreasing age of onset of T2DM, particularly with increasing obesity in the young and in non-Europid populations.³⁹

In addition to DM, dysglycaemia also comprises other disorders of glucose metabolism called impaired fasting glucose and impaired glucose tolerance, often referred to as ‘pre-diabetes’, that reflect the intermediate states in the natural history of progression from normoglycaemia to T2DM.^10,23,25 It is common for such individuals to oscillate between different glycaemic states as can be expected when the continuous variable such as blood glucose is dichotomized. It also important to note that people with impaired glucose tolerance have an increased risk for CVD, cancer, and all-cause mortality, whereas people with impaired fasting glucose do not.³

Impaired glucose tolerance can only be recognized by the results of an oral glucose tolerance test: 2 h post-load plasma glucose of at least 7.8 and less than 11.1 mmol/L (≥140 and <200 mg/dL). A standardized 2 h oral glucose tolerance test is performed in the morning after an overnight fast (8–14 h). One blood sample should be taken before, and another 120 min after intake of 75 g glucose dissolved in 250–300 mL water ingested within approximately 5 min (note that the timing of the test begins when the person starts to drink).

The WHO criteria^23,27 are based on fasting plasma glucose and 2 h post-challenge glucose concentrations, and it is recommended to use a 2 h oral glucose tolerance test in the absence of marked fasting hyperglycaemia.²³ The ADA criteria encourage the use of HbA1c and fasting glucose determinations, and oral glucose tolerance test, in that order.¹⁰ The argument for measuring fasting plasma glucose or HbA1c over 2 h post-load plasma glucose is primarily related to feasibility. The advantages and disadvantages of using glucose testing and HbA1c testing are summarized in a WHO report from 2011.²⁷ The diagnostic criteria adopted by WHO and ADA^10,25 (Table 19.2.1) for the intermediate levels of hyperglycaemia are similar for impaired glucose tolerance, but differ for impaired fasting glucose; the ADA lower threshold for impaired fasting glucose is 5.6 mmol/L (101 mg/dL)^10,25 while WHO recommends that the cut-off point of 6.1 mmol/L (110 mg/dL) should be retained.²³ ADA is also proposing to use HbA1c for the identification of intermediate hyperglycaemia,¹⁰ whereas WHO is explicitly stating that HbA1c values below 6.5% have no clinical interpretation.²⁷

The glucose concentration can be determined from any blood-derived specimen; whole blood, capillary blood, venous serum, or venous plasma. However, they all have different characteristics and different fluid volume. Therefore, to standardize glucose determinations, venous plasma measures have been recommended.^10,23 Measurements based on venous whole blood tend to give results 0.5 mmol/L (9 mg/dL) lower than plasma values. Since capillary blood is often used for point-of-care testing devices, it is important to underline that capillary values may differ from plasma values more in the post-load than in the fasting state. A comparative study suggests that the cut-off points for diabetes, impaired fasting glucose, and impaired glucose tolerance differ when venous whole blood and capillary blood are used, as outlined in Table 19.2.2.⁴⁰

Classification depends on whether only fasting plasma glucose is measured or if it is combined with a 2 h post-load plasma glucose value or HbA1c measurement. Each of these three measurements indicates different physiological phenomena. A normal fasting plasma glucose reflects an ability to maintain adequate basal insulin secretion in combination with hepatic insulin sensitivity sufficient to control hepatic glucose output, especially during the night when hepatic glucose production should shut down.⁴¹ High fasting glucose is often associated with obesity and non-alcoholic fatty liver. An individual with a normal fasting glucose level or impaired fasting glucose may have impaired glucose tolerance or even DM if investigated with a glucose load during an oral glucose tolerance test. A post-load glucose level within the normal range requires an appropriate insulin secretory response and adequate insulin sensitivity in peripheral tissues. High post-challenge or postprandial glucose is a sign of an inadequate pancreatic beta-cell function.⁴² The first-phase insulin secretion as a rapid response to carbohydrate intake is gradually diminishing, leading to high glucose levels after a meal or carbohydrate load.

HbA1c is an indirect marker of glycaemia. HbA1c is a term used to describe a series of stable minor haemoglobin components formed slowly and non-enzymatically from haemoglobin and glucose through glycation.^43,44 The clinical utility of HbA1c as a tool to assess the glycaemic control and to predict risk of complications of DM has been confirmed by several studies since the mid 1970s.⁴⁵ Glycation is the non-enzymatic attachment of free aldehyde groups of carbohydrates (e.g. glucose) to the unprotonated free amino groups of proteins (such as haemoglobin). Glycation alters the structure and function of several soluble and insoluble proteins, as well as the structure and function of basement membrane components. These changes are slow and cumulative, resulting in a long time lag between the diagnosis of DM and the onset and progression of the complications of DM.^46,47,48 Since haemoglobin is part of red blood cells that are relatively short living, the glycation process of a new haemoglobin molecule depends on red cell turnover. Thus, HbA1c indicates an average of blood glucose levels over the past 3 months. However, HbA1c does not inform about blood glucose values on a daily basis. In addition, the presence of haemoglobinopathies and several other interferences may make the interpretation of HbA1c assay results difficult.^49,50 A list of potential interferences regarding HbA1c can be found at: http://www.ngsp.org/interf.asp.

It is a well-known fact that blood glucose levels vary and the term ‘glucose variability’ may have different definitions. Most commonly it is associated with the within-day fluctuations since the blood glucose level rises and falls, particularly as a consequence of meals. However, it can also relate to changes in glycaemia over longer periods of time, such as the daily, weekly, or monthly changes in glucose concentration in blood circulation. Although it is believed that HbA1c is stable, glycaemic variability can also be expressed as the change in HbA1c over time.

ADA has provided recommendations on the confirmation of DM diagnosis.¹⁰ Unless there is a clear clinical diagnosis (e.g. classic symptoms of hyperglycaemia and a random plasma glucose 11.1 mmol/L or higher), a second test is required for confirmation of diagnosis of DM. It is recommended that the same test be repeated without delay using a new blood sample on a separate day for confirmation because there will be a greater likelihood of concurrence. If two different tests (such as HbA1c and fasting plasma glucose or 2 h post-load plasma glucose) are both above the diagnostic threshold, this also confirms the diagnosis. On the other hand, if a person has discordant results from two different tests, then the test result that is above the diagnostic cut-point should be repeated. The diagnosis of DM is then made on the basis of the confirmed test. For example, if the DM criterion of the HbA1c (two results both >6.5% (48 mmol/mol)) but not fasting plasma glucose (both values <7.0 mmol/L), that person should nevertheless be considered to have DM.

Since all the tests have pre-analytic and analytic variability, it is possible that an abnormal result (i.e. above the diagnostic threshold), when repeated, will produce a value below the diagnostic cut-point. This scenario is likely for fasting plasma glucose and 2 h plasma glucose if blood samples for the glucose assay are (i) taken into a wrong type of tube (a tube with Na-citrate is recommend), or (ii) samples remain at room temperature (it is recommended to keep samples in ice water), or (iii) are not centrifuged promptly (immediately or within 30 min is recommended), or (iv) the person has not been fasting properly (leads to a false-positive fasting plasma glucose result). If test results are near the margins of the diagnostic threshold for DM, it is advised to follow the person with a repeat of the test in about 3–6 months. In addition, it is important to pay attention to the analytical method when interpreting assay results. This applies to both glucose and HbA1c determinations, and false-positive results are not uncommon. Therefore, it is necessary to repeat blood glucose or HbA1c determination when high values are detected and the aim is to diagnose diabetes. The most frequent assay problems occur with point-of-care devices that are not properly calibrated or the user makes errors in sample handling.

T2DM does not cause specific symptoms for many years, which explains why approximately half of the cases of T2DM remain undiagnosed at any time.^16,51 Population testing of blood glucose is not recommended due to the poor sensitivity of random blood glucose and HbA1c to correctly identify people with T2DM and/or correctly exclude people without DM. In addition, there is a lack of evidence that the prognosis of T2DM can be improved by early detection and treatment of T2DM.^52,53 Screening of hyperglycaemia should therefore be targeted to high-risk individuals. The ADDITION Study (Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care) did, however, provide evidence that the risk of CVD events is low in screen-detected people with T2DM. Screening may have facilitated risk reduction, and therefore screening for T2DM might be beneficial.⁵³ Moreover, there is an increasing interest in identifying people with impaired glucose tolerance, since most of them will progress to T2DM, and this progression can be retarded by lifestyle interventions.^6,7,13,54 The probability of a false-negative test result, compared with the oral glucose tolerance test, is substantial when attempting to detect DM by measuring only fasting plasma glucose and/or HbA1c (i.e. these are insensitive methods).^55,56,57

The approaches for early detection of T2DM and other disorders of glucose metabolism are (i) using demographic and clinical characteristics and previous laboratory tests to determine the likelihood for T2DM; and (ii) collecting questionnaire-based information that provides data on the presence of aetiological risk factors for T2DM. These approaches leave the current glycaemic state ambiguous and glycaemia testing is necessary as the second step to accurately define whether T2DM and other disorders of glucose metabolism exist. However, the results from such a simple first-level screening can markedly reduce the number of patients who need to be referred for further testing of glycaemia and other CVD risk factors. The first option is particularly suited for those with pre-existing CVD and women with previous gestational diabetes, while the second screening option is better suited for the general population and also for overweight/obese people.

Several diabetes risk scores for DM have been developed. Most perform well, and usually it does not matter which one is used as underlined by a systematic review.^58,59,60 The FINnish Diabetes RIsk SCore (FINDRISC; http://www.diabetes.fi/english) is the most commonly used to screen for DM risk in Europe (Figure 19.2.1).

This tool predicts the 10-year risk of T2DM, including the presence of asymptomatic DM and impaired glucose tolerance, with 85% accuracy.^59,60 It has been validated in most European populations and is available in almost all European languages. A study in Spanish people with high risk (i.e. >12/26 points in the FINDRISC), revealed that 8.6% had undiagnosed T2DM by oral glucose tolerance test, while only 1.4% had a HbA1c level greater than 6.5% confirming the relative insensitivity of HbA1c for detecting undiagnosed T2DM as the second step of a screening programme for asymptomatic T2DM.²⁸

It is necessary to separate individuals into three different scenarios: (i) the general population; (ii) people with assumed metabolic abnormalities (e.g. obese, hypertensive, or those with a family history of DM); and (iii) patients with diagnosed prevalent CVD. Testing for hyperglycaemia should be part of the regular examination of patients with prevalent CVD, and this may start with fasting plasma glucose and HbA1c determination and followed in patients without diabetes by an oral glucose tolerance test, since many of these people may have DM detected by elevated 2 h post-load plasma glucose only.¹⁶ In the general population and in people with assumed metabolic abnormalities, the appropriate screening strategy is to start with a DM risk score supplemented by an oral glucose tolerance test in individuals with a high risk-score value.^59,60

Since DM results from an interaction between predisposing genetic factors and environmental/lifestyle exposure, there has been a lot of interest in developing a DM risk prediction tool based on genetic markers that can be measured relatively easily with modern genotyping technology (see also Chapters 16.1–16.4).²¹ Therefore, screening for genetic susceptibility may offer another way to detect DM and disorders of glucose metabolism. Today more than 50 genetic marker loci for T1DM have been identified,¹⁹ and more than 120 loci for T2DM.²¹

Maturity-onset diabetes of the young (MODY) is rare and it belongs to the ‘other types of diabetes’ category.⁶¹ It is frequently characterized by onset of hyperglycaemia at an early age (classically before the age of 25 years, although diagnosis may occur at older ages). MODY is characterized by impaired insulin secretion with minimal or no defects in insulin action (in the absence of coexistent obesity). It is inherited in an autosomal dominant pattern with abnormalities in at least 13 genes on different chromosomes identified to date. A diagnosis of MODY should be considered in individuals who have atypical DM and multiple family members are affected and do not have characteristics of T1DM or T2DM, although admittedly ‘atypical diabetes’ is becoming increasingly difficult to precisely define in the absence of a definitive set of tests for either main type of DM. Individuals in whom monogenic DM is suspected should be referred to a specialist for further evaluation if available, and consultation is available from several centres. Readily available commercial genetic testing following the specified criteria now enables a cost-effective genetic diagnosis of MODY.^62,63

For T1DM, human leucocyte antigen haplotypes provide by far the best tool to identify the underlying genetic susceptibility,^18,19 and they can be determined with reasonable accuracy. There are, however, two major issues regarding screening for T1DM risk: first, according to the twin studies only about 30–40% of people who are genetically susceptible will develop the disease.²⁰ Second, at present we do not have methods to prevent T1DM even in genetically high-risk individuals such as siblings of patients who have T1DM.⁶⁴ Therefore, genetic screening for T1DM cannot be recommended, although in families with a child diagnosed with young-onset T1DM, genotyping of siblings may provide evidence to exclude the probability of T1DM, or to suggest such a possibility exists, in which case active early monitoring of symptoms of DM may help to detect the disease very early on and thereby to avoid acute complications such as ketoacidosis at diagnosis.³²

For T2DM, genetic risk scores have been developed and their predictive value for DM tested. In fact, the easiest way is to check family history. However, information about family history is always either incomplete or inaccurate and changes over time. A genetic risk score based on genotyping the known susceptibility markers can be used to predict T2DM.^65,66 Such a genetic score seems to add to the prediction, but only very little after taking into account other risk factors for T2DM. Although the genetic susceptibility to DM is important in DM, there is no doubt that unhealthy dietary habits and a sedentary lifestyle are of major importance for the development of T2DM,^67,68 even in people with a high genetic background.⁶⁹

‘Precision medicine’ based on genetics, other biomarkers, and lifestyle characteristics of a person may offer a novel solution to use detailed profiling of people for the most efficient management of DM and other disorders of glucose metabolism. A recent British study compared the uptake of physical activity among three groups of people: (i) those who after genotyping were told that they had a high genetic risk for T2DM; (ii) those who received information that due to their lifestyle they were at high risk of T2DM; and (iii) those who were serving as ‘usual care’ controls. No differences in their physical activity uptake were seen between groups.⁷⁰ In the Finnish Diabetes Prevention Study, people with a positive versus negative family history of DM and those who had a high versus low T2DM genetic risk score all benefitted equally from lifestyle intervention.⁶⁹ Thus, currently it is not possible to propose new evidence-based recommendations based on profiling people by genetic risk scoring for precision medicine. Nevertheless, individual characteristics must be applied as part of the usual clinical management of patients with any evidence-based guidelines.

Although the genetic susceptibility to DM is important in DM, there is no doubt that unhealthy dietary habits and a sedentary lifestyle are of major importance for the development of T2DM. As reviewed in the European evidence-based guideline for the prevention of T2DM,⁶ randomized controlled trials demonstrate that lifestyle modification, based on modest weight loss and increased physical activity, prevents or delays progression in high-risk individuals with impaired glucose tolerance. Thus, those at high risk for T2DM and those with established impaired glucose tolerance should be given appropriate lifestyle counselling. A tool kit, including practical advice for healthcare personnel, has recently been developed.⁷¹ It was estimated that one needs to provide lifestyle intervention for 6.4 high-risk individuals for an average of 3 years to prevent one case of diabetes. Thus, the intervention is highly efficient.⁵⁴ A 12-year follow-up of men with impaired glucose tolerance who participated in the Malmö Feasibility Study⁷² revealed that all-cause mortality among men in the former lifestyle intervention group was lower (and similar to that in men with normal glucose tolerance) than that among men who had received ‘routine care’ (6.5 vs 14.0 per 1000 person years; p = 0.009). Participants with impaired glucose tolerance in the 6-year lifestyle intervention group in the Chinese Da Qing study⁷³ had, 20 years later, a persistent reduction in the incidence of T2DM and an insignificant reduction of 17% in CVD death compared with control subjects. Moreover, the adjusted incidence of severe retinopathy was 47% lower in the intervention than in the control group, which was interpreted as being related to the reduced incidence of T2DM.⁷⁴ During an extended 7-year follow-up of the Finnish Diabetes Prevention Study,¹³ there was a marked and sustained reduction in the incidence of T2DM in people who had participated in the lifestyle intervention (on average 4 years). In the 10-year follow-up, total mortality and CVD incidence were not different between the intervention and control groups, but the Diabetes Prevention Study participants, who had impaired glucose tolerance at baseline, had lower all-cause mortality and CVD incidence compared with a Finnish population-based cohort of people with impaired glucose tolerance.⁷⁵ During the 10-year overall follow-up of the US Diabetes Prevention Program Outcomes Study, the incidence of T2DM in the original lifestyle intervention group remained lower than in the control group.⁷⁶

The Glucose And Myocardial Infarction (GAMI) study showed the high prevalence of glucose perturbations in people with acute coronary syndromes (ACS) without a history of DM.⁷⁷ They were all subjected to an oral glucose tolerance test about 5 days after onset of ACS symptoms. Only 33% had normal glucose tolerance, while 34% had impaired glucose tolerance, and 33% previously undetected T2DM. The Euro and China Heart Surveys^78,79 recruited patients with stable and unstable coronary artery disease, and confirmed the results of the GAMI study in larger populations from several countries, including people with acute and stable coronary artery disease. In the Euro Heart Survey on Diabetes and the Heart (n = 4961, 25 countries), the prevalence of known DM was 31%, while 12% had newly detected DM, 25% impaired glucose tolerance, and 3% impaired fasting glucose, leaving only 32% with normal glucose regulation.⁷⁸ In a study in India among people with ACS and without a history of DM, 84% had glucose perturbations: impaired fasting glucose or impaired glucose tolerance in 46% and undiagnosed DM in 38%.⁸⁰ These studies all demonstrated that a substantial proportion of people with glucose disturbances would have remained undetected without an oral glucose tolerance test.⁸¹ A similar pattern has subsequently been shown in patients with cerebrovascular and peripheral vascular disease.⁸² In an Austrian study, 238 consecutively admitted acute stroke patients were screened for glucose perturbations using an oral glucose tolerance test in the first and second weeks after the stroke event: 20% had normal glucose levels, 20% had previously known DM, 16% were classified as having newly diagnosed DM, 23% impaired glucose tolerance, and 1% impaired fasting glucose. The remaining 20% had transient hyperglycaemia or missing data in the second oral glucose tolerance test. Subsequently it was shown that newly detected glucose disturbances in these studies had a negative prognostic implication in ACS and stroke.^82,83

HbA1c has been recommended as a diagnostic tool for DM in the general population.^10,27 HbA1c, like other parameters of glycaemia, shows a graded association with CVD risk when evaluated one by one.^84,85,86 However, studies that compared all three main glycaemic parameters—fasting plasma glucose, 2 h post-load plasma glucose, and HbA1c—simultaneously for mortality and CVD risk revealed that the association is strongest for 2 h post-load plasma glucose, and that the risk observed with fasting plasma glucose and HbA1c is no longer significant after controlling for the effect of 2 h plasma glucose.^87,88

The use of HbA1c levels in people with CVD and without a history of DM to detect previously unrecognized T2DM or other disorders of glucose metabolism has only recently been studied in a systematic way comparing the sensitivity of HbA1c with fasting plasma glucose and 2 h post-load plasma glucose. An Indian study reported that 27% of newly diagnosed ACS patients with previously undiagnosed DM had HbA1c levels less than 6.0%.⁶⁵ Hage and colleagues⁸⁹ screened 174 patients with ACS, of whom 27 had T2DM according to the oral glucose tolerance test. Fasting plasma glucose failed to detect 63% and HbA1c 93% of these patients with DM. Similar findings have been reported in patients with ACS selected for further investigation due to elevated admission glucose⁹⁰ and in patients referred for coronary angiography.⁹¹ In EUROASPIRE IV, a cross-sectional survey of patients aged 18–80 years with coronary artery disease in 24 European countries, 4004 patients with no reported history of DM had fasting plasma glucose, 2 h post-load plasma glucose, and HbA1c measured.⁹² All participants were divided into different glycaemic categories according to the ADA and WHO criteria for dysglycaemia. Using all screening tests together, 29% had previously undetected DM. Out of these patients, the proportion identified by fasting plasma glucose alone was 75%, by 2 h post-load plasma glucose alone 40%, and by HbA1c alone 17%, while the combination of fasting plasma glucose plus HbA1c identified 81%, and the standard oral glucose tolerance test (fasting plasma glucose plus 2 h post-load plasma glucose combined) 96%. Only 7% were detected by all three methods simultaneously. Thus, almost one in five patients with DM would have remained undetected if fasting plasma glucose and HbA1c had been the only screening tools, and in addition all patients with impaired glucose tolerance would also have remained undetected (Figure 19.2.2).

There are many pros and cons to be considered when deciding which test for glycaemia will be used.^27,93 2 h oral glucose tolerance test is definitely the most sensitive and HbA1c is clearly the least sensitive test for identifying previously undiagnosed glycaemic perturbations in the general population as well as in patients with coronary heart disease.