3. Abnormalities of Glucose Metabolism and Cardiovascular Disease
3.1 Definition, Classification and Diagnosis
DM is a condition defined by an elevated level of blood glucose. The classification of DM is based on recommendations from the World Health Organization (WHO) and the American Diabetes Association (ADA).[2]–[6] Glycated haemoglobin A1c (HbA1c) has been recommended as a diagnostic test for DM,[7,8] but there remain concerns regarding its sensitivity in predicting DM and HbA1c values <6.5% do not exclude DM that may be detected by blood glucose measurement,[7]–[10] as further discussed in Section 3.3. Four main aetiological categories of DM have been identified: type 1 diabetes (T1DM), T2DM, 'other specific types' of DM and 'gestational DM' (Table 3).[2]
Type 1 diabetes is characterized by deficiency of insulin due to destruction of pancreatic beta-cells, progressing to absolute insulin deficiency. Typically, T1DM occurs in young, slim individuals presenting with polyuria, thirst and weight loss, with a propensity to ketosis. However, T1DM may occur at any age,[11] sometimes with slow progression. In the latter condition, latent auto-immune DM in adults (LADA), insulin dependence develops over a few years. People who have auto-antibodies 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.[12,13] Auto-antibodies 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 Caucasian individuals.[14]
Type 2 diabetes is characterized by a combination of IR and beta-cell failure, in association with obesity (typically with an abdominal distribution) and sedentary lifestyle—major risk factors for T2DM. Insulin resistance and an impaired first-phase insulin secretion causing post-prandial hyperglycaemia characterize the early stage of T2DM. This is followed by a deteriorating second-phase insulin response and persistent hyperglycaemia in the fasting state.[15,16] T2DM typically develops after middle age and comprises over 90% of adults with DM. However, with increasing obesity in the young and in non-Europid populations, there is a trend towards a decreasing age of onset.
Gestational diabetes develops during pregnancy. After delivery, most return to a euglycaemic state, but they are at increased risk for overt T2DM in the future. A meta-analysis reported that subsequent progression to DM is considerably increased after gestational DM.[17] A large Canadian study found that the probability of DM developing after gestational DM was 4% at 9 months and 19% at 9 years after delivery.[18]
Other specific types of diabetes include: (i) single genetic mutations that lead to rare forms of DM such as maturity-onset DM of the young; (ii) DM secondary to other pathological conditions or diseases (pancreatitis, trauma or surgery of the pancreas) and (iii) drug- or chemically induced DM.
Disorders of glucose metabolism, impaired fasting glucose (IFG) and IGT, often referred to as 'pre-diabetes', reflect the natural history of progression from normoglycaemia to T2DM. It is common for such individuals to oscillate between different glycaemic states, as can be expected when the continuous variable PG is dichotomized. IGT can only be recognized by the results of an oral glucose tolerance test (OGTT): 2-hour post-load plasma glucose (2hPG) ≥7.8 and <11.1 mmol/L (≥140 and <200 mg/dL). A standardized OGTT is performed in the morning after an overnight fast (8–14 h). One blood sample should be taken before and one 120 min after intake, over 5 min, of 75 g glucose dissolved in 250–300 mL water (note that the timing of the test begins when the patient starts to drink).
Current Clinical Criteria Issued by the World Health organization and American Diabetes Association. [3,8] The WHO criteria are based on fasting plasma glucose (FPG) and 2hPG concentrations. They recommend use of an OGTT in the absence of overt hyperglycaemia.[3] The ADA criteria encourage the use of HbA1c, fasting glycaemia and OGTT, in that order.[8] The argument for FPG or HbA1c over 2hPG is primarily related to feasibility. The advantages and disadvantages of using glucose testing and HbA1c testing are summarized in a WHO report from 2011,[7] and are still the subject of some debate (see Section 3.3). The diagnostic criteria adopted by WHO and ADA (Table 3) for the intermediate levels of hyperglycaemia are similar for IGT but differ for IFG. The ADA lower threshold for IFG is 5.6 mmol/L (101 mg/dL),[8] while WHO recommends the original cut-off point of 6.1 mmol/L (110 mg/dL).[3]
To standardize glucose determinations, venous plasma measures have been recommended.[3,8] 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, it is important to underline that capillary values may differ from plasma values more in the post-load than in the fasting state. Therefore, a recent comparative study suggests that the cut-off points for DM, IFG and IGT differ when venous blood and capillary blood are used as outlined in Table 4.[19]
Classification depends on whether only FPG is measured or if it is combined with 2hPG. An individual with IFG in the fasting state may have IGT or even DM if investigated with an OGTT. A normal FPG reflects an ability to maintain adequate basal insulin secretion, in combination with hepatic insulin sensitivity sufficient to control hepatic glucose output. A post-load glucose level within the normal range requires an appropriate insulin secretory response and adequate insulin sensitivity in peripheral tissues. It is important to pay attention to the analytical method when interpreting samples. This applies to both glucose and HbA1c determinations.
3.2 Epidemiology
The International Diabetes Federation's global estimates for 2011 (Table 5) suggest that 52 million Europeans aged 20–79 years have DM and that this number will increase to over 64 million by 2030.[1] In 2011, 63 million Europeans had IGT. A total of 281 million men and 317 million women worldwide died with DM in 2011, most from CVD. The healthcare expenditure for DM in Europe was about 75 billion Euros in 2011 and is projected to increase to 90 billion by 2030.
A problem when diagnosing T2DM is the lack of a unique biological marker—besides post-prandial plasma glucose (PG)—that would separate IFG, IGT, or T2DM from normal glucose metabolism. T2DM develops following a prolonged period of euglycaemic IR, which progresses with the development of beta-cell failure to frank DM with increased risk of vascular complications. The present definition of DM is based on the level of glucose at which retinopathy occurs, but macrovascular complications such as coronary, cerebrovascular and peripheral artery disease (PAD) appear earlier and, using current glycaemic criteria, are often present at the time when T2DM is diagnosed. Over 60% of people with T2DM develop CVD, a more severe and costly complication than retinopathy. Thus, CVD risk should be given a higher priority when cut-points for hyperglycaemia are defined and should be re-evaluated based on the CVD risk.
The Diabetes Epidemiology: COllaborative analysis of Diagnostic criteria in Europe (DECODE) study (Figure 2) reported data on disorders of glucose metabolism in European populations.[20] The limited data on HbA1c in these populations indicate major discrepancies, compared with results from an OGTT,[21] although this was not confirmed in the Evaluation of Screening and Early Detection Strategies for T2DM and IGT (DETECT-2) as further elaborated upon in Section 3.3.[22] In Europeans, the prevalence of DM rises with age in both genders. Thus <10% of people below 60 years, 10–20% between 60 and 69 years and 15–20% above 70 years have previously known DM and in addition similar proportions have screen-detected asymptomatic DM.[20] This means that the lifetime risk for DM is 30–40% in European populations. Similarly, the prevalence of IGT increases linearly from about 15% in middle aged to 35–40% in elderly Europeans. Even HbA1c increases with age in both genders.[23]
Figure 2.
Mean FPG fasting (two lower lines) and 2hPG (two upper lines) concentrations (95% confidence intervals shown by vertical bars) in 13 European population-based cohorts included in the DECODE study.20 Mean 2hPG increases particularly after the age of 50 years. Women have significantly higher mean 2hPG concentrations than men, a difference that becomes more pronounced above the age of 70 years. Mean FPG increases only slightly with age. FPG = fasting plasma glucose; 2hPG = 2-h post-load plasma glucose.
3.3 Screening for Disorders of Glucose Metabolism
Type 2 diabetes mellitus does not cause specific symptoms for many years, which explains why approximately half of the cases of T2DM remain undiagnosed at any time.[20,23] Population testing of blood glucose to determine CV risk is not recommended, due to the lack of affirmative evidence that the prognosis of CVD related to T2DM can be improved by early detection and treatment.[24,25] Screening of hyperglycaemia for CV risk purposes should therefore be targeted to high-risk individuals. The Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION) study provided evidence that the risk of CVD events is low in screen-detected people with T2DM. Screening may, however, facilitate CV risk reduction and early detection may benefit progression of microvascular disease, which may make screening for T2DM beneficial.[26] In addition, there is an interest in identifying people with IGT, since most will progress to T2DM and this progression can be retarded by lifestyle interventions.[27]–[31] The diagnosis of DM has traditionally been based on the level of blood glucose that relates to a risk of developing micro- rather than macrovascular disease. The DETECT-2 study analysed results from 44 000 persons in nine studies across five countries.[22] It was concluded that a HbA1c of >6.5% (48 mmol/L) and an FPG of >6.5 mmol/L (117 mg/dL) together gave a better discrimination in relation to the view—adopted by the ADA[6] and WHO[7]—that, for general population, screening an HbA1c >6.5% is diagnostic of DM, but between 6.0–6.5%, an FPG needs to be measured to establish a diagnosis. Caveats exist in relation to this position, as extensively reviewed by Hare et al.[32] Problems exist in relation to pregnancy, polycystic ovary syndrome,[33] haemoglobinopathies and acute illness mitigating against its use under such circumstances. Moreover, the probability of a false negative test result, compared with the OGTT, is substantial when attempting to detect DM by measuring only FPG and/or HbA1c in an Asian population.[34] A study in Spanish people with high risk, i.e. >12/26 points in the FINnish Diabetes RIsk SCore (FINDRISC) study, revealed that 8.6% had undiagnosed T2DM by the OGTT, whilst only 1.4% had an HbA1c >6.5%, indicating a further need to evaluate the use of HbA1c as the primary diagnostic test in specific populations.[9] There remains controversy regarding the approach of using HbA1c for detecting undiagnosed DM in the setting of coronary heart disease and CV risk management,[7]–[10,32] although advocates argue that HbA1c in the range 6.0–6.5% requires lifestyle advice and individual risk factor management alone, and that further information on 2hPG does not alter such management.
The approaches for early detection of T2DM and other disorders of glucose metabolism are: (i) measuring PG or HbA1c to explicitly determine prevalent T2DM and impaired glucose regulation; (ii) using demographic and clinical characteristics and previous laboratory tests to determine the likelihood for T2DM and (iii) collecting questionnaire-based information that provides information on the presence of aetiological risk factors for T2DM. The last two approaches leave the current glycaemic state ambiguous and glycaemia testing is necessary in all three approaches, 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 numbers who need to be referred for further testing of glycaemia and other CVD risk factors. Option two is particularly suited to those with pre-existing CVD and women with previous gestational DM, while the third option is better suited to the general population and also for overweight/obese people.
Several DM risk scores for DM have been developed. Most perform well and it does not matter which one is used, as underlined by a recent systematic review.[35] The FINnish Diabetes RIsk SCore (www.diabetes.fi/english) is the most commonly used to screen for DM risk in Europe (Figure 3).
Figure 3.
FINnish Diabetes RIsk SCore (FINDRISC) to assess the 10-year risk of type 2 diabetes in adults. (Modified from Lindstrom et al. 36 available at: www.diabetes.fi/english).
This tool, available in almost all European languages, predicts the 10-year risk of T2DM—including asymptomatic DM and IGT—with 85% accuracy.[36,37] It has been validated in most European populations. It is necessary to separate individuals into three different scenarios: (i) the general population; (ii) people with assumed abnormalities (e.g. obese, hypertensive, or with a family history of DM) and (iii) patients with prevalent CVD. In the general population and people with assumed abnormalities, the appropriate screening strategy is to start with a DM risk score and to investigate individuals with a high value with an OGTT or a combination of HbA1c and FPG.[36,37] In CVD patients, no diabetes risk score is needed but an OGTT is indicated if HbA1c and/or FPG are inconclusive, since people belonging to these groups may often have DM revealed only by an elevated 2hPG.[38–41]
3.4 Disorders of Glucose Metabolism and Cardiovascular Disease
Both undiagnosed T2DM and other disorders of glucose metabolism are risk factors for CVD. The most convincing evidence for such relationship was provided by the collaborative DECODE study, analysing several European cohort studies with baseline OGTT data.[42–44] Increased mortality was observed in people with DM and IGT, identified by 2hPG, but not in people with IFG. A high 2hPG predicted all-cause and CVD mortality after adjustment for other major cardiovascular risk factors, while a high FPG alone was not predictive once 2hPG was taken into account. The highest excess CVD mortality in the population was observed in people with IGT, especially those with normal FPG.[44] The relationship between 2hPG and mortality was linear, but this relationship was not observed with FPG (Figure 4).
Figure 4.
Hazard ratios and 95% confidence intervals (vertical bars) for CVD mortality for FPG (hatched bars) and 2hPG (dotted bars) intervals using previously diagnosed DM (dark bar) as the common reference category. Data are adjusted for age, sex, cohort, body mass index, systolic blood pressure, total cholesterol, and smoking. (Adapted from refs.42,43).
CVD = cardiovascular disease; DM = diabetes mellitus; FPG = fasting plasma glucose; 2hPG = 2-h post-load plasma glucose.
Several studies have shown that increasing HbA1c is associated with increasing CVD risk.[45–47] Studies that compared all three glycaemic parameters—FPG, 2hPG and HbA1c —simultaneously for mortality and CVD risk revealed that the association is strongest for 2hPG and that the risk observed with FPG and HbA1c is no longer significant after controlling for the effect of 2hPG.[48,49]
Women with newly diagnosed T2DM have a higher relative risk for CVD mortality than their male counterparts.[20,50–52] A review on the impact of gender on the occurrence of coronary artery disease (CAD) mortality reported that the overall relative risk (the ratio of risk in women to risk in men) was 1.46 (95% CI 1.21–1.95) in people with DM and 2.29 (95% CI 2.05–2.55) in those without, suggesting that the well-known gender differential in CAD is reduced in DM.[53] A meta-analysis of 37 prospective cohort studies (n = 447 064 DM patients) aimed at estimating sex-related risk of fatal CAD, reported higher mortality in patients with DM than those without (5.4 vs. 1.6%, respectively).[54] The relative risk, or hazard ratio (HR), among people with and without DM was significantly greater among women (HR 3.50; 95% CI 2.70–4.53) than in men (HR 2.06; 95% CI 1.81–2.34). Thus the gender difference in CVD risk seen in the general population is much smaller in people with DM and the reason for this is still unclear. A recent British study revealed a greater adverse influence of DM per se on adiposity, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and downstream blood pressure, lipids, endothelial dysfunction and systemic inflammation in women, compared with men, which may contribute to their greater relative risk of CAD.[55] Also, it seems that, compared with men, women have to put on more weight—and therefore undergo bigger changes in their risk factor status—to develop DM.[56]
3.5 Delaying Conversion to Type 2 Diabetes Mellitus
Unhealthy dietary habits and a sedentary lifestyle are of major importance in the development of T2DM.[57,58] As reviewed in the European evidence-based guideline for the prevention of T2DM,[59] randomized clinical trials (RCTs) demonstrate that lifestyle modification, based on modest weight loss and increased physical activity, prevents or delays progression in high-risk individuals with IGT. Thus, those at high risk for T2DM and those with established IGT should be given appropriate lifestyle counselling (Table 6). A tool kit, including practical advice for healthcare personnel, has recently been developed.[60] The seemingly lower risk reduction in the Indian and Chinese trials was due to the higher incidence of T2DM in these populations and the absolute risk reductions were strikingly similar between all trials: approximately 15–20 cases per 100 person-years. It was estimated that lifestyle intervention has to be provided to 6.4 high-risk individuals for an average of 3 years to prevent one case of DM. Thus the intervention is highly efficient.[31] A 12-year follow-up of men with IGT who participated in the Malmö Feasibility Study[61] 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 IGT in the 6-year lifestyle intervention group in the Chinese Da Qing study had, 20 years later, a persistent reduction in the incidence of T2DM and a non-significant reduction of 17% in CVD death, compared with control participants.[62] 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.[63] During an extended 7-year follow-up of the Finnish DPS study,[27] there was a marked and sustained reduction in the incidence of T2DM in people who had participated in the lifestyle intervention (for an average of 4 years). In the 10-year follow-up, total mortality and CVD incidence were not different between the intervention and control groups but the DPS participants, who had IGT at baseline, had lower all-cause mortality and CVD incidence, compared with a Finnish population-based cohort of people with IGT.[64] During the 10-year overall follow-up of the US Diabetes Prevention Programme Outcomes Study, the incidence of T2DM in the original lifestyle intervention group remained lower than in the control group.[65]
3.6 Recommendations for Diagnosis of Disorders of Glucose Metabolism
Eur Heart J. 2013;34(39):3035-3087. © 2013 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.
