Risk of Cardiovascular Disease in Prediabetes

The American Diabetes Association (ADA) has recently introduced the term pre-diabetes in an attempt to simplify what has become an increasingly confusing literature on impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) (see also Chapter 11). In fact, pre-diabetes was introduced as an official term nearly 40 years ago, although with an entirely different definition (World Health Organization, 1965), and some may argue that it may be a misleading label for some subjects with intermediate metabolic states who might never go on to develop frank diabetes. The term IGT has been in use since 1979 and is defined by a fasting plasma venous glucose level of < 7.0mmol/l and a 2-h post-glucose load level between 7.8 and 11.0mmol/l. The concept of IFG was introduced more recently (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997) and is defined by a fasting glucose level between 6.1 and 6.9. Whether, as in the diagnosis of diabetes, classification should be confirmed by repeat testing has not as yet been established in official guidelines.

The terms IGT and IFG are not mutually exclusive, but certainly identify different subgroups of the population with metabolic dysregulation. This is understandable when the relevant physiological contributing factors are examined. Impaired glucose tolerance is mostly dependent on peripheral insulin resistance in association with failure of sufficient insulin production to buffer the glucose excursion associated with absorption of a glucose load. Impaired fasting glucose is more dependent on hepatic insulin resistance, which results in insufficient inhibition of fasting gluconeogenesis, in association with inadequate basal insulin production to overcome hepatic dysfunction. Depending on the age, sex and ethnic mix of a population, the prevalences of IGT and IFG can vary but in general more people have IGT than IFG, with a smaller group having both (Unwin etal., 2002). Risk of future diabetes is greatest if both IGT and IFG are present, and IGT appears to be more predictive than IFG, although if the cut-off for IFG is lowered to the most recent ADA definition (> 5.6 mmol/l) (American Diabetes Association, 2004a) then the sensitivity of IFG rivals that of IGT (Shaw etal., 1999; Gabir etal., 2000; Unwin etal., 2002).

Both IGT and IFG also predict CVD incidence. In parallel with the meta-regression analysis described above, analyses from the DECODE study (combining data from 13 prospective European studies) have demonstrated all-cause mortality hazard ratios of 1.20 (95% CI 1.04-1.38) for IFG and 1.50 (95% CI 1.33-1.69) for IGT when compared with normoglycaemia. However, when the analyses were confined to CVD events and adjusted for body mass index (BMI), systolic blood pressure (SBP), cholesterol and smoking, IGT remained a significant predictor (hazard ratio 1.34; 95% CI 1.14-1.57) whereas the effect of IFG was lost (hazard ratio 1.09; 95% CI 0.90-1.30), implying that a 2-h oral glucose tolerance test (OGTT) level may be the optimal glucose parameter for cardiovascular event prediction. The question remains whether there are mechanistic explanations for these observations - for example, could exaggerated postprandial glucose excursions play a key role in accelerating atheromatous lesions? Or could peripheral insulin resistance, to which IGT is strongly related, be exerting an influence on risk, possibly via circulating factors such as adipocytokines? There is no doubt that measurement of blood glucose (either fasting or post-glucose load) remains a useful tool to identify individuals at risk of both T2D and CVD, but it should be viewed as a continuous risk variable to be interpreted in conjunction with other risk markers associated with the metabolic syndrome. The resulting 'big picture' estimate of risk is important for designing strategies to target certain groups for primary prevention of T2D and CVD.

Of course, we should be able to glean useful information about the relative contribution of hyperglycaemia to cardiovascular risk from intervention studies designed to demonstrate significant delay or prevention of diabetes, defined by glycaemic thresholds. These studies will be summarised in detail in the next section. If an intervention were simply to reduce blood glucose levels then any associated reduction in cardiovascular outcomes could be ascribed to a glucose effect. However, as we will go on to discuss, most of the published studies in pre-diabetic subjects involve interventions that impact on other facets of the metabolic syndrome, potentially resulting in reduced cardiovascular risk via glucose-independent mechanisms.

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