The Importance of Hyperglycemia in the Nonfasting State to the Development of Cardiovascular Disease

I. Introduction II. Correlation Between Hyperglycemia and CVD A. Type 2 diabetes B. Elevated glucose concentrations in the nondiabetic range C. Atherosclerosis in subjects with asymptomatic hyperglycemia III. Causal Relationship of Postprandial Hyperglycemia to CVD A. Direct effects of hyperglycemia B. Insufficient insulin production C. Insulin resistance and hyperinsulinemia D. Association with risk factors for CVD IV. Therapeutic Interventions for Type 2 Diabetes A. Insulin therapy B. Sulfonylureas C. Biguanides D. Acarbose V. Studies to Prevent Type 2 Diabetes VI. Conclusions CARDIOVASCULAR disease (CVD) is a major cause of morbidity and mortality in patients with diabetes. It is also responsible for significant morbidity and mortality in the nondiabetic population. The development of strategies to recognize individuals with a risk of CVD and of interventions to reduce this risk would therefore be of considerable value both medically and economically. Much research over the last 30–40 yr has investigated risk factors for CVD. A link between glycemia in the nonfasting state (“postprandial hyperglycemia”) and CVD was first suggested in the 1950s and has now been demonstrated, as discussed further in this paper. While postprandial hyperglycemia is probably one of many risk factors, evidence indicating that there is a causal link between elevated blood glucose levels and the development of atherosclerosis suggests that therapeutic interventions to improve glycemic control may reduce the risk of CVD. Much of the data suggesting that glycemia in postprandial hyperglycemia is a risk factor for atherosclerosis, in fact, has derived from studies after glucose challenge rather than after a mixed meal. Strictly speaking, these data might apply most closely to subjects who ingest large amounts of soda (containing sugar), which is common enough in Western society. Few data have been collected on glucose levels following mixed meals although there is a considerable amount of data that postprandial triglyceride levels are consistent risk factors for atherosclerosis (1, 2). One issue that is currently unresolved is what proportion of the elevated HBA1c is due to postprandial glucose levels compared with basal glucose levels. It is clear that in the early phases of diabetes, HBA1c levels show modest elevations of postprandial plasma glucose but basal glucose levels (fasting) are still in the nondiabetic range. This article reviews the evidence for a close association between hyperglycemia (in particular, postprandial hyperglycemia) and the development of CVD. Therapeutic strategies to reduce postprandial hyperglycemia and the risk of CVD are also discussed. Subjects with type 2 diabetes have an increased risk of developing CVD in comparison with nondiabetic subjects. This was initially demonstrated in the results of the Framingham study (3), which reported a 4-fold increase in women and a 2-fold increase in men compared with nondiabetic subjects. Similar results have been obtained in other studies (4, 5). The risk of CVD is increased at the time of diagnosis and is independent of the duration of diabetes in some studies (6–8), thus suggesting that factors before the development of overt diabetes contribute to the risk of CVD. This is also suggested by the finding of increased cardiovascular risk factors before the onset of type 2 diabetes (9). The results of various studies suggest a relationship between hyperglycemia and the development of CVD in patients with type 2 diabetes. For example, the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) reported a significant association between glycosylated hemoglobin levels, a measure of long-term blood glucose levels, and mortality from ischemic heart disease (10). This relationship was stronger in younger-onset diabetic subjects (i.e., type 1) rather than in older-onset diabetic subjects (i.e., type 2 diabetic subjects) (10). A 1% rise in glycosylated hemoglobin cardiovascular mortality in younger-onset diabetic subjects was associated with a 20% rise in ischemic heart disease mortality in type 2 diabetic subjects (10). In a group of patients with older-onset diabetes, the hazard ratio for a 1% change in glycosylated hemoglobin was 1.10 (95% confidence interval, 1.04–1.17). Similarly, Standl et al. (11) found in a multivariate analysis that levels of HbA1c, von Willebrand factor protein, and age were the major determinants for CVD-related mortality in a study involving 290 patients with type 2 diabetes (Munich General Practitioner Project). Another study, involving 1059 patients with type 2 diabetes followed for 7 yr, found that high fasting plasma glucose levels (>13.4 mmol/liter) were associated with a 2-fold increase in the risk of coronary heart disease (CHD) mortality and morbidity (12). The risk was further increased to 3-fold in patients who simultaneously had high fasting plasma glucose levels and low high-density lipoprotein (HDL) cholesterol, low HDL-cholesterol ratio, or high total triglycerides. Evidence to suggest that the risk of CVD is particularly associated with postprandial hyperglycemia rather than fasting hyperglycemia comes from a German study, the Diabetes Intervention Study (DIS), that comprised approximately 1000 patients with newly diagnosed type 2 diabetes (13, 14). The 11-yr follow up to the DIS study reported an extremely high incidence of myocardial infarction for patients included in this study compared with nondiabetic control subjects included in another study, the Monitoring of Trends of Cardiovascular Diseases and their Determinants (MONICA) study, which was conducted over the same period. Multivariate analysis revealed that postprandial blood glucose, but not fasting blood glucose levels, was a risk factor for myocardial infarction in the DIS population (Fig. 1). These results were particularly interesting since postprandial glucose levels are quite variable, and thus we might expect them to be less predictive than fasting glucose levels. Triglyceride levels and elevated blood pressure were also risk factors. The risk of myocardial infarction was also related to the degree of control of postprandial blood glucose. Incidence of myocardial infarction (▪) and mortality rate (□) in relation to the quality of control of fasting glucose and postprandial blood glucose: 11-year follow-up of the Diabetes Intervention Study. [Adapted with permission from M. Hanefeld et al.: Diabetologia 39:1577–1583, 1996 (14 ). © Springer-Verlag.] The study of Lehto et al. (12) has shown that the association of glucose with CHD in type 2 diabetic subjects is independent of conventional risk factors; in contrast, a number of studies (15–18) have not shown that the relation between glycemia and CHD is not independent of conventional cardiovascular risk factors. Moreover, in data from the Wisconsin Epidemiological Study of Diabetic Retinopathy (19), no information was available on HDL cholesterol, an important predictor of CHD in diabetic subjects (12, 17). However, it may not be correct to adjust for other cardiovascular risk factors if the effect of glucose on macrovascular disease is mediated through these risk factors (“over-adjustment”). The decision on whether or not to adjust cannot be made on epidemiological or statistical grounds but depends instead on the biological model used for glucose and macrovascular disease. A similar issue could be raised for insulin and CVD, which will be discussed later. The results of these and other studies suggest a possible causal link between postprandial hyperglycemia and the development of CVD in patients with type 2 diabetes. The relationship between hyperglycemia and CVD has also been extensively investigated in epidemiological studies in subjects with the prediabetic condition that is often referred to as impaired glucose tolerance (IGT). (Strictly speaking, prediabetic refers to subjects who, from longitudinal data, are known to convert to diabetes. Subjects with IGT have a markedly increased risk of type 2 diabetes, but not all subjects with IGT convert to type 2 diabetes.) Subjects with IGT show elevated postprandial glucose levels, but fasting blood glucose levels are usually within the normal range, and both fasting and postprandial blood glucose levels are lower than those used to define type 2 diabetes. IGT was formally defined by the World Health Organization (WHO) in 1979 and revised in 1985. Studies before 1979 used their own definitions for this condition but also provide informative results. Various studies have investigated the prevalence of CVD in individuals with IGT and in control populations with normal glucose tolerance (NGT). An increased prevalence of CVD in subjects with IGT has been reported in most studies. For example, the Da Qing study (20) found 4% of subjects with IGT had ECG abnormalities compared with 0.4% of the control population, while Ohlson et al. (21) also reported an increased prevalence of CVD in subjects with IGT in a study involving men aged 67 yr. Rewers et al. (22) observed a 2-fold increase in CHD in non-Hispanic white individuals with IGT compared with those with NGT. In contrast, the prevalence of CHD in Hispanic individuals in this study was similar for those with IGT and those with NGT. This suggests ethnicity may influence the effect of IGT on CHD. Prospective epidemiological studies provide further evidence for a link between IGT and development of CVD. The results from the most important of these studies are summarized in Table 1. Most of these studies show a significant correlation between the risk of CVD and postprandial hyperglycemia. The association appears to be weaker in elderly subjects. Summary of prospective studies investigating correlations between hyperglycemia and prevalence of CHD Summary of prospective studies investigating correlations between hyperglycemia and prevalence of CHD The results of many of these studies suggest that dysglycemia is a continuous risk factor for CVD. Thus in the Honolulu Heart Study (32), the risk of CHD was found to increase continuously with increasing 1-h plasma glucose levels (P < 0.001). Similarly in the Rancho Bernardo study (33) involving 3458 subjects with fasting plasma glucose levels <7.8 mmol/liter and no history of diabetes, age-adjusted ischemic heart disease mortality rates were found to increase by approximately 2-fold in men as their fasting glucose level increased from 5 to 7 mmol/liter. Coutinho et al. (34) found, in a meta-cohort of studies involving largely nondiabetic populations, that the risk of CVD increased continuously with glucose levels of greater than 4.2 mmol/liter and, thus, Gerstein and Yusuf (35) have suggested that the term “dysglycemia” might be used. These findings suggest the view that glucose levels in the nondiabetic range might be associated with increased macrovascular disease. Thus, the risk of CVD begins in the prediabetic state. This probably explains why the risk of CVD is present at diagnosis of type 2 diabetes and is not related to the duration of diagnosed diabetes in many studies. A number of other issues may confound the relation of IGT with CVD. Balkau et al. (36) suggest that the relation between hyperglycemia and CVD in nondiabetic men is most pronounced in subjects likely to have IGT or undiagnosed non-insulin-dependent diabetes mellitus. Yudkin et al. (37) suggested that at least some of the CVD risk may be due to the misclassification of undiagnosed diabetes. Lastly, the risk of CVD in IGT subjects might be high only in those subjects who ultimately develop type 2 diabetes; this possibility, however, has not been examined. Further support for the correlation between hyperglycemia and the development of CVD comes from recent studies of changes in the arterial wall in diabetic patients and in nondiabetic subjects with elevated postprandial blood glucose levels. Japanese investigators have used B-mode ultrasonography to investigate changes in the thickness of the wall of the carotid artery, characteristic of atherosclerosis (38). In one study, the investigators measured the thickness of the intima medial wall thickness of the carotid artery in nondiabetic subjects with 2-h blood glucose levels greater than 6.7 mmol/liter (n subjects (n and patients with type 2 diabetes (n The nondiabetic subjects with postprandial hyperglycemia were those with 2-h glucose levels of greater than mmol/liter and those with 2-h between 6.7 and mmol/liter for intima medial wall thickness for all with IGT (i.e., and type 2 were greater than those of and no significant were between the asymptomatic hyperglycemia and the group with type 2 diabetes. have suggested a relation between glucose and carotid artery wall thickness in nondiabetic subjects The suggest that changes to develop in the prediabetic state postprandial blood glucose levels are only elevated normal levels. This has important for therapeutic as will be discussed in this evidence for a relation between postprandial hyperglycemia and CVD epidemiological data to have not the causal association between glycemia and CVD. Various possible for the association have been suggested 1. A hyperglycemia has a effect on to Hyperglycemia insulin Atherosclerosis results from effects of insulin resistance and hyperinsulinemia may be responsible for Hyperglycemia may be a but not a cause of these Hyperglycemia may be associated with various risk factors for as and In this hyperglycemia is a of abnormalities but is not related to the development of These possible will now be discussed. is evidence for effects of high blood glucose levels on effects in to increased blood glucose levels, while develop in to of hyperglycemia. 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An observed association between hyperinsulinemia and CVD may thus in an association with hyperglycemia. Hyperglycemia in association with risk factors for CVD as insulin and It is thus possible that the association of hyperglycemia with CVD a link with these other factors that could the of hyperglycemia. Thus, while it has not been that hyperglycemia is the major factor to the development of CVD, the association between postprandial hyperglycemia and the risk of CVD and evidence for effects of elevated glucose concentrations suggest that hyperglycemia is to factors, as insulin and may contribute to the development of but may or may not the for hyperglycemia. 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