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

Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7873

	Abstract

Top Abstract I. Introduction II. Correlation Between... III. Causal Relationship of... IV. Therapeutic Interventions... V. Studies to Prevent... VI. Conclusions References

 

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

	I. Introduction

Top Abstract I. Introduction II. Correlation Between... III. Causal Relationship of... IV. Therapeutic Interventions... V. Studies to Prevent... VI. Conclusions References

 
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 HBA_1c is due to postprandial glucose levels compared with basal glucose levels. It is clear that in the early phases of diabetes, HBA_1c 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.

	II. Correlation Between Hyperglycemia and CVD

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A. Type 2 diabetes
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, 7, 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 HbA_1c, 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.

View larger version (11K): [in this window] [in a new window]   Figure 1. 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 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.

B. Elevated glucose concentrations in the nondiabetic range
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.

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.

C. Atherosclerosis in subjects with asymptomatic hyperglycemia
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 = 112), healthy male subjects (n = 55), and patients with type 2 diabetes (n = 211). The nondiabetic subjects with postprandial hyperglycemia were subdivided into those with 2-h glucose levels of greater than 7.8 mmol/liter (IGT) and those with 2-h values between 6.7 and 7.7 mmol/liter (non-IGT).

Values for intima medial wall thickness for all three groups with IGT (i.e., IGT, non-IGT, and type 2 diabetes) were significantly greater than those of age-matched controls, and no significant differences were seen between the two asymptomatic hyperglycemia groups and the group with type 2 diabetes. Two additional reports have suggested a relation between glucose and carotid artery wall thickness in nondiabetic subjects (39, 40). The above reports suggest that atherosclerotic changes start to develop in the prediabetic state when postprandial blood glucose levels are only moderately elevated above normal levels. This has important implications for therapeutic intervention, as will be discussed later in this article.

	III. Causal Relationship of Postprandial Hyperglycemia to CVD

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Although evidence for a relation between postprandial hyperglycemia and CVD exists, epidemiological data to date have not clearly resolved the causal association between glycemia and CVD. Various possible explanations for the association have been suggested including:

1. A direct effect: hyperglycemia has a direct effect on endothelial cell function leading to atherosclerotic changes.

2. Hyperglycemia reflects insufficient insulin production. Atherosclerosis results from effects of reduced ß-cell function.

3. Increasing insulin resistance and hyperinsulinemia may be responsible for atherosclerotic changes. Hyperglycemia may be a marker but not a cause of these changes.

4. Hyperglycemia may be associated with various risk factors for CHD, such as dyslipidemia, hypertension, and abdominal obesity. In this case, hyperglycemia is a marker of metabolic abnormalities but is not causally related to the development of atherosclerotic changes.

These possible associations will now be discussed.

A. Direct effects of hyperglycemia
There is much evidence for toxic effects of high blood glucose levels on cell function. Some effects occur rapidly in response to increased blood glucose levels, while others develop slowly in response to prolonged periods of hyperglycemia. It seems likely that both types of changes contribute to the development of atherosclerosis.

Various studies have shown that elevated glucose levels can alter the activity of protein kinase C (PKC), a key enzyme in signaling transduction pathways (41, 42, 43, 44, 45, 46, 47). This is an immediate effect of hyperglycemia although there is evidence to suggest that the effect of hyperglycemia may persist for some time after blood glucose levels return to normal. Elevated blood glucose levels lead to increased uptake of glucose into cells. The intracellular glucose is then metabolized via the sorbitol pathway, which reduces intracellular myoinositol uptake (48, 49). De novo synthesis of diacylglycerol is also increased which, in turn, leads to activation of PKC. Various cellular changes found to be associated with elevated glucose concentrations are probably mediated via the activity of PKC, e.g., increased secretion of endothelin, a cytokine believed to be involved in the development of atherosclerosis (50), increased secretion of collagen IV and fibronectin (46, 51), and increased expression of adhesion molecules on the vascular endothelium, involved in macrophage migration (52). The involvement of PKC has been demonstrated conclusively by Haller et al. (53) for the effect of glucose on endothelial cell permeability. Concentrations of 10–40 mmol/liter were found to significantly increase permeability. This effect was inhibited by various PKC inhibitors.

Acute hyperglycemia has also been found to induce oxidative stress, probably via the generation of free radicals. This may occur by one of three routes: autooxidation of glucose (54), labile glycation (55), or intracellular activation of the polyol pathway (56). The free radicals may then mediate some of the effects associated with acute hyperglycemia, e.g., vasoconstriction, activation of coagulation, and increased expression of adhesion molecules. These changes probably contribute to the development of atherosclerosis.

In contrast to the rapid effects described so far, which occur almost immediately in response to elevated blood glucose levels, other changes arise in response to prolonged periods of hyperglycemia. Probably the best understood change is the nonenzymatic glycosylation of proteins exposed to glucose, e.g., cell membrane proteins, circulating proteins, and structural proteins that form vessel walls. These so-called advanced-glycosylation end product (AGE) proteins accumulate over time and have been implicated in pathological changes associated with atherosclerosis (57, 58). AGEs induce excess cross-linking of collagen and other extracellular matrix proteins in many tissues including the vascular wall. Such extensive cross-linking causes covalent trapping of low-density lipoproteins (LDLs), which may then accumulate in vascular walls. Glycosylation of proteins in vessel walls probably contributes to thickening of vessel walls and loss of elasticity as well as increases in vascular permeability. AGE products have also been found to stimulate the release of cytokines that induce cell proliferation, e.g., insulin-like growth factor and tumor necrosis factor (59).

Hyperglycemia also results in glycosylation of the lipoproteins LDL and HDL, which in turn alters their functions (58, 60, 61, 62). Glycosylation of LDL disrupts recognition of LDL by LDL receptors and hence reduces uptake and catabolism. Glycosylated LDL are also more prone to oxidation. Oxidized and glycosylated LDL can induce transformation of macrophages to foam cells, a component of atherosclerotic plaques. Glycosylation of HDL reduces the capacity of this lipoprotein to transport cholesterol, which may also promote atherosclerosis.

B. Insufficient insulin production
Since tissue uptake of glucose is largely regulated by insulin, deficiencies in insulin secretion are likely to result in hyperglycemia. This means that hyperglycemia could be a marker for loss of ß-cell function. The development of CVD may thus be associated with the loss of ß-cell function and hence insufficient insulin production rather than the hyperglycemia per se.

Evidence to support a possible role for loss of ß-cell function in the development of CVD comes from the observation that subjects with elevated proinsulin levels have increased cardiovascular risk factors (63); however, it is not clear whether subjects with increased proinsulin levels have increased atherosclerosis (39, 64). The presence of these products is probably a marker of loss of ß-cell function (65), and elevated proinsulin levels are also associated with increased cardiovascular risk factors (63, 66, 67). However, it seems unlikely that loss of ß-cell function alone is sufficient to induce the pathogenic changes associated with CVD. Insufficient insulin production is more likely to be only a contributing factor.

It has been suggested that reduced ß-cell function (i.e., reduced insulin secretion) together with insulin resistance are responsible for the development of hyperglycemia. According to this hypothesis, once hyperglycemia develops, it further exacerbates insulin resistance and ß-cell dysfunction, leading to worsening of the diabetic state ("glucotoxicity"). This hypothesis would be in agreement with insufficient insulin production being a link between hyperglycemia and CVD.

It is also possible that hyperglycemia precedes the loss of ß-cell function and is triggered by insulin resistance, resulting from genetic or environmental factors. In at-risk individuals, even modest postprandial hyperglycemia may cause desensitization of ß-cells to glucose and ß-cell dysfunction. This would lead to decreased insulin secretion and hence progressively greater hyperglycemia. This hypothesis supports a direct effect of hyperglycemia on the development of CVD, as discussed above.

C. Insulin resistance and hyperinsulinemia
Hyperinsulinemia is associated with CHD (68, 69) and with many risk factors for CVD, e.g., hypertension (70), increased plasminogen activator inhibitor-1 (PAI-1) (71), elevated triglyceride levels (72, 73), and depressed levels of HDL (72, 73). Various mechanisms have been suggested by which hyperinsulinemia may promote atherosclerosis (74), such as stimulating smooth muscle proliferation and vascular growth factor production (75), increasing noradrenaline release through activation of the sympathetic nervous system (76), and stimulating renal sodium and water retention (74).

The evidence implicating insulin as a possibly atherogenic substance includes data from animal studies, in vitro studies, and prospective epidemiological studies. Many of these studies have been summarized by Stout (75). A number of early studies indicated that in cholesterol-fed animals with alloxan-induced diabetes, the expected degree of aortic atherosclerosis that usually follows cholesterol feeding failed to develop unless insulin was simultaneously administered (76, 77, 78). In one study, injection of insulin directly into the femoral artery of a dog with alloxan-induced diabetes resulted in more medial thickening and a higher cholesterol content in the vascular wall than injection of saline into the contralateral femoral artery (79). Insulin also has been shown to cause in vitro proliferation of smooth muscle cells obtained from a number of experimental animals and from humans (75, 80, 81) and to stimulate the binding of LDL to smooth muscle cells (80) and fibroblasts (82). Finally, insulin also stimulates cholesterol synthesis and the binding of LDL to cell membranes in monocytes (83, 84, 85). Thus, insulin could theoretically promote atherosclerosis by direct action on the arterial wall.

However, hyperinsulinemia is not a consistent risk factor for CVD in epidemiological studies of nondiabetic patients with CVD (86), and insulinomas are not associated with cardiovascular risk (87). Ruige et al. (88) have suggested, in a comprehensive meta-analysis of insulin and CVD, that the association is only moderate in strength and may be restricted to Caucasians. Thus the role of prolonged hyperinsulinemia and insulin resistance in the development of atherosclerosis is unclear and is difficult to distinguish from that of hyperglycemia since insulin levels in nondiabetic subjects are closely linked to blood glucose levels. An observed association between hyperinsulinemia and CVD may thus reflect, in part, an association with hyperglycemia.

D. Association with risk factors for CVD
Hyperglycemia commonly occurs in association with risk factors for CVD such as hypertension, insulin resistance, hypertriglyceridemia, and microalbuminuria (72). It is thus possible that the association of hyperglycemia with CVD reflects a link with these other factors that could precede the appearance of hyperglycemia.

Thus, while it has not been proved conclusively that hyperglycemia is the major factor leading to the development of CVD, the strong association between postprandial hyperglycemia and the risk of CVD and evidence for direct toxic effects of elevated glucose concentrations suggest that hyperglycemia is causally linked to atherosclerosis. Other factors, such as insulin resistance, ß-cell dysfunction, and hyperinsulinemia, may well contribute to the development of pathological changes, but may or may not play the central role implicated for hyperglycemia. A central role of postprandial hyperglycemia in the development of atherosclerosis has important implications for therapeutic intervention both in patients with diabetes and subjects with IGT who are also at increased risk of CVD.

	IV. Therapeutic Interventions for Type 2 Diabetes

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Many studies have investigated various strategies aimed at reducing the risk of CVD both in patients with diabetes and in subjects with IGT. While diet and exercise regimens form the basis of all strategies, the long-term benefits of such regimens, when used alone, have proved rather disappointing. In most subjects, pharmacological intervention is probably necessary to have an impact on the long-term complications arising from hyperglycemia. Therapies that have been investigated to date include insulin, sulfonylureas, biguanides, and, more recently, the -glucosidase inhibitor, acarbose. Each of these agents will now be discussed.

A. Insulin therapy
The impact of insulin therapy on CVD in patients with type 2 diabetes is controversial. While results from the Diabetes Control and Complications Trial (DCCT) (89) clearly indicate that intensive insulin therapy reduces the risk of microvascular disease and showed a trend toward reducing the risk of CVD in patients with type 1 diabetes, results in patients with type 2 diabetes are less clear.

A Japanese study comparing intensive and conventional insulin therapy in patients with type 2 diabetes observed a trend toward reduced CVD for intensive therapy (90), whereas the University Group Diabetes Program (UGDP) (91) found no difference in CVD over a 6–13 yr follow-up of patients with type 2 diabetes randomized to standard or variable dose insulin therapy. The Feasibility Trial of the Veteran Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (92) also reported no significant differences between conventional and intensive insulin therapy, although the final report showed a trend toward increased risk of CVD (93). Interim results from the UKPDS have not detected differences in cardiovascular or risk factors (such as blood pressure, HDL cholesterol, or triglycerides) despite better glycemic control for insulin therapy compared with diet although the differences in glycemic control are only modest (94).

It is possible that the beneficial effects of insulin therapy on glycemic control may be counterbalanced by adverse effects on CVD risk. This suggestion comes from the results of a study in Pima Indians, which reported a direct relationship between insulin use and fatal coronary disease (95).

The discrepancies between studies may reflect differences in the insulin regimens and doses given as well as differences in the patient populations. Theoretically, higher daily doses would be expected to give better glycemic control. However, the doses that can be administered are restricted by the risk of hypoglycemia, especially in middle-aged and elderly patients, and also by long-term weight gain. Insulin therapy has not been investigated in subjects with IGT and is probably inappropriate because of the risk of inducing hypoglycemia as well as limited patient acceptance.

The use of very short-acting insulin analogs (Humalog) may reduce postprandial glucose concentrations without increasing the risk of hypoglycemia. These agents need to be studied in clinical trials to assess both long-term safety and whether the shorter period of hyperinsulinemia may provide benefits with respect to atherosclerosis.

B. Sulfonylureas
Sulfonylureas have been the principal agents in the treatment of type 2 diabetes over the past 30 yr. By stimulating insulin secretion, sulfonylureas reduce fasting blood glucose levels and have been shown to reduce HbA_1c levels by 20% (96, 97, 98). However, in the long term, normal glycemic control cannot be maintained in approximately 50% of patients, who later require additional or alternative therapies. This probably reflects the fact that sulfonylureas are unable to stop the underlying progression of the disease. This has been clearly demonstrated in the UKPDS study, which compared the effects of diet, glibenclamide, chlorpropamide, metformin, and insulin in newly diagnosed subjects with type 2 diabetes. An interim analysis revealed that over the course of 6 yr (94), fasting blood glucose levels rose progressively and thus neither sulfonylureas, metformin, nor insulin was able to prevent the progression of diabetes. Insulin sensitivity remained constant throughout the 6-yr period, but ß-cell function showed a steady decline.

Few studies have investigated the effects of sulfonylureas on CVD. The longest completed clinical trial is that of the UGDP (99), which involved 1027 patients with type 2 diabetes. This compared the impact of 1) insulin, at a fixed or variable dose; 2) the sulfonylurea, tolbutamide; and 3) the biguanide, phenformin, with placebo. A significantly increased incidence of CVD was seen in the group receiving tolbutamide. The UKPDS is also investigating the effects of sulfonylureas on CVD. Although this study has not yet been completed, the fact that none of the therapy groups has yet been terminated suggests that a clinically significant increase in CVD has not emerged in the sulfonylurea group. This study is due to be presented at the 1998 European Association for the Study of Diabetes (EASD) meeting in Barcelona and should then yield more definite data on the impact of these agents on CVD.

C. Biguanides
Metformin, the only drug of this class that remains widely available for the treatment of type 2 diabetes, has been extensively employed over the last 35 yr. The mechanism of action of metformin is not fully understood but involves reduction of gluconeogenesis and hence hepatic glucose output, as well as stimulation of peripheral glucose uptake. Metformin therapy is not associated with weight gain or risks of hypoglycemia. It has thus been investigated in subjects with IGT as well as in type 2 diabetes.

Few studies have investigated the impact of biguanides on cardiovascular complications. One such study is the ongoing UKPDS, which is investigating the effects of metformin. The results of this study are expected in 1998. Meanwhile, effects of metformin on risk factors for CVD, such as lowering of circulating triglycerides, reducing blood pressure, and reduction of PAI-1, have been reported in various studies (100, 101, 102, 103, 104, 105). Another randomized study (the UGDP) has investigated the effects of the biguanide, phenformin, in patients with type 2 diabetes (106). This study observed a statistically significant increase in CVD. However, the results of this study are controversial due to the low rate of CVD in the placebo group. Thus, conclusive evidence for a possible effect of metformin on CVD in patients with type 2 diabetes or in subjects with IGT has yet to be reported. This issue will be examined in the Diabetes Prevention Project (DPP), a US clinical trial investigation on prevention of type 2 diabetes in subjects with IGT.

D. Acarbose
There is much interest in the potential of acarbose to reduce the risk of CVD in patients with type 2 diabetes or in subjects with IGT. This -glucosidase inhibitor delays the absorption of carbohydrate from the intestine and so reduces the postprandial rise in blood glucose. Because of the mode of action, many subjects may experience gastrointestinal discomfort initially, although these symptoms usually decrease by starting with a low dose and seem to diminish with time. Acarbose thus acts directly to prevent hyperglycemia, a key factor in the development of CVD. Since acarbose acts on the absorption rather than the tissue uptake of glucose, it does not have the potential to induce hypoglycemia when used as monotherapy. This, together with the favorable safety profile of acarbose and its lack of impact on body weight, may make this agent particularly well suited for long-term use to prevent the development of CVD in both patients with type 2 diabetes and in subjects with IGT.

Acarbose is effective at decreasing postprandial hyperglycemia in patients with type 2 diabetes (107). This has also been demonstrated by Chiasson et al. for subjects with IGT (108). In a pilot study, Chiasson found that acarbose produced a significantly greater reduction in 12-h plasma glucose and insulin AUC compared with placebo. Insulin sensitivity was also significantly improved compared with placebo by the end of the 4-month treatment period.

The UKPDS has been extended to include a group receiving acarbose therapy. The results for the first year of this study report a slight decrease in fasting plasma glucose levels for patients receiving acarbose compared with a slight increase in patients receiving placebo. This result suggests that acarbose may be able to halt the progressive increase in fasting plasma glucose levels that is indicative of the course of the disease. In this respect, acarbose may differ from other antidiabetic agents that do not halt the underlying loss of ß-cell function.

Acarbose has also been found to have an impact on risk factors for atherosclerosis. In addition to reducing postprandial hyperglycemia, acarbose also reduces fasting hyperglycemia without increasing insulin levels and reduces postprandial hypertriglyceridemia and total cholesterol (109). This suggests acarbose may potentially be able to reduce the risk of CVD in high-risk subjects.

Various long-term randomized studies are now investigating the possible impact of acarbose on CVD. One such study is the EDIP study, which is investigating the impact of acarbose monotherapy on the development of diabetes and CVD in patients with early postprandial diabetes. This placebo-controlled study aims to recruit 100 patients to each treatment group over the course of 1 yr and follow patients for a further 5 yr. The primary outcome measure is the change in fasting plasma glucose, which will determine whether controlling postprandial hyperglycemia retards the progression toward type 2 diabetes, while secondary outcome measures include the impact on microvascular and macrovascular complications, insulin sensitivity, insulin secretion and clearance, and overall glycemic control.

	V. Studies to Prevent Type 2 Diabetes

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The NIH in the United States initiated a study to prevent (and/or delay) type 2 diabetes in subjects with IGT (fasting plasma glucose, 95–125 mg/dl) and 2-h glucose 140–199 mg/dl). The study will eventually enroll 4000 subjects at 26 centers in the United States. In April 1998 recruitment was 60% complete and was on target to finish by July 1999. The three arms are: 1) usual care; 2) intensive lifestyle; and 3) metformin. The period of follow-up is from 3 to 6 yr. In addition to the primary prevention of diabetes, secondary endpoints include the assessment of intima media wall thickness of the common and internal carotid arteries by B-mode ultrasound, which may permit the assessment of whether potentially insulin-sensitizing interventions may slow progression of atherosclerosis. Several other studies to prevent type 2 diabetes are being carried out with different agents. The effects of acarbose on CVD are secondary endpoints in two studies of acarbose in subjects with IGT. The Early Diabetes Intervention Trial (EDIT) is using a factorial design to compare acarbose vs. metformin vs. placebo vs. acarbose plus metformin in subjects with a fasting plasma glucose level in the range of 5.5–7.7 mmol/liter. The primary endpoint of this study is the rate of progression to type 2 diabetes, while secondary endpoints include signs of cardiovascular or microvascular disease, ß-cell function, and insulin sensitivity. The STOP-NIDDM study is a large international study involving centers in Canada, Germany, Scandinavia, Spain, and Israel. Subjects with IGT are randomized to receive acarbose or placebo for 3 yr and will be assessed for progression to type 2 diabetes, cardiovascular events, blood pressure, insulin sensitivity, hyperinsulinemia, and lipid profiles.

	VI. Conclusions

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There is now substantial evidence linking hyperglycemia with the development of CVD. Since most of the day is spent in the postprandial state, it seems reasonable to assume that postprandial hyperglycemia may play a critical role. Indeed, in some studies, postprandial hyperglycemia may be a stronger risk factor for CVD than fasting glycemia.

Possible explanations for the association between postprandial hyperglycemia and CVD include a direct causal link and various indirect links involving insulin sensitivity, hyperinsulinemia, and other risk factors for CVD. Evidence for a number of pathological effects of high glucose concentrations suggests that hyperglycemia is probably a direct cause of at least some of the changes associated with atherosclerosis. This has prompted investigations of therapeutic interventions to reduce postprandial hyperglycemia with the aim of also reducing the risk of CVD. No conclusive results have been produced as yet, but the results of several ongoing studies, expected within the next few years, should clarify the value of such interventions and may provide further evidence for the role of postprandial hyperglycemia in the development of CVD. The results of these studies could have far-reaching implications for the management of patients with diabetes, and in particular for subjects with IGT who are at high risk of developing atherosclerosis.

	Footnotes

 
Address reprint requests to: Steven M. Haffner, M.D., Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7873 USA.

	References

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