28 Diabetes Mellitus and Heart Disease

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From: Contemporary Cardiology: Diabetes and Cardiovascular Disease, Second Edition Edited by: M. T. Johnstone and A. Veves © Humana Press Inc., Totowa, NJ

28 Diabetes Mellitus and Heart Disease

Michael T. Johnstone, ^MD , ^CM , ^FRCP(

⁾ and George P. Kinzfogl, ^MD

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INTRODUCTION

Editor’s Note: The aim of this chapter is to not only serve as a review of the topic of diabetes mellitus and coronary artery disease, but also to serve as a synopsis of the chapters that have covered diabetes, risk factors, and macrovascular disease (except for peripheral arterial disease.

Heart disease was thought to be associated with diabetes as early as 1883 when Vegley

recommended testing the urine of patients with angina for glucose (1). However, as more

diabetic patients survived with the discovery of insulin and improved treatments for renal

failure and infection, there was a marked relative increase in morbidity and mortality

from cardiovascular disease (CVD). Diabetes is the seventh leading cause of death in the

United States, with much of that mortality as a result of CVD (2). However because these

statistics are based on the underlying cause of death, they underestimate the true impact

of diabetes on mortality.

Ultimately, atherosclerosis accounts for 65–80% of all deaths among North American diabetic patients, compared with one-third of all deaths in the general North American population (3–5). A two- to fourfold excess in coronary artery disease (CAD) mortality among diabetic individuals has been noted in a number of prospective studies encom- passing a variety of ethnic and racial groups (6). Diabetes also increases the likelihood of severe carotid atherosclerosis (7,8) and mortality from stroke is increased almost threefold in diabetic patients (9). Both type 1 and type 2 diabetes mellitus (DM) are therefore powerful and independent risk factors for CAD, stroke, and peripheral arterial disease (3,9,10). Furthermore, when patients with diabetes develop clinical events, they sustain a worse prognosis compared with nondiabetics (11). Coupled with these macrovascular complications are such microvascular complications as retinopathy, neu- ropathy and nephropathy, all of which accounts for most of the morbidity and mortality associated with DM. Thus, although diabetes may be a problem of glucose metabolism, the American Heart Association (AHA) has recently stated that, “diabetes is a cardiovas- cular disease” (3).

EPIDEMIOLOGY

More than 10 million Americans carry the diagnosis of DM and another 5 million are estimated to have undiagnosed diabetes (3). The prevalence of type 2 diabetes, which accounts for 90% of all cases of diabetes, is increasing in the United States and around the world because of the advancing age of the population, improved screening and detec- tion, and the increase in risk factors such as obesity and physical inactivity. A growing ethnic diversity in the United States, including ethnic groups that are particularly suscep- tible to type 2 diabetes, such as Hispanics, blacks, and South Asians also contribute to the increasing prevalence of diabetes (3,12). The obesity epidemic will result in an increasing number of patients of DM. Obesity now affects 18% of the US population in 1998 (13).

The problem of obesity is anticipated to grow with the increasing weight of the US population. Between 1991 and 1998, the body weight of the American male has increased by 3%, whereas that of the American female has increased by 5%.

Diabetes and Cardiovascular Mortality

A meta-analysis of several studies estimated the risk of death from CAD in patients with diabetes is 2.58 in men and 1.85 in women (14). These values are in contrast to the Rancho Bernado study (15), which followed subjects ages 40 to 79 for 14 years and found that although death rates were also increased in diabetics, the risk factor-adjusted relative odds was 3.3 in women and 1.9 in men. Factors associated with an increase in mortality rates of diabetics include male gender, black race, longer duration of diabetes, and insulin use (16). Overall, CVD, which includes CAD and cerebrovascular disease, accounts for 65% of all deaths among diabetics. Although much of this data is based on findings in patients with type 2 diabetes, patients with type 1 diabetes have similar causes of death including CAD and renal failure (17,18).

As a result of diabetes, life expectancy is shortened, on average, 9.1 fewer years of life

for diabetic men and 6.7 for diabetic women relative to their nondiabetic counterparts

(19). Haffner and colleagues examined the mortality in 1000 type 2 diabetic and 1300

nondiabetic Finnish subjects and found that the mortality of the diabetics was similar to

the nondiabetics who had a myocardial infarction (MI) (20) (Fig. 1). This data suggests

that caregivers should treat individuals with type 2 diabetes as if they had experienced a

MI. Mukamal (21) studied 1935 patients hospitalized with an acute MI and found that the mortality of the diabetic patients in the short-term period was similar to those of the nondiabetic patients who had a previous MI and twice those that of the nondiabetics who had suffered their first acute coronary event. Malmberg evaluated the findings of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry and found that diabetic patients hospitalized for unstable angina or a non-Q wave MI had the same long-term morbidity and mortality as nondiabetic patients with established CVD (22).

Over the past three decades, there has been a significant decrease in cardiovascular mortality in the United States. However, the effect on mortality in patients with diabetes has lagged well behind the general population (23). The death rate of nondiabetic men with CAD decreased by 36.4% compared to 13.1% for diabetic men. The death rate for nondiabetic women decreased by 27% compared to a 23% increase for diabetic women (23).

Prevalence and Risk Factors for Coronary Artery Disease in Insulin-Dependent Diabetes Mellitus

Long-term follow-up of patients with type 1 DM has demonstrated that the first cases of clinically manifest CAD occur late in the third decade or in the fourth decade of life regardless of whether diabetes developed early in childhood or in late adolescence. CAD risk increases rapidly after the age of 40, and by the age of 55 years, 35% of men and women with type 1 DM die of CAD (18) compared with 8% for nondiabetics. Women with type 1 DM lose most of their inherent protection from CAD observed in nondiabetic women is (18,24,25). The occurrence of severe coronary atherosclerosis in a subset of type 1 DM patients before the age of 55 regardless of whether diabetes developed in childhood or adolescence, suggests that diabetes mainly accelerates the progression of early atherosclerotic lesions that commonly occur, even in the absence of diabetes, at a young age in the general population (18).

Fig. 1. Kaplan–Meier estimates of the probability of death from coronary heart disease in 1059 subjects with 2ype 2 diabetes and 1378 nondiabetic subjects with and without prior myocardial infarction. Error bars denote 95% confidence intervals. (Reproduced with permission from ref. 20.)

Diabetic nephropathy, which develops in approx 30% to 40% of type 1 DM patients, dramatically increases the prevalence of CAD (18,26). Patients with persistent pro- teinuria followed in the Steno Memorial Hospital had a 37-fold increased mortality from CVD relative to the general population although patients without proteinuria had a car- diovascular mortality that was only 4.2 times higher (26). Type 1 DM patients followed from the onset of microalbuminuria, developed CAD eight times more frequently than in patients without microalbuminuria (27). Krolewski and associates reported that the risk of development of CAD in patients with persistent proteinuria was 15 times higher compared with those without proteinuria (17) Angiographic studies have shown that nearly all patients with diabetic nephropathy over the age of 45 have one or more clini- cally significant coronary stenoses (28). Microalbuminuria in type 1 DM is therefore, not only a marker for renal disease, but also a potent risk marker of CAD.

Several mechanisms contribute to the atherosclerotic process in the presence of dia- betic nephropathy including hypertension, lipid abnormalities, fibrinolysis and coagula- tion alterations, all of which are detectable in the early stages of diabetic nephropathy when renal function is still normal (29). Hypertension is frequently present in patients with diabetic nephropathy even when the creatinine concentrations remain normal and can intensify CAD in type 1 DM patients. Diabetic nephropathy is associated with an atherogenic lipoprotein profile that includes elevated low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, decreased high-density lipoprotein (HDL) levels, and elevated lipoprotein (a) levels (30–32). Furthermore, a hypercoagulable state, characterized by increased plasminogen activator inhibitor (PAI)-1, factor VII, and (plasma) fibrinogen levels, has been described in microalbuminuric type 1 DM patients (33). Finally, reduced renal function leads to the accumulation of advanced glycosylation end-products (AGE) in the circulation and tissue (34,35).

The risk for the development of diabetic nephropathy is only partially determined by glycemic control, and is highly influenced by genetic susceptibility (26,27). Several studies have established that a genetic susceptibility contributes to the high prevalence of CAD among type 1 patients with nephropathy. CAD is twice as common a cause of death among parents of diabetic patients with nephropathy then among parents of dia- betic patients without nephropathy. Among diabetics with nephropathy, those who had a cardiovascular event are six times more likely to have a familial history of CVD then those who had no such event. A history of CVD in both parents or in the father of type I DM patient increases the risk of nephropathy in the offspring 10- and 3-fold respectively (36). Parents of diabetic offspring with nephropathy also have higher levels of blood pres- sure (BP) then do parents whose diabetic offspring do not have diabetic nephropathy (37).

Interestingly, recent studies have shown that an association between angiotensin- converting enzyme (ACE) inhibitors I/D polymorphism, potentially affecting the level of angiotensins and kinins in the kidney can affect the development of renal disease in type I DM patients (38). The same polymorphism has been linked to MI in nondiabetic subjects (39), and in type I (40,41) and type 2 (42) patients.

Prevalence and Risk Factors for Coronary Artery Disease in Noninsulin-Dependent Diabetes Mellitus

Type 2 DM increases relative risk of CVD by two- to fourfold compared to the general

population (43–46). The increased cardiovascular risk is particularly high in women. The

protection that premenopausal women have against atherosclerosis is almost completely

lost when diabetes is present (47,48).

Although traditional risk factors play an important role in the development of athero- sclerosis in diabetic subjects, the rate of cardiovascular mortality and morbidity in dia- betics exceeds that predicted by these risk factors by 50%. Several other risk factors may account for this discrepancy. Possible nontraditional risk factors include insulin resis- tance, insulin levels, and hyperglycemia.

Many of these type 2 diabetic patients have several of these risk factors for CAD. The term, “metabolic syndrome” was first used by Gerald Reaven in 1988 (49) to describe this clustering of risk factors including hypertension, dyslipidemia, hyperglycemia and insu- lin resistance. The National Cholesterol Education Panel (NCEP) Adult Treatment Panel III (ATPIII)guidelines for cholesterol management in 2001 recognized that the metabolic syndrome or atherogenic dyslipidemia as a collection of the risk factors mentioned above, and abdominal obesity.

PATHOPHYSIOLOGY OF DIABETIC CARDIOVASCULAR COMPLICATIONS

The increased risk of CVD in diabetics is partly explained by the clustering of risk factors including dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and prothrombotic factors. Some of these risk factors will be described in detail in this chapter.

Insulin Levels, Insulin Resistance, and Hyperglycemia

Insulin resistance that is present many years or more before the clinical onset of overt diabetes resistance is associated with other atherogenic risk factors such as hypertension, lipid abnormalities, and a procoagulant state (50–56) (Table 1), that promotes atheroscle- rosis many years before overt hyperglycemia ensues (57,58). Indeed, several studies have shown an inverse correlation between insulin sensitivity and atherosclerosis (59–61).

Investigators using the Bruneck Study database suggest (62) that these risk factors are present in 84% of patients with type 2 diabetes. Thus, an increased prevalence of CAD is apparent in patients with impaired glucose tolerance (44,46,63) and in newly diagnosed type 2 subjects (64,65). The duration of insulin resistance among hyperglycemic and diabetic individuals probably contributes to the development atherosclerosis. However, no obvious association between the extent or severity of macrovascular complications and the duration or severity of type 2 (24,66) has been found, which most likely stems from the fact the duration of insulin resistance is often unknown.

Another possibility is that the serum insulin level and not insulin resistance may have direct cardiovascular effects. Despres (67) and colleagues followed 2000 nondiabetic men without clinically overt CAD for 5 years and found that those subjects who had a cardiovascular event had 18% higher serum insulin levels than controls.

Serum glucose levels may be an important risk factor for CVD. Anderssen and col- leagues (68) demonstrated that the fasting serum glucose levels are independently related to all-cause and cardiovascular mortality. The San Antonio Heart Study (69) showed similar findings with subjects in the highest quartile of fasting glucose levels had a 4.7 times greater risk of CVD than the lowest two quartile levels combined.

The direct relationship between glucose levels and CVD is also seen in patients with

type 1 diabetes. A 1% increase in glycosylated hemoglobin levels doubled the increase

in CVD (70). Several studies have shown a direct relationship with the level of serum

glucose on clinical events, including MI and strokes, with glucose levels ranging from

abnormal glucose tolerance test to frank diabetes (71–73). This graded effect of serum

glucose on clinical events may in part be as a result of a direct effect on the vasculature as evidenced by a similar direct relationship of serum glucose levels to the intima-media thickness (IMT) of the carotid (as a marker for the presence and degree of atherosclero- sis). The Atherosclerosis Risk in Communities study demonstrated that the effect of fasting glucose tolerance on carotid wall thickness in individuals free of symptomatic CVD (8).

The level of chronic hyperglycemia, as determined by measurements of glycosylated hemoglobin, may also be an independent risk factor for coronary heart disease, particu- larly in women (74,75). Recent prospective studies demonstrated that microalbuminuria in type 2 diabetic patients, is also an independent predictor of increased cardiovascular mortality (76,77). In a substudy of the Heart Outcomes Prevention Evaluation Study (HOPE) trial, the MICRO-HOPE demonstrated that increasing levels of microalbuminuria correlated with an increased risk of major cardiovascular events (MI, stroke, cardiovascu- lar death, and a secondary endpoint of hospitalization for heart failure) (211). Insulin resistance may play an important role as a risk factor in the development of diabetic CVD.

Hyperinsulinemia may be the mechanism by which the effect of hyperglycemia results in atherosclerosis. Insulin is elevated in patients with the metabolic syndrome. The pos- sibility that insulin resistance could result in an increase in CVD was first demonstrated in population studies, which showed an association between fasting insulin levels and cardiovascular mortality (59,78–80). In the Insulin Resistance Atherosclerosis Study, subjects were evenly divided between patients with normal serum glucose, hyperglyce- mia with normal glucose tolerance along with diabetes. The relationship of insulin levels and CVD is further strengthened by basic research studies which showed the effect of insulin on various possible mediators for the development of atherosclerosis, specifically the increase in PAI-1 and the mitogenic effect on smooth muscle cells (SMC) in vitro (81).

Dyslipidemia

An important mechanism for the development of diabetic atherosclerosis is dyslipidemia (see also Chapter 15).

The central feature of diabetic dyslipidemia is increased levels of VLDLs, as a result of both increased production of VLDL, and decreased catabolism of triglyceride-rich lipoproteins, including chylomicrons. Increased hepatic production of VLDL is in

Table 1

Cardiovascular Risk Factors Associated With Insulin Resistance Hypertension (50,51)

Abdominal obesity (56,52) Dyslipidemia (53–55,281)

Increased VLDL-triglyceride Decreased HDL

Small dense atherogenic LDL particles Postprandial lipemia

Elevated PAI-1 activity (57)

Numbers in parenthesis represent reference citations. VLDL, very low- density lipoprotein; HDL, high-density lipoprotein; LDL,low-density lipoprotein; PAI-1, plasminogen activator inhibitor.

response to increased fatty acid delivery from (a) decreased free fatty acid (FFA) uptake from the striated muscle and (b) increased delivery of the FFAs from the increased adipose tissue associated with central obesity.

The increase in triglyceride-rich lipoproteins not only accumulates because of increased VLDL production but also as a result of decreased catabolism of triglyceride lipoproteins.

Lipoprotein lipase, which plays an important role in the metabolism of triglyceride-rich lipoproteins and in particular chylomicrons, is decreased in uncontrolled type 2 diabetes.

The increased triglyceride-rich lipoproteins provide an increased substrate for the cholesterol ester transfer protein. This promotes the flux of cholesterol from HDL par- ticles, which result in decreased HDL levels, a common finding in type 2 DM. Yet other mechanisms must be involved because low HDL levels can occur in the absence of hypertriglyceridemia. The degree of HDL reduction is not related to the degree of control of diabetes or the mode of treatment in type 2 diabetes. One mechanism for the protective effect of HDL against atherosclerosis may be as a result of its ability to prevent oxidation of LDL. There may be qualitative differences in the HDL from patients of poorly con- trolled DM, which may make it a less effective antioxidant than HDL from normal individuals (82).

Although the dyslipidemia of DM is not characterized by marked elevations of LDL, there are differences in the LDL type found in type 2 diabetics. Specifically, the LDL is smaller and denser than typical LDL particles (83). These smaller denser LDL particles have a greater tendency to undergo oxidation, which accelerates the atherosclerotic process.

Increased Oxidative Stress in Diabetes Mellitus

There is recent evidence that increased oxidative stress in DM contributes to the development of diabetic complications (84). This increased stress may in part be as a result of the decreased availability of antioxidants such as ascorbic acid, vitamin E, uric acid, and glutathionine. Additionally, there may be increased lipid peroxidation products and superoxide anion products. The increase in these products along with the production of superoxide anion production observed in diabetic patients may lead to altered vascular function (84–86).

This increased in oxidative stress may be the result of several pathways including AGE production, small, dense LDL formation, altered polyol activity, or imbalance in the redox state (87). The activation of this polyol pathway is as a result of the conversion of glucose to sorbitol via aldolase reductase, which has been associated with microvascular complications (88,89).

The recent data from the HOPE trial have shown that the treatment with the antioxidant vitamin E at 400 IU per day for a mean of 4.5 years had no apparent effect on cardiovas- cular morbidity or mortality in both diabetics and nondiabetics (90). Dr. King’s group (see Chapter 2) has demonstrated rather intriguing results demonstrating that high-dose vitamin E therapy (1800 IU per day) normalizes retinal hemodynamic abnormalities and improves renal function without improving glycemic control in type I diabetic patients of short duration (91). Whether this effect is via antioxidant-dependent or -independent pathways remains to be elucidated.

Oxidative stress also precedes the formation of some AGEs including pentosidine and

N-(carboxymethyl) lysine (CML) and the activation of the diacylglycerol-protein kinase

C pathway (DAG-PKC).

Advanced Glycation End-Products in Diabetes Mellitus

Those products, which occur as a result of the nonenzymatic glycation of both lipids and proteins, are termed AGEs (see also Chapter 11). Initially a labile covalent bond develops between the aldehyde of the glucose molecule and the amino acid side chain on both sugars and lipids. Specifically, glucose is covalently bound mainly to lysine residues in proteins, forming fructose-lysine residues. This reaction, results in the development of a Schiff base, which, in turn, undergoes another chemical reaction to form a ketoamine, termed an Amadori product. These products result in cumulative oxidative damage to proteins. These products include CML (92) and pentosidine (93). The increased levels of pentosidine and CML correlate with the severity of diabetic complications including nephropathy, retinopathy, and vascular disease. One such Amadori product is glycated hemoglobin A1c, which is commonly used to monitor glycemic control in diabetic patients. Because both free radical oxidation and glycation are involved, these sub- stances are also called glyoxidation products.

AGEs crosslink to the proteins composing the extracellular matrix (ECM) and vascu- lar basement membrane, which result in reduced solubility and decreased enzymatic digestion (94,95). AGE formation prevents proper assembly of basement proteins thereby altering its function. This in turn may alter the ability of cells to bind to their substrates.

AGEs are also derived from oxidation of lipids (96,97). The side chains of unsaturated fatty acids chains undergo oxidation, which yield reactive carbonyl-containing frag- ments (MDA, glyoal, 4-HNE) and then react with amino groups, mainly lysine residues.

Enhanced glycation, oxidation and glyoxidation of lipoproteins have been postulated as a possible cause for the development of diabetic macrovascular disease. Certainly there are increased levels of AGE-modified LDL apoprotein and LDL lipid relative to nondiabetics (98). This would suggest that even in the face of similar glycemic control and other cardiovascular risk factors, the development of diabetic vascular complications would depend on differences of oxidative stress and the tissue level of antioxidants.

The evidence for this possible role of these altered lipoproteins include the presence of oxidized lipoproteins in the vessel wall (99,100) and the demonstration of lesion regression with antioxidants (101). One study (102) showed the susceptibility to oxida- tion of LDL correlated with the degree of atherosclerosis in 35 male survivors of a MI.

Vlassara (103) identified a specific receptor for AGEs on monocyte/macrophages, termed RAGE (receptor for AGEs). The subsequent interaction with the AGE and its receptor may induce the release of cytokines tumor necrosis factor and interleukin-1 (104). Other cytokines that have been demonstrated include the synthesis and release of procoagulant activity and platelet-activating factor by endothelial cells (105,106) and the induction of platelet-derived growth factor-AA, which can be indirectly responsible for fibroblast and smooth muscle proliferation (107). Furthermore increased RAGE interac- tion has been shown to result in the enhanced expression of the vascular cell adhesion molecule (108–110), which in turn results in increased atherogenesis.

The important role of RAGE in the development of atherosclerosis was further strength-

ened by the demonstration that usually atherosclerotic apolipoprotein E-knockout mice

had less atherosclerosis when they were administered an antibody-fragment, which neu-

tralized RAGE (111). This effect was seen without any effect on glycemic control or

lipoprotein profile.

Thrombosis and Fibrinolysis in Diabetes Mellitus

Plaque disruption with overlying thrombosis is a major cause of acute coronary syn- dromes (ACS) including MI and sudden death and strokes (see also Chapter 6). Because patients with both type I and particularly type II DM have higher rates of both ACS than the nondiabetic population, heightened arterial prothrombotic reactivity may play a piv- otal role in the development of these macrovascular complications.

There are three underlying mechanisms for this prothrombosis. This includes height- ened platelet reactivity, increased procoagulant activity, and decreased antithrombotic and fibrinolytic activity. The principal components of a thrombus include platelets and fibrin. The coagulation is initiated by the exposure of tissue factor within the arterial plaque at time of plaque disruption. This results in the activation of factor VII/VIIa, which forms the tenase complex with factors X and V resulting in the activation of thrombin.

Thrombin stimulates platelet reactivity and the conversion of fibrinogen to fibrin, pro- ducing a thrombus.

The platelets of diabetic individuals appear to have increased adherence to the vessel wall an increased circulating platelet mass (112). Platelet aggregometry studies which measures in vitro platelet reactivity have demonstrated increased aggregation of platelets in response to agonists adenosine diphosphate, collagen, and thrombin and even sponta- neous aggregation of platelets without any agonist (113–117). Assessment of platelet reactivity in vivo by measurement of blood or urine metabolites released from activated platelets like thromboxane B2 are increased relative to normal healthy controls (113,114).

Patients with DM have increased concentrations of fibrinogen, von Willebrand factor and factor VII (118–120). Although the mechanisms of the increased concentrations of these factors have yet to be elucidated, the level of serum fibrinogen correlates with the level of proinsulin and insulin in the blood (121). However, the plasma level of fibrinogen level is not reduced with improved metabolic control nor is there a reduction of plasma prothrombin fragment 1 + 2, a cleavage product of prothrombin.

Several reports indicate that the activity of antithrombotic factors, including protein C and anti-thrombins, are decreased in diabetic subjects, which further potentiates the hypercoaguable state (122–125).

Fibrinolysis is also impaired in diabetic individuals, particularly type 2 diabetics (126,127). This impairment may be as a result of the increased activity of PAI-1 in the blood, which counteracts native tissue plasminogen activator (t-PA) or t-PA’s action to induce fibrinolysis. PAI-1 is elevated not only in resting states but also in response to physiological stimuli. The serum level of PAI-1 may be elevated as a result of several factors including elevated serum insulin, serum lipids, and glucose levels (128). The impairment of the fibrinolysis system can potentially exacerbate the development and persistence of thrombi, resulting in an increased risk of vascular occlusion.

Endothelial Function and Diabetes Mellitus

Alterations in endothelial function may play an important role in the development of diabetic complications (see also Chapters 2 and 10). Decreased blood flow in many organs has been reported, including the kidney, retina, and peripheral retinal nerves.

Recent diabetics have decreased retinal blood flow on the basis of increased vascular

resistance. The mechanism of this increased vascular resistance is probably in part as a

result of the increase in the intercellular signal transduction kinase, protein kinase C

(PKC) (129-132). This increase in PKC may result in an increase in endothelin-1. It has been documented that abnormalities in hemodynamic profiles precede diabetic nephr- opathy. This increase in glomerular filtration is probably as a result of the effect of hyperglycemia has on arteriolar resistance.

The vascular endothelium has been shown to be important in modulating blood cell–

vessel wall interaction, regulating blood flow, angiogenesis, lipoprotein metabolism, and vasomotion. An important mediator in maintaining vascular homeostasis is endothelium- derived relaxing factor (EDRF) (133). EDRF has since been found to be nitric oxide (NO) (134). The release of NO activates soluble guanylate cyclase, resulting in the formation of cyclic guanosine monophosphate (cGMP), which, in turn, activates cGMP-dependent protein kinases resulting in vascular smooth muscle relaxation (135–138). Alterations in its elaboration or activity may play an important role in the initiation and progression of both micro- and macrovascular disease. Several studies have shown that endothelial- dependent vasodilator function is impaired in patients with type 1 DM without hyperten- sion and dyslipidemia (139). This is in contradistinction to patients with type 2 DM, which have an impairment of both endothelial-dependent and endothelial-independent (smooth muscle) vasodilator function (140,141).

Although the mechanism for the impaired endothelial-dependent vasodilation is un- known, several possibilities are present. Acute hyperglycemia impairs endothelial-de- pendent vasodilation in both macro- and microvessels (142). Normally, insulin also may play a role. Insulin results in vasodilation in part as a result of NO production. However, glucose clamp experiments with insulin infusion in type 2 diabetic subjects have shown little improvement in endothelial-dependent vasodilation relative to nondiabetic subjects (142). As stated previously, there appears to be an increase in oxygen-derived free radi- cals in the diabetic state. Several studies have shown that high doses of vitamin C can improve endothelial-dependent vasodilation in both type 1 and type 2 diabetics (143,144).

Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes, suggesting that mechanisms than dyslipidemia are responsible for endot- helial dysfunction (145).

Another possible culprit for this impairment of endothelial function found in diabetic individuals may be the endogenous competitive inhibitor of NO synthase, asymmetric dimethylarginine (ADMA) (146). ADMA has been found to be elevated in diabetic subjects (147,148).

CLINICAL FEATURES OF CARDIOVASCULAR DISEASE IN DIABETES MELLITUS

Angiographic Features of CAD in Diabetic Patients

Autopsy, angiographic, and angioscopic studies have documented the severe and

diffuse nature of the atherosclerotic coronary involvement in diabetic patients. Early

autopsy data has shown that diabetic patients have a greater number of coronary vessels

involved with more diffuse distribution of atherosclerotic lesions (149,150). Large

angiographic studies comparing diabetics to matched controls in the setting of acute MI

(151), elective angioplasty (152), or prior to coronary bypass surgery (153) have all

shown that diabetes is associated with significantly more severe proximal and distal CAD

(Table 2). An important finding regarding the pathogenesis of ACS is the autopsy (154)

and angioscopic (155) evidence suggesting a significant increase in plaque ulceration and

thrombosis in diabetic compared to nondiabetic patients.

Silent Ischemia

The propensity of diabetic patients to present with either silent or unrecognized MI is well established (156,157). Atypical symptoms such as confusion, dyspnea, fatigue, or nausea and vomiting were the presenting complaint in 32% to 42% of diabetic patients with MI compared to 6% to 15% of nondiabetic patients (156,158). Several groups have reported that the detection of silent ischemia using various noninvasive techniques in- cluding treadmill exercise testing (159,160) ambulatory holter monitoring (161), or exercise thallium scintigraphy (162–165), is more common in diabetics than in nondiabetics. This finding, however, is not supported by all studies (166,167).

A plausible explanation for painless infarction and ischemia episodes in diabetics is autonomic neuropathy with involvement of the sensory supply to the heart is. In autopsies of diabetic patients who died of silent MIs, typical diabetic neuropathic changes were found in the intracardiac sympathetic and parasympathetic fibers (168), and several studies correlated abnormalities in autonomic function in patients with silent ischemia (159,161,163,169). The anginal perceptual threshold—the time from the onset of myo- cardial ischemia (assessed by ST-segment depression) to the onset of chest pain during exercise testing is prolonged in diabetic patients compared with nondiabetics. This delay in the perception of pain may be related to the impairment of autonomic nervous function (169). This association of silent ischemia with autonomic neuropathy was strengthened with the recent results of the Detection of Ischemia in Asymptomatic Diabetics (DIAB) study (170), which found that 22% of asymptomatic patients had abnormal stress perfu- sion tests. Abnormal results were not associated with traditional risk factors but rather a low heart rate response to Valsalva maneuvers, indicating this association with auto- nomic neuropathy.

Table 2

Angiographic Studies in Diabetic Patients^a

% of patients Patients (n) with multivessel disease^b

Study (reference) Diabetics Nondiabetic Diabetic Nondiabetic p Value

TAMI (151) 148 923 65^c 46 0.0001

TIMI-II (382) 439^d 2900 40.8 26.8 < 0.001

Orlander (180) 236 348 58.2 41.6 < 0.001

Stein et al. (152) 1133 9300 32.4^e 28.2 < 0.004

BARI (228) 353 1476 46 40 < 0.05

NHLBI (247) 281 1833 27.7 17.7 < 0.01

CASS (153) 317 1843 85.8 77.7 < 0.001

aBecause most patients undergoing initial angioplasty have single-vessel disease, they have milder coronary artery disease than patients with acute myocardial infarction who have an array of single-, double-, and triple-vessel disease, or patients undergoing coronary bypass grafting who usually have double- and triple- vessel disease.

bMultivessel disease is defined by the presence of two or more vessels with at least one stenosis >75%.

cFor men. Corresponding values for women are 63% and 41%.

dNot all patients underwent angiography.

ePatients were selected for angioplasty and therefore this study includes a larger portion of patients with single-vessel disease.

TAMI, Thrombolysis and Angioplasty in Myocardial Infarction; TIMI, Thrombolysis in Myocardial Infarction; BARI, Bypass Angioplasty Revascularization Investigation; NHLBI, National Heart, Lung, and Blood Institute; CASS, Coronary Artery Surgery Study.

ACUTE CORONARY SYNDROMES IN DIABETIC PATIENTS Acute ischemic events represent a major cause of death in the diabetic population (64).

Diabetics who suffer MIs have a higher mortality than nondiabetics both in the acute phase and on long-term follow-up. Numerous studies have shown that in-hospital mor- tality rates from MIs in diabetic patients are 1.5- to twofold higher than in nondiabetic patients (151,171–174). DM remains an independent predictor for a poor prognosis in the thrombolytic era. In the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trials the in hospital mortality rate was nearly twice as high in patients with diabetes, with more congestive heart failure (CHF) and twice the rate of clinically recognized reinfarction (151). In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO)-I trial, mortality at 30 days was highest among diabetic patients treated with insulin (12.5%) compared with noninsulin- treated diabetic (9.7%) and nondiabetic (6.2%) patients (p < 0.001) (175). Similar results have been reported from the other large studies (176–178). Diabetes is also a risk factor for cardiogenic shock in the setting of acute ischemic syndromes (179). Overall, despite the overall improvement in survival from an acute MI with thrombolysis, the in-hospital mortality rates in diabetics remain 1.5–2 times higher than in nondiabetics (175,178).

Increased in-hospital mortality among diabetic patients with acute MI is predomi- nantly as a result of a higher increased incidence of CHF (172,174,180,181), although increased reinfarction, infarct extension, and recurrent ischemia have also been reported (172–174,181,182).

Studies using serial determinations of total creatine kinase activity (180,181), radio- nuclide ventriculography (183), or echocardiography have shown no evidence that dia- betic patients sustain more extensive infarctions than their nondiabetic counterparts (184).

Thus, CHF and cardiogenic shock are more common and more severe in diabetic subjects than would be expected from the size of the index infarction (178,180,181,183,185,186).

The observation that clinical manifestations of heart failure occur in diabetic patients despite a modest decrease in left ventricular ejection fraction (LVEF), led to the sugges- tion that pre-existing diastolic dysfunction is a major culprit of the congestive symptoms (174). Indeed, subclinical diabetic cardiomyopathy, which is characterized by diastolic dysfunction (187), is likely to be an important factor in this setting.

However, it should be emphasized that a reduction in both LVEF (183,188) and the regional ejection fraction (EF) of the noninfarcted myocardium (151,183,187) have been well-documented in diabetic patients following MI compared with nondiabetics. One such study examined early angiography in the TAMI cohort and found worse noninfarct zone ventricular function in diabetics (151) relative to the nondiabetic controls.

The performance of the left ventricle following MI is largely determined by extent of coronary disease (189) and the quality of collateral circulation. Thus, the diffuse nature of coronary atherosclerosis (Table 2) in diabetes may contribute to systolic dysfunction of the noninfarcted myocardium. Moreover, a recent study has shown that diabetic pa- tients have a reduced ability to develop collateral blood vessels in the presence of CAD (190), a finding that may also explain the more frequent occurrence of postinfarction angina and infarct extension (173,174,182,184) in diabetic subjects.

Diabetic patients surviving MI also suffer high late mortality rates compared with

nondiabetics (174,182,191–193). Late mortality is mainly related to both recurrent MI

and the development of new congestive heart failure (176,178,184,192–194).

MEDICAL THERAPY OF CORONARY ARTERY DISEASE IN DIABETIC PATIENTS

Diabetes exerts a deleterious effect on both short- and long-term course following MI through diverse mechanisms, some of which (e.g., cardiomyopathy) cannot be modified at the time of presentation. Because diabetic patients are at greater risk, application of effective preventive and treatment measures may result in a particularly large survival benefit.

Insulin

One possible mechanism for the increased mortality of diabetic patients with acute MI may be the altered metabolism of the myocardium. The diabetic state results in increased fatty acid metabolism, compromising glycolysis in both ischemic and nonischemic ter- ritories. FFAs and their intermediates may potentiate ischemic injury. One way to attenu- ate FFA oxidation is by the infusion of insulin-glucose. It was that rationale that led Malmberg and colleagues (195) to evaluate the effect of insulin-glucose infusion fol- lowed by multidose insulin treatment in diabetic patients (Diabetes Mellitus Insulin- Glucose Infusion in Acute Myocardial Infarction [DIGAMI] study) (Fig. 2). Diabetic patients with an acute MI within the previous 24 hours were randomized to two separate arms. Insulin-glucose infusion was given for the first 24 hours and until stable normoglycemia. in the experimental arm. Then subcutaneous multidose insulin was given to maintain normoglycemia for a 3-month period. Control patients received stan- dard coronary care unit care and did not receive insulin unless clinically indicated.

The 3-month mortality was not significantly different between the control and experi- mental groups. However, the 1-year mortality was 18.6% in the experimental group and 26% in the control group, or a relative risk reduction of approx 30%. This improvement of mortality continued for 3.4 years, with an absolute reduction of mortality of 11% (196).

A recent study investigating the benefit of glucose–insulin–potassium (GIK) infusion as adjunctive therapy to percutaneous transluminal coronary angioplasty (PTCA) in acute ST-elevation MI (Glucose-Insulin-Potassium Study ) demonstrated a significant reduction in the 30-day mortality but only if those patients that had no signs or symptoms of heart failure (195). There was a 3% absolute risk reduction (1.2% vs 4.2%) in the 30- day mortality seen in those patients presenting with Killip Class I and who received GIK.

Aspirin

Studies have shown an increased platelet adhesiveness and aggregability (197), with a concomitant increased release of thromboxane A2 (114) in diabetic subjects. Based on these data, several authors stated that diabetics may require larger doses of aspirin to suppress thromboxane A2 synthesis (114,198). Furthermore, in the International Study of Infarction Survival-2 there was no reduction in mortality in diabetics receiving 160 mg of aspirin daily (199).

The Antiplatelet Trialist Collaboration meta-analysis quantified the benefit of aspirin

in diabetic patients who have had a previous cardiovascular event (200). The relative

benefit on vascular events was 17% in the diabetic patients and 22% in those without

diabetes. Although the number was lower for diabetic patients than for nondiabetic

patients in terms of percentage benefit, the absolute number of events prevented was

similar in the two groups (38 ± 12 per thousand compared with 36 ± 3 per thousand,

respectively) probably because of the higher event rates in diabetic patients. Data from

the US Physicians’ Health Study and the Early Treatment Diabetic Retinopathy Study (ETDRS) indicates that aspirin may also be efficacious as primary prevention in diabetic patients (201).

A major risk of aspirin therapy is gastric mucosal injury and gastrointestinal hemor- rhage. These effects are dose-related and are reduced to placebo levels when enteric- coated preparations of 75–325 mg per day are used once daily (202). The ETDRS established that aspirin therapy is not associated with an increased risk of retinal or vitreous hemorrhage using serial retinal photography.

The American Diabetes Association recommends the use of aspirin therapy (81–325 mg per day) as secondary prevention in any patient with evidence of large vessel disease.

Aspirin is also recommended as primary prevention in diabetic patients with the follow- ing: (a) family history of CAD, (b) cigarette smoking, (c) hypertension, (d) obesity, (e) albuminuria, (f) LDL greater than 130 mg/dL (g) HDL less than 40 mg/dL, (h) triglyc- erides over 250 mg/dL (202).

G-Blockers

G-blockers are effective in reducing reinfarction and sudden death in diabetic patients, perhaps to a greater extent than in nondiabetics. Early treatment of MI with G-blockers resulted in a 37% mortality reduction in diabetics compared with a 13% mortality reduc- tion in all patients, whereas long-term mortality reduction was 48% and 33% in diabetics and all patients, respectively (203).

Fig. 2. Actuarial mortality curves in the patients receiving insulin-glucose infusion and in he control goup of the present Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction study during 1 year of follow-up. Numbers below graph, number of patients at different times of observation. Active, patients receiving infusion; Con. Int., confidence interval. (Repro- duced with permission from ref. 195.)

In a controlled study evaluating the use of atenolol in patients with, or at risk for CAD who had noncardiac surgery, diabetes was the strongest predictor of death after 2 years follow-up, with twice the mortality compared with nondiabetics (204). Compared with nondiabetic patients, diabetic patients on atenolol had no increased risk of death, whereas those given placebo had a fourfold increase in risk (204). It should be emphasized that the deterioration in glycemic control or blunted counterregulatory response to hypogly- cemia are seldom a serious clinical problem, especially when cardioselective G1-blockers are used (203,205).

Angiotensin-Converting Enzyme Inhibition

ACE inhibition is now unequivocally associated with a substantial mortality reduction in patients surviving MI with left ventricular dysfunction (EF <40%) (206). The Italian Study Group for Streptokinase in Myocardial Infarction-3 investigators compared the effect of early administration (within 24 hours of admission) of lisinopril in patients with and without diabetes presenting with MI (207). Compared to placebo, lisinopril dramati- cally reduced both 6 week (30% vs 5%) and 6-month (20% vs 0%) mortality in diabetics vs nondiabetics. These finding are corroborated by subgroup analysis of the Survival and Ventricular Enlargement Study (SAVE) study (208). A retrospective analysis of data from the Trandolapril Cardiac Evaluation study, a randomized, double-blind, placebo- controlled trial evaluating trandolapril in patients after acute MI with an EF less than or equal to 35%, has shown a 36% reduction of death from any cause and a 62% reduction in the risk of progression to severe heart failure (209). Recently, the HOPE study has shown that ramipril substantially lower the risk of death, MI, stroke, coronary revascularization, heart failure, and complications related to DM in a high-risk group of patients with pre-existing vascular disease (210,211) (Fig. 3). Interestingly, there was also a 33% relative risk reduction in the incidence of new cases of DM in the ramipril arm of the HOPE study.

ACE inhibitors have become the primary agents of choice for the treatment of hyper- tension associated with DM, because they do not adversely affect the glycemic control and lipid profile (212,213). In fact, ACE inhibitors may actually enhance insulin sensi- tivity in noninsulin-dependent diabetes mellitus (NIDDM) patients, with or without hypertension (214–216). ACE inhibitors are especially desirable in patients with evi- dence of diabetic nephropathy.

Serum potassium and creatinine should be monitored closely in the first few weeks of therapy. A rapid decline in renal function can occur in patients with bilateral renal artery stenosis, which is more common in diabetics. Hyporeninemic hypoaldosteronism (type IV renal tubular acidosis) is frequently associated with diabetes and predisposes the patients to clinically significant hyperkalemia when ACE inhibitors are initiated.

Glycoprotein IIb/IIIa Antagonists

These antiplatelet agents have become an important therapeutic modality in the treat-

ment of unstable angina and non-Q wave MIs. In particular, these agents have been shown

to be equal if not more beneficial in the diabetic population than its nondiabetic counter-

part. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients

Limited by Unstable Signs and Symptoms (PRISM-PLUS) study (217,218) compared

heparin to heparin and the glycoprotein (Gp)IIb/IIIa inhibitor tirofiban in 1208 patients,

with 362 patients being diabetic. The cumulative end-point at 7 days of death, MI,

Fig. 3.Kaplan–Meier survival curves for study participants with diabetes in the HOPE Study comparing the use of ramipril (—) vs placebo (-). (Reproduced with permission from ref. 211.)

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refractory angina or re-hospitalizations for unstable angina was reduced from 21.4% on heparin alone and 14.8% on heparin plus tirofiban in the diabetic group and 16.7% on heparin alone to 12.4% with the addition of tirofiban in the nondiabetic group. There was no difference in the ability of the standard dose of tirofiban required to result in an over 80% inhibition of platelet aggregation after a 12-hour infusion in the diabetic and non- diabetic patients, despite the hyperaggregability of diabetic platelets.

The EPILOG study (219), which evaluated percutaneous coronary angioplasty plus the GpIIb/IIIa, abciximab to angioplasty alone, found no significant difference in acute events although the longer-term follow-up revealed a higher rate of subsequent revascularization involving the target vessel in diabetic subjects. The Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT) (220), which evaluated coro- nary stenting plus abciximab and heparin vs stenting plus heparin alone demonstrated a marked decrease of target vessel revascularization in diabetic patients. The rate of target vessel revascularization in diabetic patients randomized to stenting and heparin was 16.6% although those randomized to stenting and abciximab had a rate of 8.1%, a 50%

decrease. One recent study (221) did not demonstrate a difference in efficacy between two GpIIb/IIIa receptor inhibitors, abciximab or tirofiban, when used in diabetic patients undergoing percutaneous coronary intervention (PCI).

Thrombolytic Therapy

Thrombolytic therapy is of substantial benefit in diabetic patients. In the GUSTO-I angiographic substudy, early infarct-related artery patency (TIMI flow grade 3) and reocclusion rates were similar among diabetics and nondiabetics (222). Diabetic patients treated with various fibrinolytic agents benefit by the same mortality reduction as non- diabetic patients (151,223) (Table 3). In an overview of fibrinolytic trials in patients with MI, the relative reduction in 35-day mortality was slightly, but not significantly, greater in diabetic patients than in nondiabetic patients (21.7% vs 14.3%) (223). In these trials, no increase in serious bleeding complications or stroke was observed in patients with diabetes. Retinal bleeding is an extremely uncommon complication of thrombolytic therapy in diabetic patients. In the GUSTO-I study, 300 of 6011 diabetic patients had proliferative retinopathy, but none developed intraocular hemorrhage (224). It is unlikely that thrombolytic therapy would increase vitreous hemorrhage, which is the result of vitreous detachment in patients with diabetic retinopathy. Thus, the concern that many clinicians have, regarding thrombolytic therapy in patients with diabetic retinopathy, is not supported by the results of large clinical trials. It is probably unjustified to deny these patients the proven life saving benefit of thrombolysis.

REVASCULARIZATION PROCEDURES IN DIABETIC PATIENTS

Because CAD is a major health problem in patients with diabetes, the need for

revascularization procedure arises frequently (see also Chapters 25, 26). Therefore, many

diabetic patients require some form of revascularization procedure. Significant and in-

creasing proportion of patients undergoing angioplasty is diabetic. In the 1977 to 1981

National Heart, Lung, and Blood Institute (NHLBI) registry, 9% of patients undergoing

angioplasty were diabetics (225). Recent large trials suggest that the prevalence of dia-

betes in patients undergoing angioplasty increased to approx 17% to 19% (226,227). The

influence of diabetes on outcome after revascularization procedures received attention

following the results of the Bypass Angioplasty Revascularization Investigation (BARI)

Table 3 Effect of Thrombolytic Therapy in Diabetic Patients ThrombolyticPatients (n)In-hospital/short term ortality (%) Study (reference)agentNondiabeticsDiabeticsNondiabeticsDiabeticsp Value ISIS-2(199)SK1569412878.911.8bNR FTT collaborativeSK, rt-PA,3881445298.713.6cNR group(223)UK, APSAC TAMI(151)rt-PA, UK923148611< 0.02 International t&#8209;PA/rt-PA, SK80558337.5d11.8< 0.001e Streptokinase mortality trial GISSI-2(178)rt-PA, SK806912665.8f8.7NR TIMI(382)rt-PA29004394.110.2 GUSTO(222)rt-PA, SK3470561256.210.6< 0.0001 h

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study, which suggested that diabetic patients with significant CAD involving the left anterior descending coronary artery had improved mortality if they underwent a coro- nary artery bypass grafting (CABG) (228). The results of the Coronary Angioplasty vs Bypass Revascularization Investigation investigators (229) demonstrated that the mortality of diabetics is double that of nondiabetics, independent of the means of revascularization, be it CABG or PTCA. Among diabetics or nondiabetics there was no significant mortality difference between PTCA or CABG, although there was a trend favoring CABG, especially in the diabetic population (229).

Percutaneous Coronary Interventions

PCI provides effective relief of angina in most patients and performed with similar success in diabetics as in nondiabetics (152). However, increased restenosis rates in diabetic patients greatly limit long-term benefit from such interventions. The importance of diabetes as a clinical risk factor restenosis after PCI has been demonstrated in multiple studies. The initial report from the NHLBI Angioplasty Registry indicated that the angiographic restenosis rate in diabetic patients was 47%, as compared to 32% in non- diabetic patients (230), and subsequent studies have reported restenosis rates of 49%-71% among diabetic patients (231–236). New angioplasty devices also initially failed to make any major impact on the restenosis rate among diabetics. Diabetes is associated with a twofold increase in recurrent clinical events after directional coronary atherectomy (237) (238,239), have with higher restenosis rates after excimer laser angioplasty (240). Recently, intracoronary stents have been shown to decrease restenosis compared with PTCA (241). Even with stents, several groups have reported that diabetic patients have higher restenosis rates compared to nondiabetic patients (242–245) al- though this finding is debated (246).

The full impact of the higher PCI restenosis, on cardiovascular morbidity of diabetic patients is significant. Numerous studies have shown that diabetic patients experience a greater need for repeat revascularization (angioplasty or CABG), a high cardiac event rate, and lower overall survival rates, following coronary angioplasty compared with their nondiabetic counterparts (152,237,239,247–250). Recent data from the EPISTENT and other studies (251) suggest that the combination of stenting with platelet GpIIb/IIIa blockade may decrease the incidence of death, MI, and target-vessel revascularization among diabetic patients (252).

Although vessel recoil may also contribute to loss of luminal size, the increased restenosis rate seen in diabetics following stent placement underscores the role of enhanced SMC proliferation as the major mechanism for restenosis in these patients, because coronary artery stenting decreases elastic recoil and vascular spasm at the treated site (244). In a study using intravascular ultrasound, exaggerated intimal proliferation was found in diabetic patients at the site of angioplasty-induced arterial injury, and this proliferative response was particularly striking in restenotic lesions (253). Thus, the diabetic state promotes SMC proliferation and ECM deposition following arterial injury.

Surprisingly, the possibility that strict glycemic control may reduce restenosis rates

among diabetics (254) has not been addressed clinically or experimentally. There are

studies ongoing, which are examining means to reduce the restenosis rate including

G-radiation (ANTI-PrOliferative Effect of Beta-Radiation on Restenosis Prevention

in Diabetic Patients after Coronary Stent Implantation).

In diabetic subjects with restenosis post-PCI, there is a reduced intimal hypercellular tissue in the restenotic lesion relative to nondiabetic patients (255). Sobel’s group has found an increase in the intramural synthesis of PAI-1 in the vessel walls of experimental rabbits that were subjected to experimental angioplasty (256,257). PAI-1 synthesis is stimulated by insulin. In turn, PAI-1 may inhibit the remodeling and proteolysis that normally occurs post PCI, resulting in the accumulation of the ECM and lipid, with a relative decrease in the relative amount of SMC migration and proliferation. One recent development has suggested that haptoglobin phenotype may determine which diabetic patients may develop restenosis after coronary stent implantation (258).

Coronary Artery Bypass Surgery

CABG is effective in relieving anginal symptoms in diabetic patients as in nondiabetic patients (153) (see also Chapter 26). Diabetes is not associated with increased perioperative mortality during bypass graft surgery, although wound infections and the average hospital stay are increased (259,260). Several reports have noted decreased survival of vein grafts in diabetic patients (261–263). Intimal proliferation that causes luminal loss in the first years following bypass surgery with venous conduit may be accelerated in diabetics (264). In contrast, the benefit of internal mammary artery (IMA) conduits is well documented among diabetics (263,265). Data from the Duke registry indicate that the long-term benefit of one IMA graft is at least as great in patients with diabetes as in those without (265). Nonetheless, long-term survival rate after bypass surgery remains consistently lower in diabetic then in nondiabetic patients (265–267).

Percutaneous Coronary Intervention vs Coronary Artery Bypass Surgery in Multivessel CAD

Coronary angioplasty with or without stenting has been widely accepted as the initial revascularization procedure for treatment of most single-vessel CAD, although CABG has been the standard form of revascularization for multivessel disease. However, in the last decade, angioplasty has been proposed and evaluated as an alternative to CABG in patients with multivessel disease.

The influence of diabetes on outcome after PCI for patients with multivessel disease received attention following the results of the Bypass Angioplasty Revascularization Investigation (BARI) study (228). The BARI study enrolled 1829 patients (including 353 diabetics) with angiographycally documented multivessel CAD and either clini- cally severe angina or objective evidence of marked myocardial ischemia requiring revascularization. Cause of death was classified as cardiac if occurring less than one hour after onset of cardiac symptoms or within one hour to 30 days after a documented or probable MI, or occurring as a result of intractable CHF, cardiogenic shock, or other documented cardiac cause.

A review of 5-year all-cause mortality rates showed a near doubling of mortality

among diabetics on insulin or oral therapy assigned to multivessel angioplasty compared

with those assigned to surgery (35% vs 19%, p = 0.003). In contrast, the 5-year mortality

in nondiabetics and diabetics not on drug treatment was 9% with both revascularization

strategies. Cause-specific 5.4-year cardiac mortality rates were three-and-a-half times

higher in the PTCA group (20.6 % vs 5.8%) (228). These results raised concern about

selection of revascularization procedures in diabetic patients with multivessel coronary

artery disease, and prompted a NHLBI clinical alert stating that CABG should be the

preferred initial revascularization choice in medically treated diabetics with multivessel CAD (268).

A subsequent report from the BARI investigators indicated that the survival benefit of CABG is limited to diabetics receiving an IMA graft. Cardiac mortality after 5.4 years was 2.9% when IMA was used and 18.2% when only saphenous vein graft (SVG) con- duits were used. The latter rate was similar to patient receiving PTCA (20.6%) (269). The mortality benefit afforded by IMA was most apparent in those experiencing MI during follow-up (an effect seen also in nondiabetic patients). The cardiac death rate in those diabetics sustaining MI was 36% for diabetics who had a PTCA, 60% for those diabetics who underwent a CABG with only an SVG, and only 7.4% for diabetics who had a CABG with a LIMA. For diabetic patients not sustaining post-randomization MI, a less marked but nonetheless substantial decrease in cardiac mortality was associated with IMA use (5 year cardiac death rates without MI: diabetics who underwent PTCA, 16.8%; diabetics who had a CABG with SVG, 10.7%; TDM-IMA, 1.8%). As an IMA graft is less suscep- tible to atherosclerosis it may provide an alternative source of perfusion to maintain ventricular function in regions of hypoperfusion resulting from coronary occlusion.

Three recent studies examined the effect of revascularization strategies in diabetic patients. In a large prospective cohort of 3220 patients with multivessel disease, of whom 770 (24%) were diabetics, Barsness and associates evaluated the relationship between diabetes and survival after revascularization with either PTCA or CABG (270). Although diabetes was strongly associated with a worse long-term prognosis, the 5-year survival for diabetics undergoing PTCA was 76%, whereas for nondiabetics the rate was 88%.

Similarly, in the group of patients undergoing CABG, 5-year survival was 74% in dia- betics and 86% in patients without diabetes. Unlike other studies, however, there was no significant differential effect of diabetes on outcome between patients treated with PTCA and those treated with CABG. In a similar study, Weintraub (271) and associates prospec- tively compared the outcome of PTCA (n = 834) and CABG (n = 1805) in diabetic patients with multivessel coronary disease using an observational database. Corrected for baseline differences, there was no difference in survival for the group as a whole. How- ever, in the insulin-requiring subgroup, 5- and 10-year survival rates were 68% and 36%

after PTCA and 75% and 47% after CABG, respectively.

Gum and associates performed a retrospective outcome analysis of 525 diabetic patients who underwent coronary revascularization. Overall actuarial survival curves showed a nonsignificant trend favoring the CABG group for survival at 6 years (30% vs 37%; p = 0.04) (248).

A crucial question is why CABG may be superior to PTCA in diabetic patients in the setting of multivessel disease. The only difference between the diabetic groups in the BARI study is the revascularization procedure chosen. Hence, the prognosis difference is likely to be related to the relative efficacy of these revascularization procedures.

The major advantage of CABG over PTCA is the ability to achieve complete

revascularization (272,273). The superiority of CABG over angioplasty in providing

complete revascularization is exemplified in the BARI study itself. In the BARI popu-

lation, 3.1 grafts were placed per patient undergoing CABG (274), whereas the mean

number of successfully treated lesions in the PTCA group was 2 (269). Similar numbers

are reported by other studies comparing multivessel angioplasty and CABG (248,

270,271).

Previous CABG studies have emphasized that complete revascularization is essential for obtaining survival benefit in patients with multivessel disease (273). If complete revascularization (which is accomplished almost exclusively through CABG surgery) is essential for survival benefit, the successful application of multivessel angioplasty (which entails a selective high-priority lesion-targeting strategy) requires that a comparable proportion of myocardium supplied through high-priority lesions be revascularized by each of the two strategies. Because when multivessel angiograplasty is preformed, mul- tiple treatment sites can result in restenosis independently (243), it is likely that this goal is frequently not achieved in diabetic patients given their high restenosis rates (Table 2).

Thus, the worse outcome of diabetic patients undergoing PCI may be mediated in part by the frequent occurrence of incomplete revascularization (248). Van Belle and colleagues suggest that restenosis, especially in its occlusive form is a major determinant of long- term mortality in diabetic patients after coronary angioplasty. When these investigators studied 604 diabetic patients who underwent angioplasty, followed by a 6-month follow- up angiogram and long-term follow-up. They found the group, which had no restenosis, had a 10-year mortality of 24% compared to a 35% mortality in the group with nonocclusive restenosis and a 59% mortality in the group that had occlusive restenosis (p < 0.0001) (256,275). The impact of incomplete revascularization may be more pro- nounced in view of the more diffuse and distal CAD (153,247) and worse coronary vasodilatory reserve in diabetic patients (276). Thus PTCA, rather then leading to increased mortality, may fail to alter the aggressive natural course of CAD in diabetic patients (269). The use of sirolimus-coated stents reduces restenosis post-PCI signifi- cantly, especially in diabetics, which may improve the long term outlook in diabetic patients undergoing multivessel PCI.

MANAGEMENT OF RISK FACTORS

It is important to identify the risk factors of an individual patient to develop a plan for risk reduction. The goals for risk reduction are summarized in Table 4, adapted from a review from an AHA Executive Summary (277).

Cholesterol Reduction

The Scandinavian Simvastatin Survival Study (4S) has demonstrated the effectiveness of cholesterol-lowering therapy (278,279) for secondary prevention of death and morbid- ity in patients with angina or prior infarction (see also Chapter 15). Compared with the placebo group, the relative total mortality and cardiovascular mortality were 0.57 and 0.64, respectively.

Subjects in the 4S study had relatively high LDL cholesterol levels at baseline (~185 mg/dL). However, the majority of patients with coronary disease (including diabetics) have lower LDL cholesterol levels. The Cholesterol and Recurrent Events study (CARE), which included 586 diabetic patients, determined the effect of cholesterol-lowering therapy in patients with coronary disease with average cholesterol levels (mean 139 mg/

dL). In the 586 diabetic subjects with CAD, 40 mg of pravastatin was associated with a 25% decrease in coronary events and revascularization procedures, similar to a 23%

decrease observed in nondiabetic patients (280).

These results strongly suggest that cholesterol lowering improves the prognosis of

diabetic patients with CAD. The absolute clinical benefit achieved by cholesterol low-

ering may be greater in diabetic than in nondiabetic patients with CAD because diabetic