Abbreviations

Abstract

Particularities of CAD in patients with DM

Metabolic abnormalities associated with DM

Insulin resistance

Hyperglycemia

Dyslipidemia

Management of CAD in patients with DM

Behavioral recommendations

Control of hyperglycemia

Lipid-lowering therapy

Control of hypertension

Other therapeutic considerations

Thrombolytic agents

Insulin-glucose infusion

Antiplatelet agents and anticoagulants

Beta-blockers

Angiotensin-converting enzyme inhibitors

Percutaneous coronary revascularization in patients with symptomatic CAD and DM

Role of balloon angioplasty

Short- and long-term follow-up

Role of coronary stenting

In-hospital outcomes

Short- and long-term follow-up

Mechanisms of restenosis and role of insulin

Role of glycoprotein IIb/IIIa platelet receptor antagonists

Cabg in patients with symptomatic CAD and DM

Summary and future directions

References and Notes

 

Abstract

OBJECTIVES

The aim of this review is to discuss the particularities of coronary artery disease (CAD), the effect of intensive medical management and the outcome of percutaneous and surgical revascularization in patients with diabetes mellitus (DM).

BACKGROUND

CAD represents the leading cause of death in patients with DM. Numerous clinical, biological and angiographic risk factors have been shown to be associated with CAD in diabetic patients.

METHODS

Metabolic abnormalities in patients with DM including insulin resistance, hyperglycemia and dyslipidemia are briefly discussed. Then the potential roles of medical management and of percutaneous and surgical coronary revascularization are more extensively reviewed.

RESULTS

More vigorous control of hyperglycemia, hyperlipidemia, hypertension and other risk factors may be of crucial importance for risk reduction. Despite remarkable progress in recent years, the choice of a coronary revascularization strategy remains a challenge in these patients. Diabetic patients with CAD are predisposed to higher cardiovascular events after balloon angioplasty. Whether stenting and new antiplatelet drugs improve the results of percutaneous revascularization in this population needs further evaluation. The superiority of the surgical approach is also not definitely established. Therefore, many aspects of coronary revascularization are still unclear in these patients.

CONCLUSIONS

The results of ongoing randomized trials comparing multiple coronary stents to bypass surgery will likely provide some answers to our questions and additional randomized trials evaluating intensive diabetic control with or without coronary revascularization are needed to determine the best therapeutic approach in these patients.

Abbreviations DM=diabetes mellitus; IRDM=insulin-requiring diabetes mellitus; NIRDM=non-insulin-requiring diabetes mellitus; CAD=coronary artery disease; CABG=coronary artery bypass grafting; PTCA=percutaneous transluminal coronary angioplasty; MI=myocardial infarction; TVR=target vessel revascularization; IMA=internal mammary artery
Diabetes mellitus (DM) is associated with a markedly increased prevalence of coronary artery disease (CAD). The overall prevalence of CAD, as assessed by various diagnostic methods, is as high as 55% among adult patients with DM, compared with 2% to 4% for the general population (1). Diabetes mellitus also represents an independent risk factor for increased mortality and morbidity [1] [2] [3] [4]. The cardiovascular mortality rate is more than doubled in men and more than quadrupled in women who have DM, compared with their nondiabetic counterparts (2,4) (2,4), and post-MI prognosis is also worse in these patients [5] [6] [7] [8]. Moreover, DM is a recognized risk factor for poor outcome after either percutaneous [9] [10] [11] [12] [13] [14] [15] [16] [17] or surgical [18] [19] [20] [21] [22] coronary revascularization. Yet, up to 25% of patients referred for such procedures are diabetics [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]. In spite of tremendous recent progress in these procedures, the optimal therapeutic strategy in diabetics remains controversial (14,17) (14,17).

This review describes specific aspects of CAD in diabetics, particularly its clinical, angiographic, metabolic and biological features. It also discusses the effects of intensive medical management as well as early and late outcome after percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) in an attempt to determine an optimal therapeutic strategy in this patient population.

Particularities of CAD in patients with DM

Several clinical, angiographic and biological features are associated with CAD in diabetic patients; they constitute potential risk factors and confer a poor prognosis ( [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47], Table 1). Endothelial dysfunction [31] [32] [33] [34] [35] [36] [37], platelet and coagulation abnormalities [38] [39] [40] [41] [42] [43] [44] [45] [46] and metabolic disorders [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] associated with DM play a major role in the accelerated atherosclerotic process and in the formation of coronary thrombosis, and they contribute substantially to the complex healing process after arterial wall injury. Angiographic features related particularly to diffuse and distal coronary disease may lead to incomplete revascularization or increase the risk of surgical or percutaneous intervention in these patients [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]. The risk of morbidity and mortality is also increased by several unfavorable clinical characteristics that are more common in diabetic patients [6] [7] [8] [9] [10] [11] [12].

Table 1. Potential Risk Factors Associated with Diabetes Mellitus legend

Clinical     Older patients (6,9,26,28)     Female gender (6,9,11,27,28)     Obese (6,9,11,26)     High prevalence of high blood pressure (9,11,13,26,28)     More severe angina (9,13)     Congestive heart failure antecedents (9,11,13,27)     Previous MI (6,13,27,28)     Previous CABG (6,26,28)     Worse post-MI prognosis (4–8)     Biological     Endothelial dysfunction (31,32) with reduced coronary flow reserve (33–35)     Endothelial cell multiplication and migration abnormalities (36,37)     Increased platelet activity (38–40)     Increased thromboxane A2 secretion (42)     Increased platelet activated fraction (41)     Higher fibrinogen and factor VII levels (43)     Lower antithrombin III and plasma fibrinolytic activity (43)     Role of insulin and insulin-like growth factor (32,44)     High plasminogen activator inhibitor 1 (45,46)     Angiographic     Diffuse and distal CAD (6,13)     Extensive disease with angiographically small reference vessels (6,29)     Multivessel disease (5–7,9,13,26,28)     Frequent left main disease (6,13)     Poorer coronary collateral vessel development (30)     Lower ejection fraction (10,11)     More thrombus formation (47)

legend]CAD = coronary artery disease; CABG = coronary artery bypass graft; MI = myocardial infarction.

Metabolic abnormalities associated with DM

Insulin resistance
This metabolic syndrome, first described by Reaven, has been proposed as a unifying concept in an attempt to explain the different abnormalities frequently observed in patients with non-insulin-requiring DM (NIRDM) (48,49) (48,49). It regroups hyperinsulinemia and several cardiovascular risk factors for CAD, including abnormal lipid profile, impaired glucose tolerance, hypertension and upper-body obesity (48,49) (48,49). Increased plasminogen activator inhibitor-1 (PAI-1), reduced vasodilatory response to acetylcholine and the presence of microalbuminuria have also been described as part of this syndrome (50). The effect of hyperinsulinemia on the occurrence of CAD has been studied in various large prospective studies, but as yet, no unequivocal relationship has been established [51] [52] [53] [54]. A meta-analysis done by Ruige et al. (53), regrouping data from 12 prospective studies evaluating this association, found that hyperinsulinemia was a weak risk indicator for CAD and that the relationship was influenced by patients' ethnic background and the type of insulin assay involved in these studies. Many cross-sectional studies have indicated that insulin resistance is associated with ultrasonographically or angiographically assessed atherosclerosis even in the absence of other risk factors [55] [56] [57] [58]. However, there is still controversy about the mechanisms by which the insulin resistance syndrome appears to induce, or at least enhance, atherogenesis. This syndrome may be related to common cardiovascular risk factors or may be directly accelerated by hyperinsulinemia (44,50,52,59) (44,50,52,59) (44,50,52,59) (44,50,52,59). Reaven hypothesized that insulin resistance and compensatory hyperinsulinemia might be the primary events causing hypertension, leading subsequently to an increased risk of CAD (59). However, the exact role of insulin remains controversial because epidemiological and experimental data suggest that insulin does not accelerate atherosclerosis (58,60) (58,60). Moreover, recent data suggest that impaired microvascular function may be a central mechanism linking insulin sensitivity to increased blood pressure, and therefore to macrovascular disease in insulin resistance states (61).

Hyperglycemia
Traditional risk factors account only for 25%–50% of the increase in risk of CAD in diabetics (62). Thus, there can be little doubt that hyperglycemia and lipid abnormalities associated with DM play an important role in the pathogenesis of CAD in these patients. Several prospective studies have reported that poor glycemic control predicts CAD risk in diabetic patients [63] [64] [65]. The important Finnish study of Lehto et al. (63) in more than 1,000 diabetic patients showed that the simultaneous presence of high fasting blood glucose levels and abnormal lipid profile is associated with a threefold increase in the risk of CAD mortality and morbidity at seven years.

Hyperglycemia appears to be involved in each step of the atherosclerotic process. Acutely it attenuates endothelium-dependent vasodilatation in humans in vivo (66) and leads to adverse modifications in lipid (32,62,67,68) (32,62,67,68) (32,62,67,68) (32,62,67,68) and coagulation factors (43,62) (43,62). Chronic hyperglycemia can glycosylate proteins and damage the kidneys, leading to vascular damage and secondary hypertension (32,44,62) (32,44,62) (32,44,62). It may also exert direct toxic effects on the vasculature, potentiating the development of atherosclerosis (36,44) (36,44). Finally, there is unequivocal evidence that hyperglycemia interacts with other CAD risk factors to exacerbate the risk of CAD mortality (2).

Dyslipidemia
Hypertriglyceridemia associated with atherogenic, small and dense low-density lipoprotein (LDL) cholesterol and decreased levels of high-density lipoprotein (HDL) cholesterol are the most common abnormalities in type II DM (44,67) (44,67). Triglycerides' baseline levels change with the development of diabetes, and they are correlated with levels of fasting hyperglycemia; control of hyperglycemia improves but does not normalize these abnormalities (68). Although there is still no consensus on the best marker of CAD in diabetics (44,67,69) (44,67,69) (44,67,69), strategies based essentially on LDL-cholesterol reduction in these patients have recently provided unequivocal arguments for the role of these abnormalities in diabetic vasculopathy [44] [45] [46] [47] [48] [49].

In summary, metabolic abnormalities associated with DM play an important role in the formation and acceleration of atherosclerosis. Their control can possibly exert a notable benefit in CAD prevention in these patients.

Management of CAD in patients with DM

It has been shown that, even without prior myocardial infarction (MI), diabetic patients have the same level of cardiovascular risk as nondiabetics having sustained an MI (73), suggesting perhaps that all type II diabetic patients should undergo secondary prevention. However, there is also substantial evidence that most patients with DM do not receive optimal recommended treatment (74,75) (74,75), especially regarding the use of lipid-lowering drugs and angiotensin-converting enzyme inhibitors.

Behavioral recommendations
Cigarette smoking is an independent predictor of mortality in patients with DM (2,3,76) (2,3,76) (2,3,76). It is particularly hazardous in diabetic women with insulin-requiring DM (IRDM) because it more than doubles their risk of cardiac mortality (76). Cigarette smoking cessation is strongly recommended for all diabetic patients (2,4,75,76) (2,4,75,76) (2,4,75,76) (2,4,75,76). Weight loss and increased physical activity are also strongly indicated because of their beneficial effects in improving lipid profile, insulin resistance, glycemic control, hypertension, obesity, and platelet and coagulation abnormalities (75,77) (75,77).

Control of hyperglycemia
Recent studies show that intensive glycemic control is highly effective in preventing and retarding microvascular and, to a lesser degree, macrovascular complications in both type I and type II DM [78] [79] [80] [81]. The Diabetes Control and Complications Trial (DCCT) provided definite evidence of major reduction in chronic microvascular complications among a group of type I diabetic patients with tight glycemic control (78) and suggested a potential beneficial effect of this strategy on macrovascular disease. Tight glycemic control reduced major macrovascular events by one-half in diabetics compared with conventionally treated patients (79). However, this reduction did not reach statistical significance. The randomized United Kingdom Prospective Diabetes Study (UKPDS) (80) has reported that, over 10 years of follow-up, intensive glycemic control by either insulin or sulphonylureas significantly reduced (by 25%) the risk of microvascular complications in NIRDM patients. Diabetes-related mortality and MI incidence were also reduced by 10% and 16% respectively, but these reductions did not reach statistical significance (80). A similar reduction was observed in diet-treated obese NIRDM patients taking metformin (81). In addition, a recent retrospective study has reported that optimal glycemic control in diabetic patients can favorably influence major cardiac events following PTCA (82).

Lipid-lowering therapy
Although no published studies have specifically investigated the effects of lipid-lowering therapy on the development of CAD in diabetic patients, some solid arguments support the efficacy of this therapy in primary and secondary prevention trials [69] [70] [71] [72]. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) (70) indicated that, in diabetic patients with hypercholesterolemia, normal triglycerides and established CAD, lowering LDL-cholesterol levels with the HMG CoA reductase inhibitor simvastatin was associated with a marked reduction of major CAD and related atherosclerotic events. Five-year mortality was decreased by 43% in diabetic versus 29% in nondiabetic patients. Similar outcomes were reported by the Cholesterol And Recurrent Events (CARE) trial (71), evaluating the benefits of pravastatin in patients with average cholesterol levels after MI. There was a greater benefit of pravastatin in diabetics than in nondiabetics, with greater relative risk reduction for CAD major events and for revascularization procedures during a five-year follow-up. Finally, in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial (72), pravastatin therapy also showed a 19%, albeit not statistically significant, reduction of the composite end point of CAD-related death and MI during a 6.1-year follow-up in a subgroup of diabetics with a history of MI or unstable angina and with a broad range of initial cholesterol levels.

Control of hypertension
Recent studies have shown that adequate blood pressure control markedly reduced major cardiovascular events related to macrovascular complications [83] [84] [85] [86]. An important beneficial effect on microvascular disease was also demonstrated in the UKPDS study, where blood pressure was controlled by beta-blockers or angiotensin-converting enzyme inhibitors (84). However, there is still some uncertainty concerning blood pressure levels needed for maximal benefit, as well as the optimal drug classes to be used in these patients (44,83,87) (44,83,87) (44,83,87). The recently revised guidelines for the treatment of hypertension by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommended a level around 130/85 mm Hg for diabetic patients, which is compatible with the smallest decline in renal function in these patients (83,87) (83,87). First-line therapy should be based on cardioselective beta-blockers and diuretics that have been convincingly shown to reduce mortality and morbidity in patients with diabetic nephropathy and in NIRDM patients (83). Angiotensin-converting enzyme inhibitors and calcium channel blocking agents can be added as second-line therapy. (83,87) (83,87).

Other therapeutic considerations

Thrombolytic agents
Recent studies have confirmed that DM is a major independent predictor of acute and long-term post-MI mortality and morbidity, particularly in women and in IRDM patients [5] [6] [7] [8]. Numerous factors, including more severe CAD, associated comorbidity, metabolic derangements, silent ischemia and late or atypical presentation may contribute to a lesser use of fibrinolytic agents (88) and to a worse post-MI prognosis in these patients (5,6) (5,6). An overview by the Fibrinolytic Therapy Trialists' Collaborative Group (89), including 43 073 patients among whom 4,529 were diabetics, confirmed the benefit of thrombolysis in diabetic patients. The absolute reduction in mortality was greater in diabetics than in nondiabetics (3.7% vs. 2.1%) despite a greater 35-day mortality rate in diabetics (13.6% vs. 8.7%). Diabetics also had a slightly greater absolute increase, albeit not statistically significant, in the risk of haemorrhagic stroke (0.6% vs. 0.4%), but vitreous hemorrhage was rare. Data from a recent British study suggest that retinopathy is not a contraindication to thrombolysis except in the presence of a recent vitreous hemorrhage (90).

Insulin-glucose infusion
Long-term mortality in diabetic patients hospitalized for acute MI may be reduced by an insulin-glucose infusion followed by multidose insulin treatment, as demonstrated recently by a Swedish prospective study (91,92) (91,92). Insulin therapy appears to beneficially influence all cardiovascular causes of mortality, with a particular impact on fatal reinfarction and left ventricular failure (91). Another recent study reported a favorable mortality trend following glucose-insulin-potassium infusion in acute MI patients given reperfusion therapy (93).

Antiplatelet agents and anticoagulants
Platelet and coagulation abnormalities contribute to CAD in diabetics (5,38,62) (5,38,62) (5,38,62). Although more clinical trials are needed, current evidence supports antiplatelet therapy for diabetics. The meta-analysis of the Antiplatelet Trialists' Collaboration Group included 47 000 patients (10% diabetics) and reported an important benefit of aspirin therapy in diabetics with or at an increased risk for vascular disease (94). The combined end point of vascular death, MI or stroke was 22.3% in the control group and 18.5% in those receiving aspirin. The magnitude of this benefit in diabetics was similar to that observed in nondiabetics, without an excess in bleeding complications.

Recent trials have shown that low-molecular-weight heparins are more effective than placebo and as beneficial as or more beneficial than unfractionated heparin in the acute treatment of patients with unstable angina or non-Q-wave MI [95] [96] [97]. In general, these studies show a consistent treatment effect among patient subgroups, and the ESSENCE trial in particular has shown comparable benefits in patients with or without DM (98). In the TIMI 11B trial, the superiority of enoxaparin over unfractionated heparin in preventing death and cardiac ischemic events was greatest in high-risk patients (99). In the GUSTO IIB trial, hirudin, a direct thrombin inhibitor, was modestly more effective than unfractionated heparin in the treatment of diabetic patients with acute coronary syndromes and was not associated with an increased risk (100).

Recent clinical trial evidence suggests that glycoprotein IIb/IIIa inhibitors reduce the early and mid-term incidence of death, MI and recurrent angina in patients with unstable angina or non Q-wave MI [101] [102] [103] [104] [105]. In PRISM-PLUS, the reduction in clinical events in the group receiving tirofiban plus heparin compared with that receiving heparin-only was important for both DM and non-DM subgroups (102). However, as compared with heparin therapy only, combination therapy reduced the secondary end point of death and MI to a much greater extent (88% versus 43%, p = 0.005) in diabetics than in the overall study population (103). In the PURSUIT study, death and nonfatal MI were also significantly reduced by eptifibatide therapy as compared with placebo in both DM and non-DM subgroups (104). However, compared with nondiabetics, 30-day mortality was significantly more reduced in IRDM patients (105). Finally, a meta-analysis pooling all diabetic patients in 10 recent clinical trials of the effects of glycoprotein IIb/IIIa antagonists showed that diabetics had twice the absolute reduction in event rates seen in nondiabetics (106). There was a trend favoring a DM interaction that, however, did not reach statistical significance. The efficacy and benefits of glycoprotein IIb/IIIa inhibitors in diabetic patients undergoing percutaneous coronary interventions are discussed in the next section.

Beta-blockers
Pooled trial results of beta-blockers given soon after MI have shown a 37% mortality reduction in diabetics compared with 13% in all treated patients, and a similar beneficial decrease in the incidence of reinfarction (107). These drugs are also effective in reducing mortality when given long-term after MI (107,108) (107,108).

Angiotensin-converting enzyme inhibitors
Subgroup analysis of several studies have suggested that angiotensin-converting enzyme inhibition in diabetics with acute MI is associated with larger reductions in short-term mortality and occurrence of congestive heart failure than in nondiabetic patients (109,110) (109,110). Similar data support an important long-term benefit of these drugs in diabetics suffering from acute MI with left ventricular dysfunction (111,112) (111,112). Recent results from the Danish TRACE study showed that angiotensin-converting enzyme inhibition after MI complicated by left ventricular dysfunction in diabetics saved lives and substantially reduced the risk of progression to severe heart failure (112). Furthermore, diabetic patients represent fairly large subgroups of congestive heart failure patients in whom angiotensin-converting enzyme inhibitors were extensively evaluated. In these studies, angiotensin-converting enzyme inhibitors often reduced mortality and morbidity even more in diabetic than in nondiabetic patients (113).

The final results of the Heart Outcome Prevention Evaluation (HOPE) study were reported recently (114,115) (114,115). In this trial, a predefined subgroup of 3,657 middle-aged diabetic patients at risk for renal and cardiovascular disease was randomized to receive the angiotensin-converting enzyme inhibitor ramipril or a placebo for four years. The primary end point of cardiovascular mortality, MI and stroke was reduced by 24% and mortality alone was reduced by 38% in the angiotensin-converting enzyme inhibitor group. Diabetic complications and microvascular disease were reduced by 17%. An important finding of this trial is that the reduction of outcome events was similar in patients with or without left ventricular dysfunction (115).

In summary, data from recent prospective studies have provided solid arguments for intensive glycemic, lipid and blood pressure control in diabetics. In addition, several evidence-based pharmacological treatment strategies have been convincingly shown to confer major benefit on morbidity and mortality in diabetic patients with CAD. Additional randomized studies should evaluate the role of tight metabolic control on reduction of major cardiovascular events with or without coronary revascularization.

Percutaneous coronary revascularization in patients with symptomatic CAD and DM

Role of balloon angioplasty
In-hospital outcomes. Angiographic success rates of balloon PTCA in diabetics (85%–96%) are usually similar to those observed in nondiabetics (9,13) (9,13). The composite end point of mortality, nonfatal MI and urgent revascularization was respectively 11.0% in diabetics versus 6.7% in nondiabetics in the National Heart, Lung, and Blood Institute Registry (p < 0.01), with higher mortality rates in diabetics (3.2% vs. 0.5%) (13). However, lower mortality rates (<0.5%), comparable with those of nondiabetics, were reported by other groups (9,11,15) (9,11,15) (9,11,15). There were also evident trends toward higher rates of urgent revascularization [9] [10] [11] [12] and acute coronary occlusion in diabetics (13).

Short- and long-term follow-up
It is well recognized that restenosis rates may be very high (up to 63% in some series) after PTCA in diabetics (14,116) (14,116). Late clinical outcome after PTCA in these patients is also often unfavorable. Stein et al. (9) reported that five-year MI-free survival was lower and that additional revascularization was more frequently needed in 1,133 diabetics versus 9,300 nondiabetics undergoing PTCA. Similarly, Kip et al. (13) found that nine-year mortality was twice as high in diabetic patients treated by PTCA (35.9% vs. 17.9% in nondiabetics), with significantly higher incidences of MI and repeat revascularization. In the Bypass Angioplasty Revascularization Investigation (BARI), post-PTCA five-year survival was 73.3% in diabetics versus 91.3% in nondiabetics (p < 0.0001). The benefit of CABG was most evident in IRDM patients (10,11,16) (10,11,16) (10,11,16). Similar results were observed in the Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI) (12), and a trend toward superiority of CABG was observed in the BARI registry, even though CAD was less extensive in PTCA than in surgical patients (16,17) (16,17). On the other hand, better CABG results were not observed in the small subgroups of diabetics enrolled in the first Randomized Intervention Treatment of Angina One (RITA-1) study (23) and in the Emory Angioplasty versus Surgery Trial (EAST) (24). Five-and 10-year survival rates were similar in diabetic patients undergoing PTCA versus CABG in the large nonrandomized series (n = 2,639) reported by Weintraub (15), and comparable six-year results were also reported by Gum et al. in 525 diabetics (117). Inability to fully revascularize all ischemic territories, high restenosis rates and progression of atherosclerosis leading to repeat revascularization procedures are the most frequently suggested reasons for the long-term unfavorable results [9] [10] [11] [12] [13] [14] [15].

In summary, in the majority of published series, PTCA in diabetic patients is feasible with high angiographic success rate. However, DM appears to be predictive of higher risk of in-hospital complications, substantially increased restenosis rates and relatively poor long-term outcome.

Role of coronary stenting
Most studies evaluating stenting in diabetics are retrospective, and except for the series of Elezi et al. (n = 715 diabetics) (28), have enrolled relatively small numbers of patients [116] [117] [118] [119] [120] [121].

In-hospital outcomes
Angiographic success rates of stenting in diabetics (92%–100%) are often similar to those observed in nondiabetic patients [119] [120] [121] [122]. The composite end point of mortality, nonfatal MI and urgent CABG, ranging from 0.7% to 6.75%, is similar in diabetic versus nondiabetic patients in most series (28,119) (28,119). These in-hospital complications after stent implantation compare favorably to the 3% to 11% rates reported after balloon PTCA in diabetics (9,13,15) (9,13,15) (9,13,15). However, Elezi et al. (28) have found a clear trend toward higher rates of subacute stent thrombosis in diabetics (3.2% vs. 2.0% in nondiabetics, p = 0.06). A similar trend was reported by Abizaid et al. (119) in the IRDM patients.

Short- and long-term follow-up
Ranging from 24% to 40%, angiographic restenosis rates after stenting in diabetics were higher than the 20% to 27% rates observed in nondiabetic patients (28,120) (28,120). However, some reports have found more favorable results in diabetics (116,122) (116,122). In the series reported by Van Belle et al. (116), restenosis rates were similar (25% vs. 27%) after stenting, but different (63% vs. 32%) after PTCA in diabetic versus nondiabetic patients.

In addition, major cardiac event-free survival is often lower in diabetics (28,29,119,120) (28,29,119,120) (28,29,119,120) (28,29,119,120); Elezi et al. (28) reported a one-year event-free survival in diabetics of 73.1% versus 78.8% for nondiabetics (p < 0.001). However, long-term outcome after stenting is not influenced by diabetic status, according to other groups (116,122) (116,122). Additional revascularization was increased in target or new lesions in stented diabetics (28,121) (28,121), especially in the IRDM patients (119).

On the other hand, although some reports suggest that multivessel coronary stenting is feasible in carefully selected patients (with or without DM) with a high success rate, low in-hospital major complications and favorable long-term results (123,124) (123,124), data concerning the role of this therapeutic strategy in a specific diabetic population are not available. In summary, stenting is feasible in diabetics with favorable procedural and in-hospital success rates. However, angiographic restenosis rates and long-term outcome after stenting may be worse in this population, particularly in IRDM patients.

Mechanisms of restenosis and role of insulin
The basic mechanisms responsible for restenosis after PTCA or stenting in diabetics are unclear. The metabolic, hematologic and biological abnormalities observed in these patients all participate in the complex restenotic reaction following vessel injury (32). These patients' coronary lesions are more often associated with thrombus formation at angioscopy (47), a predictor of late coronary occlusion after PTCA (125). A recent study has shown that vessel occlusion is a frequent mode of restenosis in diabetics undergoing conventional balloon angioplasty (126). Moreover, intravascular ultrasound data suggest that intimal hyperplasia is the main reason for increased restenosis in both stented and nonstented lesions in diabetics (127), and several studies have found angiographic or ultrasound evidence consistent with this mechanism (28,119,121) (28,119,121) (28,119,121). However, the results of some groups reporting favorable restenosis rates after stenting in diabetics do not appear to support the excessive intimal hyperplasia hypothesis (116,122,126) (116,122,126) (116,122,126).

On the other hand, the multiple effects of insulin can contribute to the pathogenesis of restenosis by inducing smooth muscle cell migration and proliferation and extracellular matrix production (32,44) (32,44). Hyperinsulinemia can lead to coronary vasospasm (128,129) (128,129) and to thrombus formation through stimulation of plasminogen-activator inhibitor-1 and attenuation of fibrinolytic activity (45,46) (45,46). The poor short- and long-term results of coronary revascularization in some IRDM patients also emphasize the major role of this hormone (9,11,15,16,119) (9,11,15,16,119) (9,11,15,16,119) (9,11,15,16,119) (9,11,15,16,119). In addition, hyperinsulinemia in patients with impaired glucose tolerance and mild DM induces greater intimal hyperplasia after stent implantation (130), and treatment by triglitazone, an insulin sensitizer, reduces this intimal proliferation (131).

In summary, intimal hyperplasia and late vessel occlusion are two potential mechanisms implicated in the complex phenomenon of restenosis following angioplasty in diabetics. However, further investigations should determine the mechanisms of this reaction and evaluate the pejorative role of insulin in restenosis.

Role of glycoprotein IIb/IIIa platelet receptor antagonists
Data related to the usefulness of glycoprotein IIb/IIIa receptor antagonists in diabetic patients are limited to subgroup analyses from recent prospective randomized trials. At least six trials of the effects of glycoprotein IIb/IIIa inhibitors in patients undergoing coronary interventions have been reported, four with abciximab, one with eptifibatide and one with tirofiban [25] [26] [27] [28] [29] [30]. In the EPIC trial, abciximab therapy showed a 35% reduction in the primary end point of death, MI and urgent revascularization at one month, with a similar risk reduction in DM and non-DM patients (25). At three years, however, the clinical benefits were sustained in the total population (135), whereas diabetics experienced a progressive deterioration with more clinical events than nondiabetics (136). In the EPILOG trial, abciximab therapy in diabetic patients undergoing elective PTCA led to a significant reduction of death and MI at 30 days and at six months (26). However, target vessel revascularization (TVR) at six months was reduced only in the nondiabetic subgroup, and diabetics treated with abciximab and standard-dose heparin had a marginally greater benefit than those assigned to abciximab and low-dose heparin. Pooled data from the EPIC, EPILOG and EPISTENT trials showed that abciximab decreases the one-year mortality of diabetic patients to that of placebo-treated nondiabetic patients (137). In the IMPACT-II trial, treatment with eptifibatide during coronary intervention reduced rates of early abrupt closure and ischemic events at 30 days; the benefit of therapy was similar in patients with and without DM (133). In the RESTORE trial, tirofiban reduced early cardiac events in patients undergoing PTCA for acute coronary syndromes, but this effect was no longer statistically significant at 30 days (134). Twenty percent of all patients in this trial were diabetics; however, no subgroup analysis was reported.

The EPISTENT trial was the largest study evaluating the benefit of abciximab therapy in patients undergoing coronary stenting (27,138) (27,138). It demonstrated a significant reduction of major cardiac events at 30 days and at six months in the abciximab groups compared with the stent-plus-placebo group. In addition, the combination of stenting and abciximab therapy among diabetic patients resulted in a significant reduction in six-month rates of death, MI and TVR compared with stent plus placebo or balloon angioplasty plus abciximab therapy (138). The substantial TVR reduction associated with a significant increase in angiographic net gain and a trend toward a decrease in late loss index in stented diabetics treated by abciximab versus those treated with placebo suggests for the first time a potential additional benefit of abciximab in reducing restenosis in stented diabetics (138, 139) (138, 139). In this context, the ERASER trial has provided intravascular ultrasound data suggesting that, compared with placebo, abciximab decreases neointimal proliferation in stented diabetics but not in the overall study population (140).

In summary, the EPISTENT trial demonstrates a significant reduction of major ischemic cardiac events and TVR in stented diabetic patients and confirms the net benefit of glycoprotein IIb/IIIa antagonists in this population. However, further investigations are needed to explain the interaction of abciximab with DM status and whether a similar reduction in coronary restenosis will be observed with other glycoprotein IIb/IIIa antagonists.

Cabg in patients with symptomatic CAD and DM

Diabetes mellitus is a recognized risk factor for poor early and late outcome after CABG [18] [19] [20] [21] [22], and is also identified as an important predictor of progression and occlusion of bypassed and nonbypassed coronary segments (20,24) (20,24).

As discussed above, the BARI randomized trial (10,11) (10,11), and to a lesser extent the BARI registry (16), have shown that patients with DM and multivessel disease assigned to an initial strategy of CABG have a striking reduction in cardiac mortality compared with PTCA. Post-hoc analyses were also performed in subsets of diabetic patients in three smaller randomized trials comparing PTCA and CABG. Results similar to those of BARI were obtained in one trial (12), but CABG outcome was not superior to that of PTCA in the two other trials (23,24) (23,24). Large retrospective databases of diabetic patients who have undergone coronary intervention procedures may not be suitable to compare CABG and percutaneous intervention because patients in the two treatment groups are almost certainly not comparable in terms of prognosis. Be that as it may, two large databases of patients with multivessel CAD from Emory (15) and Duke (22) university studies assessing the results of revascularization procedures in diabetic patients have been reported. In the Emory study, only the IRDM subgroup treated by PTCA had lower five- and 10-year survival rates than the CABG group (15). In the Duke study, DM was associated with worse five-year survival, but the effect of DM on prognosis was similar in both treatment strategies (22).

In patients undergoing CABG, the superiority in terms of long-term survival of internal mammary artery (IMA) conduits to the left anterior descending coronary artery over autologous saphenous vein grafts is well established (141). Therefore, it is not surprising that the benefit of CABG in the diabetic subgroup in BARI was confined to those receiving at least one IMA graft (10,11) (10,11). Whether bilateral IMA grafting confers yet an additional benefit in these patients is not known, particularly because this technique carries a greater risk of sternal wound complications in diabetics than in nondiabetics [142] [143] [144]. However, DM should not be an absolute contraindication to bilateral IMA use, which should be adjusted to the coronary bed needing revascularization and to the patient's age (144).

In summary, the superiority of CABG over PTCA in diabetics is not well established. Conclusions drawn from the diabetic subgroup of the BARI trial must be confirmed in larger randomized trials.

Summary and future directions

The optimal strategy of coronary revascularization in diabetics remains to be determined. Many biological, hematological and metabolic abnormalities predispose diabetic patients undergoing percutaneous revascularization to a high incidence of in-hospital and long-term cardiovascular events, presumably because of incomplete revascularization, high restenosis rates and CAD progression. Whether stents will improve outcome in this population is still controversial, and prospective investigation of this issue is required. Moreover, the superiority of a surgical strategy over percutaneous revascularization in this population remains unproven. These conclusions were drawn from trials done at the end of the 1980s and beginning of the 1990s, when stents were emerging and the important class of GP IIb/IIIa inhibitors had not yet been developed. These two important catheter-based advances should have a positive influence on clinical outcome in future investigations, as suggested by the results of the diabetic subgroup in the EPISTENT study. Locally delivered ionizing radiation and gene therapy may also have a potential role in this high-risk population. Furthermore, treatment advances are not confined to interventional cardiology, as less invasive surgical techniques may offer advantages over conventional CABG. Final results from the two European randomized trials of stenting versus CABG (Arterial Revascularization Therapy Study [ARTS] and Stent or Surgery [SOS]) will probably shed some new light on coronary revascularization in diabetic patients. Moreover, the demonstrated benefit of strict glycemic, lipid and blood pressure control indicate that this management strategy should be routinely enforced in these patients and that their effect after coronary revascularization should be prospectively evaluated. Data from the planned BARI-II trial, which will randomize diabetic patients and will include coronary stenting as well as intensive glycemic and lipid control, should answer the major questions concerning therapeutic strategies in this population.

In conclusion, many aspects related to coronary revascularization in diabetics remain unclear, and further randomized investigations evaluating the latest new progress in percutaneous as well as surgical revascularization will help physicians make better therapeutic decisions. Until the results of ongoing and future trials are available, management of CAD in patients with DM will continue to pose a challenge to the medical profession

[1] Fein F, Scheur J. Heart disease in diabetes mellitus: theory and practice. In: Rifkin H, Porte D Jr., editors. New York: Elsevier, 1990:812–23.

[2] Multiple Risk Factor Intervention Trial Research Group, Stamler J., Vaccaro O., Neaton J.D. and Wentworth D. Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993, 16:434-444.[Medline]

[3] Wingard DL, Barrett-Connor E. Heart disease and diabetes. In: National Diabetes DataGroup. Diabetes in America. 2^nd edition. Washington DC: Government Printing Office, 1995:429–48. (NIH publication number 95-1468).

[4] Kannel W. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J 1985, 110:1100-1107.[Medline]

[5] Jacoby R.M. and Nesto R.W. Acute myocardial infarction in the diabetic patient: pathophysiology, clinical course and prognosis. J Am Coll Cardiol 1992, 20:736-744.[Medline]

[6] GUSTO-I Investigators, Mak K.H., Moliterno D.J. and Granger C.B. et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. J Am Coll Cardiol 1997, 30:171-179.[Medline, ]

[7] Woodfield S.L., Lundergan C.F. and Reiner J.S. et al. Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. J Am Coll Cardiol 1996, 28:1661-1669.[Medline]

[8] GISSI-2 Investigators, Zuanetti G., Latini R., Maggioni A.P., Santoro L. and Franzosi P.G. Influence of diabetes on mortality in acute myocardial infarction: data from the GISSI-2 study. J Am Coll Cardiol 1993, 22:1788-1794.[Medline]

[9] Stein B., Weintraub W.S. and Gebhart S.S.P. et al. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation 1995, 91:979-989.[Medline]

[10] Bypass Angioplasty Revascularization Investigation (BARI) Investigators, Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996, 335:217-225.[Medline]

[11] BARI Investigators, Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Circulation 1997, 96:1761-1769.[Medline]

[12] CABRI. Long-term follow-up of European revascularization trials. Presented at the 68th Scientific Plenary Session XII, of the American Heart Association, Nov. 16, 1995; Anaheim, Calif.

[13] Investigators of the NHLBI PTCA Registry, Kip K.E., Faxon D.P., Detre K.M., Yeh W., Kelsey S.F. and Currier J.W. Coronary angioplasty in diabetic patients. The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 1996, 94:1818-1825.[Medline]

[14] O'Neill W.W. Multivessel balloon angioplasty should be abandoned in diabetic patients. J Am Coll Cardiol 1998, 31:20-22.[Medline, ]

[15] Weintraub W.S., Stein B. and Kosinski A. et al. Outcome of coronary bypass surgery versus coronary angioplasty in diabetic patients with multivessel coronary artery disease. J Am Coll Cardiol 1998, 31:10-19.[Medline, ]

[16] Detre K.M., Guo P. and Holubkov R. et al. Coronary revascularization in diabetic patients. A comparison of the randomized and observational components of the Bypass Angioplasty Revascularization Investigation (BARI) Circulation 1999, 99:633-640.[Medline]

[17] Kuntz R.E. Importance of considering atherosclerosis progression when choosing a coronary revascularization strategy. The diabetes-percutaneous transluminal coronary angioplasty dilemma. Circulation 1999, 99:847-851.[Medline]

[18] Morris JJ, Smith LR, Jones RH, et al. Influence of diabetes and mammary artery grafting on survival after coronary bypass. Circulation 1991;84 Suppl 3:III-275–84.

[19] Smith LR, Harrell FE, Rankin JS, et al. Determinants of early versus late cardiac death in patients undergoing coronary artery bypass graft surgery. Circulation 1991;84 Suppl III:III-245–53.

[20] Alderman E.L., Corley S.D. and Fisher L.D. et al. The CASS Participating Investigators and Staff. Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS) J Am Coll Cardiol 1993, 22:1141-1154.[Medline]

[21] Herlitz J., Karlson B.W. and Wognsen G.B. et al. Mortality and morbidity in diabetic and non-diabetic patients during a 2-year period after coronary artery bypass grafting. Diabetes Care 1996, 19:698-703.[Medline]

[22] Barsness G.W., Peterson E.D. and Ohman E.M. et al. Relationship between diabetes mellitus and long-term survival after coronary bypass and angioplasty. Circulation 1997, 96:2551-2556.[Medline]

[23] Randomized Intervention Treatment of Angina (RITA-1) Trial Participants, Henderson R.A., Pocock S.J. and Sharp S.J. et al. Long-term results of RITA-1 trial: clinical and cost comparisons of coronary angioplasty and coronary artery bypass grafting. Lancet 1998, 352:1419-1425.[Medline, ]

[24] Emory Angioplasty versus Surgery Trial (EAST), King S.B. III, Lembo N.J. and Weintraub W.S. et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. N Engl J Med 1994, 331:1044-1050.[Medline]

[25] EPIC Investigators, Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994, 330:956-961.[Medline]

[26] EPILOG Investigators, Kleiman N.S., Lincoff A.M. and Kereiakes D.J. et al. Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin. Evidence for a complex interaction in a multicenter trial. Circulation 1998, 97:1912-1920.

[27] EPISTENT Investigators, Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998, 352:87-92.[Medline, ]

[28] Elezi S., Kastrati A. and Pache J. et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 1998, 32:1866-1873.[Medline, ]

[29] Moussa I., Moses J. and Wang X. et al. Why do the coronary vessels in diabetics appear to be angiographically small? J Am Coll Cardiol 1999, 33:Suppl A:78A.[Medline, ] (abstr)

[30] Abaci A., Oguzhan A. and Kahraman S. et al. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 1999, 99:2239-2242.[Medline]

[31] Cohen R.A. Dysfunction of vascular endothelium in diabetes mellitus. Circulation 1993, 87:Suppl V:V-67-V-76.[Medline]

[32] Aronson D., Bloomgarden Z. and Rayfield E.J. Potential mechanisms promoting restenosis in diabetic patients. J Am Coll Cardiol 1996, 27:528-535.[Medline]

[33] Nahser P.J., Brown R.E., Oskarsson H., Winniford M.D. and Rossen J.D. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 1995, 91:635-640.[Medline]

[34] Yokoyama I., Momomura S.I. and Ohtake T. et al. Reduced myocardial flow reserve in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1997, 30:1472-1477.[Medline, ]

[35] Nitenberg A., Paycha F., Ledoux S., Sachs R., Attali J.R. and Valensi P. Coronary artery responses to physiological stimuli are improved by deferoxamine but not by L-arginine in non-insulin-dependent diabetic patients with angiographically normal coronary arteries and no other risk factors. Circulation 1998, 97:736-743.[Medline]

[36] Lorenzi M., Cagliero E. and Toledo S. Glucose toxicity for human endothelial cells in culture. Delayed replication, disturbed cell cycle, and accelerated death. Diabetes 1985, 34:621-627.

[37] Winocour P.D., Richardson M. and Kinlough-Rathbone R.L. Continued platelet interaction with de-endothelialized aorta associated with slower re-endothelialization and more extensive intimal hyperplasia in spontaneously diabetic BB Wistar rats. Int J Exp Pathol 1993, 74:603-613.[Medline]

[38] Winocour P.D. Platelet abnormalities in diabetes mellitus. Diabetes 1992, 41:Suppl 2:26-31.[Medline]

[39] Strano A., Davi G. and Patrono C. (review) In vivo platelet activation in diabetes mellitus. (review) Semin Thromb Haemost 1991, 17:422-425.

[40] Jilma B., Fasching P. and Ruthner C. et al. Elevated circulating P-selectin in insulin dependent diabetes mellitus. Thromb Haemost 1996, 76:328-332.[Medline]

[41] Tschoepe D., Roesen P. and Esser J. et al. Large platelets circulate in an activated state in diabetes mellitus. Semin Thromb Haemost 1991, 17:433-438.

[42] Davi G., Catalano I. and Averna M. et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990, 322:1769-1774.[Medline]

[43] Ceriello A. Coagulation activation in diabetes mellitus: a role of hyperglycemia and therapeutic prospects. Diabetologia 1993, 36:1119-1125.[Medline]

[44] Stout R.W. Insulin and atheroma: 20-year perspective. Diabetes Care 1990, 13:631-654.[Medline]

[45] Nordt T.K., Sawa H. and Sobel B.E. Induction of plasminogen activator inhibitor type-1 (PAC-1) by proinsulin and insulin in vivo. Circulation 1995, 91:764-770.[Medline]

[46] Sobel B.E., Woodcock-Mitchell J., Schneider D.J., Holt R.E., Marutsuka K. and Gold H. Increased plasminogen activator inhibitor type-1 in coronary artery atherectomy specimens from type-2 diabetic compared with nondiabetic patients. Circulation 1998, 97:2213-2221.[Medline]

[47] Silva J.A., Escobar A., Collins T.J., Ramee S.R. and White C.J. Unstable angina: a comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation 1995, 92:1731-1736.[Medline]

[48] Reaven G.M. Role of insulin resistance in human disease. Diabetes 1988, 37:1595-1607.[Medline]

[49] Stern M.P. Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents? Ann Intern Med 1996, 93:1780-1783.[Medline]

[50] Godsland I.K. and Stevenson J.C. Insulin resistance: syndrome or tendency? Lancet 1995, 346:100-103.[Medline]

[51] Laakso M., Sarlund H. and Salonen R. et al. Asymptomatic atherosclerosis and insulin resistance. Arterioscler Thromb 1991, 11:1068-1076.[Medline]

[52] Wingard D.L., Barrett-Connor E.L. and Ferrara A. Is insulin really a heart disease risk factor? Diabetes Care 1995, 18:1299-1304.[Medline]

[53] Ruige J.B., Assendelft W.J.J., Dekker J.M., Kostense P.J., Heine R.J. and Bouter L.M. Insulin and risk of cardiovascular disease. A meta-analysis. Circulation 1998, 97:996-1001.[Medline]

[54] Pyörälä M., Miettinen H., Laakso M. and Pyörälä K. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men. The 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998, 98:398-404.[Medline]

[55] Young M.H., Jeng C.Y. and Sheu W.H.H. et al. Insulin resistance, glucose intolerance, hyperinsulinemia and dyslipidemia in patients with angiographically demonstrated coronary disease. Am J Cardiol 1993, 72:458-460.[Medline]

[56] Agewall S., Fagerberg B. and Attwall S. et al. Carotid artery wall intima-media thickness is associated with insulin-mediated glucose disposal in men at high and low coronary risk. Stroke 1995, 26:956-960.[Medline]

[57] Bressler P., Bailey S.R., Matsuda M. and DeFronzo R.A. Insulin resistance and coronary disease. Diabetologia 1996, 39:1345-1350.[Medline]

[58] IRAS Investigators, Howard G., O'Leary D.H. and Zaccaro D. et al. Insulin sensitivity and atherosclerosis. Circulation 1996, 93:1809-1817.[Medline]

[59] Reaven G.M. Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996, 334:374-381.[Medline]

[60] Nordestgaard B.G., Agerholm-Larsen B. and Stender S. Effect of exogenous hyperinsulinemia on atherogenesis in cholesterol-fed rabbits. Diabetologia 1997, 40:512-520.[Medline]

[61] Serné E.H., Stehouwer C.D.A. and Maaten J.C. et al. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation 1999, 99:896-902.[Medline]

[62] Bierman E.L. Atherogenesis in diabetes. Atheroscler Thromb 1992, 12:647-656.

[63] Lehto S., Rönnemaa T., Haffner S.M., Pyörälä K., Kallio V. and Laakso M. Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes 1997, 46:1354-1359.[Medline]

[64] Wei M., Gaskill S.P., Haffner S.M. and Stern M.P. Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care 1998, 21:1167-1172.[Medline]

[65] Niskanen L., Turpeinen A., Penttila I. and Uusitupa M.I.J. Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis. Diabetes Care 1998, 21:1861-1869.[Medline]

[66] Williams S.B., Goldfine A.B. and Timimi F.K. et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998, 97:1695-1701.[Medline]

[67] Kreisberg R.A. Diabetic dyslipidemia. Am J Cardiol 1998, 82:67U-73U.[Medline, ]

[68] Stern M.P., Mitchell B.D., Haffner S.M. and Hazuda H.P. Does glycemic control of type 2 diabetes suffice to control diabetic dyslipidemia? Diabetes Care 1992, 15:638-644.[Medline]

[69] Koskinen P., Mãnttãri M., Manninen V., Huttunen J.K., Heinonen O.P. and Frick M.H. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992, 15:820-825.[Medline]

[70] Haffner S.M. The Scandinavian Simvastatin Survival Study (4S) subgroup analysis of diabetic subjects: implications for the prevention of coronary heart disease. Diabetes Care 1997, 20:469-471.[Medline]

[71] Goldberg R.B., Mellies M.J. and Sacks F.M. et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Circulation 1998, 98:2513-2519.[Medline]

[72] Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998, 339:1349-1357.[Medline]

[73] Haffner S.M., Lehto S., Ronnemaa T., Pyorala L. and Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998, 339:229-234.[Medline]

[74] Chowdhury T.A., Lasker S.S. and Dyer P.H. Comparison of secondary prevention measures after myocardial infarction in subjects with and without diabetes mellitus. J Int Med 1999, 245:565-570.

[75] American Diabetes Association, Standards of medical care for patients with diabetes mellitus. Diabetes Care 1997, 20:Suppl 1:S5-S13.[Medline]

[76] Scala M.C., Laporte R. and Dorman J. et al. Insulin dependent diabetes mellitus mortality: the risk of cigarette smoking. Circulation 1990, 82:37-43.[Medline]

[77] American Diabetes Association, Diabetes mellitus and exercise. Diabetes Care 1998, 21:Suppl 1:S40-S44.[Medline]

[78] Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993, 329:977-986.[Medline]

[79] Diabetes Control and Complications Trial (DCCT) Research Group, Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 1995, 75:894-903.[Medline]

[80] UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 1998, 352:837-853.[Medline, ]

[81] UK Prospective Diabetes Study (UKPDS) Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet 1998, 352:854-865.[Medline, ]

[82] Al-Rashdan I.R., Rankin J.M. and Elliott T.G. et al. Glycemic control and major adverse cardiac events after PTCA in patients with diabetes mellitus. J Am Coll Cardiol 1999, 33:97A.[Medline, ] (abstr)

[83] Sawicki PT, Berger M. Pharmacological treatment of diabetic patients with cardiovascular complications. J Int Med 1198;243:181–9.

[84] UK Prospective Diabetes Study (UKPDS) Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38) Br Med J 1998, 317:703-713.[Medline]

[85] Estacio R.O., Jeffers B.W. and Hiatt W.R. et al. The effect of nisoldipine as compared with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998, 338:645-652.[Medline]

[86] Hansson L., Zanchetti A. and Carruthers S.G. et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension. Principal results of the hypertension optimal treatment (HOT) randomized trial. Lancet 1998, 351:1755-1762.[Medline, ]

[87] sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, Arch Intern Med 1997, 157:2413-2446.[Medline]

[88] SAVE Investigators, Pfeffer M.A., Moyé L.A. and Braunwald E. et al. Selection bias in the use of thrombolytic therapy in acute myocardial infarction. JAMA 1991, 266:528-532.[Medline]

[89] Fibrinolytic Therapy Trialists' (FIT) Collaborative Group, Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994, 343:311-322.[Medline]

[90] Higgs E.R., Parfitt V.J., Harney B.A. and Harlog M. Use of thrombolysis for acute myocardial infarction in the presence of diabetic retinopathy in the UK, and associated ocular haemorrhagic complications. Diabetic Med 1995, 12:426-428.

[91] DIGAMI Study Group, Malmberg K., Ryden L., Hamsten A., Herlitz J., Waldenström A. and Wedel H. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J 1996, 17:1337-1344.[Medline]

[92] Malmberg K., Norhammar A., Wedel H. and Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction. Long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study. Circulation 1999, 99:2626-2632.[Medline]

[93] ECLA (Estudios Cardiologicos Latinoamérica) Collaborative Group, Diaz R., Paolasso E. and Piegas L. et al. Metabolic modulation of acute myocardial infarction: the ECLA Glucose-Insulin-Potassium Pilot Trial in Acute Myocardial Infarction. Circulation 1998, 98:2227-2234.[Medline]

[94] Antiplatelet Trialists' Collaboration, Collaborative overview of randomised trials of antiplatelet therapy–I:prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994, 308:81-106.[Medline]

[95] Fragmin during Instability in Coronary Artery Disease (FRISC) study group, Low-molecular weight heparin during instability in coronary artery disease. Lancet 1996, 347:561-568.[Medline]

[96] FRIC Investigators, Klein W., Buchwald A. and Hillis S.E. et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of instable coronary artery disease. Fragmin in Unstable Coronary Artery Disease Study (FRIC) Circulation 1997, 96:61-68.[Medline]

[97] Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group, Cohen M., Demers C. and Gurfinkel E.P. et al. A comparison of low-molecular-weight heparin with unfractionated for unstable coronary artery disease. N Engl J Med 1997, 337:447-452.[Medline]

[98] ESSENCE Study Group, Cohen M., Demers C. and Gurfinkel E.P. et al. Low-molecular-weight heparins in non-ST-segment elevation ischemia: The ESSENCE trial. Am J Cardiol 1998, 82:19L-24L.[Medline, ]

[99] Bernink P.J.L.M., Antman E.M. and McCabe C.H. et al. Treatment benefit with enoxaparin in unstable angina is greatest in patients at highest risk: A multivariate analysis from TIMI 11B. J Am Coll Cardiol 1999, 33:Suppl. A:352A.[Medline, ] (abstr)

[100] McGuire DK, Emanuelsson H, Granger CB, White HD. Diabetes mellitus is associated with worse clinical outcomes across the spectrum of acute coronary syndromes: results from GUSTO-IIb. Circulation 1999;100 Suppl I:I–432 (abstr).

[101] Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators, A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998, 338:1498-1505.[Medline]

[102] Platelet receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators, Inhibition of the platelet glycoprotein Iib/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998, 338:1488-1497.[Medline]

[103] Hermann H.C. Tirofiban—an overview of the phase III trials. J Invas Cardiol 1999, 11:Suppl C:7C-13C.

[104] PURSUIT Trial Investigators, Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998, 339:436-443.[Medline]

[105] Wright RS, Kopecky SL, Barsness GW, Tuttle RH. Impact of diabetes mellitus on outcome in non-ST elevation myocardial infarction and unstable angina: is there a benefit from treatment with eptifibatide? Circulation 1999;100 Suppl. I: I–640 (abstr).

[106] Ramanathan AV, Miller DP, Kleiman NS. Effect of GP IIb/IIIa antagonists in patients with diabetes mellitus: a meta-analysis. Circulation 1999;100 Suppl. I:I–640 (abstr).

[107] Kendall M.J., Lynch K.P., Hjalmarson A. and Kjekshus J. Beta-blockers and sudden cardiac death. Ann Intern Med 1995, 123:358-367.[Medline]

[108] Jonas M., Reicher-Reiss H. and Boyko V. et al. Usefulness of beta-blocker therapy in patients with non-insulin-dependent diabetes mellitus and coronary artery disease. Am J Cardiol 1996, 77:1273-1277.[Medline]

[109] Zuanetti G., Latini R. and Maggioni A.P. et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997, 96:4239-4245.[Medline]

[110] Survival of Myocardial Infarction Long-term Evaluation (SMILE) Study Investigators, Ambrosioni E., Borghi C. and Magnani B. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995, 332:80-85.[Medline]

[111] SAVE Investigators, Moye L.A., Pfeffer M.A. and Wun C.C. et al. Uniformity of captopril benefit in the SAVE study:subgroup analysis. Eur Heart J 1994, 15:Suppl. B:2-8.[Medline]

[112] Gustafsson I., Torp-Pedersen C. and Kober L. et al. Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. J Am Coll Cardiol 1999, 34:83-89.[Medline, ]

[113] Solang L., Malmberg K. and Ryden L. Diabetes mellitus and congestive heart failure. Eur Heart J 1999, 20:789-795.[Medline]

[114] Gerstein H.C., Bosch J. and Pogue J. et al. Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes. The MICRO-HOPE study. Diabetes Care 1996, 19:1225-1228.[Medline]

[115] The HOPE study. Results in diabetic patients. Presented at the XXIst Congress of the European Society of Cardiology, August 31, 1999; Barcelona, Spain.

[116] Van Belle E., Bauters C. and Hubert E. et al. Restenosis rates in diabetic patients: a comparison of coronary stenting and balloon angioplasty in native coronary vessels. Circulation 1997, 96:1454-1460.[Medline]

[117] Gum P.A., O'Keefe J.H. and Borkon A.M. et al. Bypass surgery versus coronary angioplasty for revascularization of treated diabetic patients. Circulation 1997, 96:Suppl 2:II7-II10.[Medline]

[118] Rozenman Y., Sapoznikov D. and Mosseri M. et al. Long-term angiographic follow-up of coronary balloon angioplasty in patients with diabetes mellitus. A clue to the explanation of the results of the BARI study. J Am Coll Cardiol 1997, 30:1420-1425.[Medline, ]

[119] Abizaid A., Kornowski R. and Mintz G.S. et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998, 32:584-589.[Medline, ]

[120] Blankenbaker R., Ghazzal Z., Weintraub W.S., Shen Y. and King S.B. III Clinical outcome of diabetic patients after Palmaz-Schatz stent implantation. J Am Coll Cardiol 1998, 31:Suppl A:415A.[Medline, ] (abstr)

[121] Alonso J.J., Fernandez-Avilés M.F. and Duran J.M. et al. Influence of diabetes mellitus on the initial and long-term outcome of patients treated with coronary stenting. J Am Coll Cardiol 1999, 33:Suppl A:98A.[Medline, ] (abstr)

[122] Bhaskaran A., Siegel R. and Barker B. et al. Stenting during coronary intervention improves procedural and long-term clinical outcomes. J Am Coll Cardiol 1999, 33:Suppl A:97A.[Medline, ] (abstr)

[123] Moussa I., Reimers B. and Moses J. et al. Long-term angiographic and clinical outcome of patients undergoing multivessel coronary stenting. Circulation 1997, 96:3873-3879.[Medline]

[124] Kornowski R., Mehran R. and Satler L.F. et al. Procedural results and late clinical outcomes following multivessel coronary stenting. J Am Coll Cardiol 1999, 33:420-426.[Medline, ]

[125] Bauters C., Lablanche J.M., McFadden E.P., Hamon M. and Bertrand M.E. Relation of coronary angioscopic findings at coronary angioplasty to angiographic restenosis. Circulation 1995, 92:2473-2479.[Medline]

[126] Van Belle E., Abolmaali K., Bauters C., McFadden E.P., Lablanche J.M. and Bertrand M.E. Restenosis, late vessel occlusion and left ventricular function six months after balloon angioplasty in diabetic patients. J Am Coll Cardiol 1999, 33:Suppl A:25A.[Medline, ] (abstr)

[127] Kornowski R., Mintz G.S. and Kent K.M. et al. Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. A serial intravascular ultrasound study. Circulation 1997, 95:1366-1369.

[128] Shinozaki K., Suzuki M. and Ikebuchi M. et al. Insulin resistance associated with compensatory hyperinsulinemia as an independent risk factor for vasospastic angina. Circulation 1995, 92:1749-1757.[Medline]

[129] Suzuki M., Nishizaki M., Arita M., Kakuta T. and Numano F. Impaired glucose tolerance with late hypersecretion of insulin during oral glucose tolerance test in patients with vasospastic angina. J Am Coll Cardiol 1996, 27:1458-1463.[Medline]

[130] Takagi T, Akasaka T, Kaji S, Ueda Y, Morioka S. Increased intimal hyperplasia after coronary stent implantation in patients with hyperinsulinemia: a serial intravascular ultrasound study. Circulation 1998;98 Suppl 1:I–229 (abstr).

[131] Takagi T., Yoshida K., Akasaka T., Hozumi T., Yamamuro A. and Morioka S. Triglitazone reduces intimal hyperplasia after coronary stent implantation in patients with type 2 diabetes mellitus: a serial intravascular ultrasound study. J Am Coll Cardiol 1999, 33:Suppl A:33A.[Medline, ] (abstr)

[132] CAPTURE Investigators, Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997, 349:1429-1435.[Medline, ]

[133] IMPACT-II Investigators, Randomized placebo-controlled trial of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997, 349:1422-1428.[Medline, ]

[134] RESTORE Investigators, Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997, 196:1445-1453.[Medline]

[135] EPIC Investigator Group, Topol E.J., Ferguson J.J. and Weissman H.F. et al. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin 36 $₃ blockade with percutaneous coronary intervention. JAMA 1997, 278:479-484.[Medline]

[136] Narins CR, Ellis SG, Hammel JP. Does abciximab improve outcome following angioplasty in diabetics? Long-term follow-up results from the EPIC Study. Circulation 1997;96 Suppl 1:I–67 (abstr.).

[137] Bhatt DL, Marso SP, Lincoff AM, Wolski KE, Ellis SG, Topol EJ. Abciximab reduces death in diabetics following percutaneous coronary intervention. Circulation 1999;100 Suppl. I:I–67 (abstr.).

[138] EPISTENT Investigators, Marso S.P., Lincoff A.M. and Ellis S.G. et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus. Results of the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial) diabetic study. Circulation 1999, 100:2477-2484.

[139] King S.B. and Mahmud E. Will blocking the platelet save the diabetic? Circulation 1999, 100:2466-2468.[Medline]

[140] ERASER Investigators, Acute platelet inhibition with abciximab does not reduce in-stent restenosis (ERASER Study) Circulation 1999, 100:799-806.[Medline]

[141] Loop F.D., Lytle B.W. and Cosgrove D.M. et al. Influence of the internal mammary artery graft on 10-year survival and other cardiac events. N Engl J Med 1986, 314:1-6.[Medline]

[142] Loop F.D., Lytle B.W. and Cosgrove D.M. et al. Sternal wound complications after isolated coronary artery bypass grafting: early and late mortality, morbidity and cost of care. Ann Thorac Surg 1990, 40:179-187.[Medline]

[143] He G.W., Ryan W.H. and Acuff T.E. et al. Risk factors for operative mortality and sternal wound infection in bilateral mammary artery grafting. J Thorac Cardiovasc Surg 1994, 107l:196-202.[Medline]

[144] Dion R., Etienne P.Y. and Verheist R. et al. Bilateral mammary grafting. Clinical, functional and angiographic assessment in 400 consecutive patients. Eur J Cardiol Thorac Surg 1993, 7:287-294.

Article Footnote.Dr. Hammoud is currently a member of the Department of Cardiology, Bahman Hospital, Beirut, Lebanon.

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