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The randomized United Kingdom Prospective Diabetes Study (UKPDS) con- |

firmed that glycemic control significantly reduced microvascular complications of type 2 diabetes and, to a lesser and not statistically significant extent, reduced

MI- and diabetes-related death (64). Recently reported studies indicate that tight glycemic control also decreased adverse cardiac events post-PCI (65). Yumoto et al. examined glycosylated hemoglobin (HbA1c) levels in diabetic patients following stenting reporting a lower mean value in patients without restenosis (6.8% vs. 7.5%; p = 0.012), suggesting an important role of glycemic control in restenosis prevention (66). The optimal choice of drug therapy to achieve glycemic control has not been determined. In the subset of patients undergoing PCI for acute MI, concern has been expressed regarding an early increased mortality in patients treated with sulfonylureas (67,68). Data from Takago and colleagues suggests that hyperinsulinemia in diabetic patients resulted in increased intimal hyperpla-sia within coronary stents (69) and that use of triglitozone, an agent that increases insulin sensitivity, reduced intimal hyperplasia (70). The ongoing BARI 2D trial in which patients undergoing PCI and medical therapy will be randomized to insulin-providing and insulin-sensitizing treatment strategies may provide some insight into the optimal agent for the post-PCI diabetic patient. Benefits of gly-cemic control in diabetics following CABG have not been carefully studied.

4. Lipid Lowering After Revascularization

Long-term follow-up data from BARI, EAST, and CABRI indicate that after PCI, progression of coronary disease in diabetics is accelerated compared to nondia-betics both at the treated site and in untreated sites (26-28). Although cholesterol lowering did not prove efficacious in reducing post-PCI restenosis in the Lova-statin restenosis trial (71), multiple beneficial effects of cholesterol-lowering therapy have been documented in this population with coronary disease including improved endothelial function and reduced cardiac events (72). More specific to the diabetic patient, in the 4S study, lowering cholesterol resulted in reduced cardiac events (11), inducing a reduction in 5-year mortality that was greater in diabetics than in nondiabetics (43% vs. 29% decrease) (73). A greater benefit in diabetics treated with HMG COA reductase inhibitors was also observed in the CARE and LIPID trials (74,75). In diabetics undergoing stent implantation, use of statins was associated with reduced clinical events and attenuation of neointimal proliferation that appeared in part independent of their cholesterol-lowering properties (76). Statins are currently regarded as first-line drugs in diabetics with elevated levels of LDL cholesterol following PCI.

Abundant data are present in the literature to confirm an important role of elevated serum lipids including LDL cholesterol, HDL cholesterol, triglycerides, apolipoprotein B, and Lp(a) in the development of saphenous vein graft athero- g sclerosis leading to late cardiac events after bypass surgery (77-83). The recently reported Post-Coronary Artery Bypass Graft (Post-CABG) trial showed that aggressive therapy to lower serum cholesterol led to a reduced progression of atherosclerosis in saphenous vein grafts (84) and this study has major implications a for the post-CABG patient. Further analysis of prognostic factors for atheroscle- |

& u rosis progression in saphenous vein grafts in patients in the post-CABG trial identified current smoking, male sex, hypertension, elevated triglycerides, and low HDL as independent predictors of graft worsening (85). The importance of vein graft atherosclerosis in the diabetic population was graphically emphasized in BARI where the 7-year survival of diabetic patients treated with CABG using only saphenous vein grafts was only 54% compared to 83% for patients receiving at least one LIMA graft (see Fig. 6). It is clear, based on BARI and previously reported work (22,34), that diabetics after CABG have a reduced longevity compared to nondiabetics, especially when dependent on saphenous vein grafts. Aggressive measures are indicated in all post-CABG patients to reduce serum LDL, elevate HDL, control blood pressure, lower triglycerides, and strongly encourage smoking cessation. The effects of rigorous glycemic control on cardiac events post-CABG have not been carefully studied.

5. ACE Inhibitors After Revascularization

The HOPE study showed that the use of ramipril in 9297 patients (38% of whom were diabetic) resulted in a significant reduction in a number of adverse endpoints, including mortality, MI, stroke, cardiac arrest, and need for subsequent revascularization (86). The beneficial effects of ACE inhibitors in diabetics may relate to their effect on oxidative stress and vasodilation. ACE inhibitors increase bradykinin levels promoting vasodilation, insulin-mediated glucose uptake, and increased nitric oxide levels (87). Use of ramipril was studied in 159 patients after elective CABG or PCI who had normal blood pressure and an ejection fraction between 30% and 50%, but no congestive heart failure, finding that the ramipril-treated group had a 58% decrease in cardiac death, MI, and CHF (p = 0.03) and a lower all-cause mortality (p = 0.05) (88).

Oosterga and colleagues studied 149 patients undergoing CABG who, like the HOPE study patients, did not have the classic indications for ACE inhibitor therapy (i.e., no hypertension or LV dysfunction). Starting 2 weeks before elective CABG, patients were randomized to receive quinapril 40 mg a day or placebo for 1 year (89). At 1 year, there was a dramatic reduction in ischemic events in the quinapril-treated patients (4% vs. 18%; p = 0.04). These protective effects occurred independent of any effect of quinapril on blood pressure. Studies of carotid intimal thickness in 732 patients >55 years of age who had vascular -o disease or diabetes and at least one additional risk factor showed that, after an average follow-up of 4.5 years, ramipril significantly slowed progression of ath- £

erosclerosis (90). These and other studies indicate that ACE inhibitors are particularly beneficial in diabetic patients with established coronary artery disease and make a strong case for their routine use when the systemic blood pressure is permissive and the drug is well tolerated. Because lipid solubility enhances tissue penetration, lipophilic ACE inhibitors (ramipril, quinapril, trandolapril, and fosinopril) may be most effective in the postrevascularization patient.

6. Beta-Blockers After Revascularization

Beta-blockers have become standard therapy following myocardial infarction in those patients with adequate left ventricular function and are used in low doses following CABG for their antiarrhythmic and anti-ischemic attributes. In diabetic patients, cardioselective beta-blockers are well tolerated and should be used in virtually all postrevascularization patients without contraindications. In the Bezafibrate Infarction Prevention (BIP) study, a substantial portion of the participants had not had prior myocardial infarction and were shown to benefit from beta blockade. Overall, beta blockade resulted in a 50% reduction in mortality in this study (10). Hypertension is prevalent in diabetic patients, and beta-blockers are first-line therapy. The importance of blood pressure control is amplified in the diabetic patients in whom a 10 mmHg reduction in blood pressure translates into an approximate 20% reduction in long-term cardiac events. Because of these potential benefits, beta-blockers are routine therapy for all patients participating in the important BARI 2D trial and should be standard therapy for all diabetic patients without contraindications following revascularization.

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