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Therapeutic Approach in Patients with
Diabetes and Coronary Artery Disease

Martial G. Bourassa, MD

Research Center, Montreal Heart Institute, Montreal, Quebec, Canada

INTRODUCTION
   Diabetes mellitus (DM) is associated with a markedly increased prevalence of coronary artery disease (CAD). The overall prevalence of CAD in diabetics is 2 to 4 times that of nondiabetics (figure 1). It may be as high as 55% among adult patients with DM, compared to 2% to 4% for the general population.

   Diabetes mellitus also represents an independent risk factor for increased mortality and morbidity in patients with CAD. The cardiovascular mortality rate is more than doubled in men and more than quadrupled in women who have DM, compared to their nondiabetic counterparts. In addition, as opposed to other medical conditions in which mortality has stabilized or has decreased in the recent past, age-adjusted death rates from DM are steadily increasing (figure 2).

   Moreover, DM is a recognized risk factor for poor outcome after either percutaneous or surgical coronary revascularization (figure 3). Yet, up to 25% of patients referred for such procedures are diabetics. In spite of tremendous recent progress in these procedures, the optimal therapeutic strategy in diabetics remains controversial.

MEDICAL MANAGEMENT OF CAD IN PATIENTS WITH DM
   It has been shown that, even without prior MI, diabetic patients have the same level of cardiovascular risk as nondiabetics having sustained an MI, suggesting that perhaps all type II diabetics should undergo secondary prevention (tables 1 and 2). However, there is substantial evidence that most patients with DM do not receive optimal recommended treatment, especially regarding the use of lipid-lowering drugs and angiotensin-converting enzyme (ACE) inhibitors.

Behavioral Considerations
   Cigarette smoking is an independent predictor of mortality in patients with DM; thus smoking cessation is strongly recommended for all diabetic patients. 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.

Control of Hyperglycemia
   Recent studies including the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetic Study (UKPDS) have shown 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. In the UKPDS, intensive glycemic control significantly reduced the risk of microvascular complications (by 25%). Diabetes-related mortality and MI incidence were reduced by 10% and 16%, respectively over a 10-year period, but these reductions did not reach statistical significance (table 3).

Lipid-Lowering Therapy
   Although no published studies have specifically investigated the effects of lipid-lowering therapy on the development of CAD in diabetic patients, subgroup analyses of the Scandinavian Simvastatin Survival Study (4S), of the Cholesterol And Recurrent Events (CARE) trial, and of the Long-term Intervention with Pravastastin in Ischemic Disease (LIPID) trial have all indicated, over a 5- to 6-year follow-up period, a greater reduction of major CAD and related atherosclerotic events in diabetics than in nondiabetics. For example, in 4S, 5-year mortality was decreased by 43% in diabetic versus 29% in nondiabetic patients (table 4).

Control of Hypertension
   Recent studies have shown that adequate blood pressure control markedly reduced major cardiovascular events related to macrovascular complications. An important beneficial effect on microvascular disease was also demonstrated in the UKPDS study (table 3). A level around 130/85 is recommended for diabetics and cardioselective beta-blockers and diuretics should be prescribed as first-line therapy.

Other Medical Considerations (table 5)
   The Antiplatelet Trialists' Collaboration Group reported an important benefit of aspirin therapy in diabetics with or at an increased risk for vascular disease. In subgroup analyses of recent trials, diabetic patients with unstable angina or non-Q-wave MI have been shown to benefit at least as much as or more than nondiabetics from low-molecular-weight heparins and glycoprotein IIb/IIIa inhibitors.

   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. These drugs are also effective in reducing mortality when given long-term after MI.

   Subgroup analysis of several studies suggest that ACE inhibition in diabetics with acute MI is associated with larger reduction in short-term mortality and occurrence of congestive heart failure than nondiabetic patients. Similar data support an important long-term benefit of these drugs in diabetics suffering from acute MI with left ventricular dysfunction. The Heart Outcome Prevention Evaluation (HOPE) has shown that, in diabetic patients, the combined endpoint of MI, stroke and cardiovascular death was reduced by 24% with ramipril, an ACE inhibitor (figure 4); progression to overt nephropathy was reduced by 17%, and development of new microalbuminutia was reduced by 10% in this trial.

   Finally, the occurrence of new diabetes mellitus, during the 4.5-year follow-up, was reduced by 31% in the overall HOPE study (figure 5).

   In summary, then, results from recent prospective studies provide 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 INTERVENTION IN PATIENTS WITH SYMPTOMATIC CAD AND DM
   According to the majority of published series, percutaneous coronary intervention (PCI) can be carried out in diabetic patients with a high degree of success in terms of angiographic outcome. Nevertheless, DM is predictive of higher rates of in-hospital complications and restenosis, as well as poor long-term outcome. In the Bypass Angioplasty Revascularization Investigation (BARI), post-PTCA 5-year survival was 73.3% in diabetics versus 91.3% in nondiabetics (p<0.0001), and overall survival was significantly better in diabetic patients randomized to coronary artery bypass grafting (CABG) than in those randomized to PTCA (80.6% versus 65.5%, p=0.003, respectively) (figure 6). Similar results were reported in the Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI), and more recently in the Emory Angioplasty versus Surgery Trial (EAST). Conversely, only a trend toward superiority of CABG was found in the BARI registry and comparable results for CABG and PTCA were reported in the first Randomized Intervention Treatment of Angina-1 (RITA-1) study and in nonrandomized retrospective studies.

   Most studies evaluating coronary stenting in diabetics show that it is associated with favorable procedural and in-hospital success rates. However, angiographic restenosis rates and long-term outcome after stenting may be worse in this patient population. Data related to the usefulness of glycoprotein IIb/IIIa antagonists, with or without coronary stenting, in diabetic patients are limited to subgroups analyses from prospective randomized trials. In the Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications (EPIC) and the Evaluation of PTCA to Improve Long-term Outcome by c7E3 GP IIb/IIIa receptor blockade (EPILOG) trials, abciximab therapy significantly reduced early clinical events after PTCA in diabetic patients. The Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT) showed a significant reduction in major ischemic events and target vessel revascularization at 1 and 6 months following abciximab therapy in stented diabetic patients (figure 7). A recently published report pooling data from all three trials showed an overall 1-year mortality reduction in diabetic patients randomized to abciximab as compared with placebo. Further investigations are needed to explain this interaction of abciximab with DM status, and to determine whether a similar benefit would be seen with other IIb/IIIa antagonists.

CABG IN PATIENTS WITH SYMPTOMATIC CAD AND DM
   DM is a recognized risk factor for poor early and late outcome after CABG and an important
predictor of progression and occlusion of bypassed and nonbypassed coronary segments. BARI has shown that patients with DM and multivessel disease assigned to an initial strategy of CABG have a striking reduction in cardiac mortality compared to PTCA. The survival benefit is limited to diabetic patients receiving an internal mammary artery graft and is related to a protective effect on mortality at the time of myocardial infarction (table 6). As stated previously, two other studies, EAST and CABRI, show results that are consistent with the BARI findings. However, the RITA-1 study, the BARI registry, and some cohort studies found no differences in mortality between CABG and PTCA. The alleged superiority of CABG over PTCA in diabetic patients requires confirmation on additional grounds. Indeed, this observation originated from trials done at the end of the 1980s and beginning in the 1990s, when stents were emerging and the important class of GP IIb/IIIa inhibitors had not been yet developed. As previously suggested, these two important catheter-based advances may significantly influence clinical outcome in future trials. Locally delivered ionizing radiation and gene therapy may also provide potential benefit in this high-risk population. Furthermore, recent treatment advances are not confined to interventional cardiology, as less invasive surgical techniques may offer definite advantages over conventional CABG.

   The final results from the two European randomized trials of stenting versus CABG, Arterial Revascularization Therapy Study (ARTS) and Stent Or Surgery (SOS), will presumably shed new light on coronary revascularization in diabetic patients with multivessel disease. Moreover, the demonstrated benefit of strict glycemic, lipid, and blood pressure control indicates that an aggressive management strategy should be routinely enforced in these patients and that its effects after coronary revascularization should be prospectively evaluated. Data from the ongoing BARI-2D trial, which randomizes diabetic patients in a 2x2 factorial design to coronary revascularization plus aggressive medical therapy versus aggressive medical therapy alone, should answer at least some of the key questions concerning the appropriate therapeutic strategies in this patient population.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
Scientific Committee
President
Dr. Armando Pacher
Technical Committee - CETIFAC
President
fgaro@fac.org.ar
fgaro@satlink.com
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rbretal@netverk.com.ar
apacher@fac.org.ar
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