Natural History of Coronary Artery Disease in Diabetes

The incidence of many manifestations of coronary artery disease (angina, myocardial infarction (MI) and sudden death) is increased in patients with type 1 and type 2 diabetes. These manifestations are more marked in women than men and CVD may be present at diagnosis of diabetes before other macro- or microvascular complications are evident.

Data on the development of clinically evident atherosclerotic disease in diabetic compared with nondiabetic subjects are somewhat controversial; in general, studies have shown that diabetics usually have more diffused disease with higher degree of coronary atherosclerosis with more triple vessel disease and fewer normal vessels.

This more severe coronary artery disease may not lead to an increased incidence of anginal symptoms because ischemia in diabetic patients may be more often silent and only discovered at exercise testing or nuclear medicine imaging. In general, patients taking insulin or with signs of organ damage (i.e. retinopathy) are at greater risk of silent ischemia: diabetic autonomic neuropathy may be one of the major factors involved. Diabetic patients with silent ischemia have a worse prognosis than nondiabetics (for example, 6-year survival was 59 vs. 82% in the CASS study).

Clinical Manifestations of CVD in Diabetic Patients

Acute Myocardial Infarction (MI ) The difference in post-MI survival between diabetic and nondiabetic pa-

tients, documented by several studies performed before the introduction of fibrinolysis, remains mostly unaffected, despite the widespread use of fibri-

nolytic agents and aspirin, which led to a marked improvement in the prognosis of acute MI patients. Data from the GISSI-2 and GUSTO-1 trials, in which

Fig. 1. Factors contributing to increased mortality in diabetic patients with acute MI.

all patients received fibrinolytic agents, show a 30–100% higher in-hospital mortality in diabetic patients compared to nondiabetics.

It appears that, although concomitant risk factors such as advanced age, history of hypertension, hyperlipidemia and increased body mass index may exert a confounding effect and contribute to a decreased survival post-MI, diabetes per se exerts an independent negative role, as consistently documented in all studies.

Mechanisms for increased mortality are shown in figure 1. Interestingly these data obtained in multicenter randomized studies, where selected patients usually receive state-of-the-art treatment, leading often to mortality rates well below the one observed in the general population, have been confirmed by observational studies where mortality rates more closely reflect those observed in current clinical practice. In the Finmonica study, 45.1% diabetic men and 38.8% diabetic women with their first MI died within 1 year, as compared to

32.6 and 20.2% in nondiabetic patients. A substantial proportion of these deaths occurred out of hospital soon after the onset of symptoms. Survival is closely linked to residual left ventricular pump function following acute MI. The increased susceptibility to cardiac failure (a 4-fold increase for women in the Framingham Study) is an important factor in reducing survival in diabetics. Two factors may explain the increased incidence of heart failure post-MI. First, more severe and diffuse coronary disease limits the coronary reserve causing noninfarcted segments to be rendered more ischemic by an infarct of comparable size. Secondly, coexistent diabetic cardiomyopathy, which is independent of the coronary disease, impairs myocardial relaxation and contractility.

Fig. 2. Event-free survival curves in the BARI trial for diabetic (TDM) and nondiabetic (all others) patients.

Unstable Angina There are few conclusive data concerning the impact of diabetes on the

prevalence or outcome of unstable angina. However, patients with diabetes who have unstable angina have increased morbidity compared with their nondiabetic counterparts. The suggestion that diabetes worsens the prognosis of unstable angina, but does not increase the incidence, is supported by other data that examine diabetic patients as subgroups in studies of unstable angina.

Coronary Angioplasty (PTCA) and Coronary Bypass Grafting (CABG )

A history of diabetes is associated with a higher incidence of complications during PTCA and CABG and to increased morbidity and mortality during follow-up. The mechanisms responsible for an increased incidence of restenosis after PTCA are several. Interestingly, in the BARI trial comparing PTCA and CABG in patients with multivessel disease, diabetic patients treated with PTCA had a higher incidence of mortality (35 vs. 19%, p=0.02) as compared with CABG, whereas no difference was observed in nondiabetic patients (fig. 2).

A further analysis of the data indicated that the difference was mainly due to

a lower mortality for the patients undergoing internal mammary grafting, whereas patients with saphenous vein grafts only had a similar mortality compared to patients treated with PTCA. In contrast, data from a large consecutive series of patients in one center did show that diabetics (24% of the total population) had a worse outcome after both PTCA and CABG, with an effect that was similar in both treatment groups, thus questioning the data a lower mortality for the patients undergoing internal mammary grafting, whereas patients with saphenous vein grafts only had a similar mortality compared to patients treated with PTCA. In contrast, data from a large consecutive series of patients in one center did show that diabetics (24% of the total population) had a worse outcome after both PTCA and CABG, with an effect that was similar in both treatment groups, thus questioning the data

Heart Failure Several studies documented an increased incidence of heart failure even

in the absence of overt ischemic heart disease. Epidemiological data from the Framingham Study show that diabetic subjects have a much higher risk of developing heart failure. Men aged 45–74 had a 2-fold increased risk and women had a 5-fold increase in risk.

Diabetic cardiomyopathy presents with features of systolic and diastolic dysfunction, although the diastolic filling defect predates the development of systolic ventricular dysfunction. Diastolic dysfunction is related to the duration of diabetes. As already discussed, heart failure is also common in patients with diabetes mellitus and is more common than expected following MI. Two reasons which have been postulated to explain this are, firstly, the extent and severity of the occlusive coronary artery disease and secondly, the presence of a specific diabetic heart muscle disease.

Management of CVD in Diabetic Patients

Treatment of Diabetic Patients with Acute MI So far, only one prospective study, the DIGAMI trial (see below) evaluated

specifically the effect of pharmacological treatment on prognosis of diabetic patients after acute MI, while most of the information on the effect of commonly used cardiovascular drugs in diabetics with MI has been obtained only from retrospective subgroup analyses of some large trials or as nonrandomized comparisons between control and drug-treated patients. The evidence for several classes of drugs will be discussed below.

Insulin-Glucose Infusion. In the DIGAMI study, 620 diabetic patients were randomized to receive either standard treatment (n>314) or an intensive treatment (n>306) with insulin-glucose infusion targeted to achieve a tight control of glycemic levels. The insulin treatment was then continued long term. Data showed that this ‘intensive’ hypoglycemic treatment was associated with

Fig. 3. Mortality curves in the DIGAMI trial.

a lower 1-year morbidity and mortality (8.6 vs. 18.0% intensive vs. traditional treatment, p>0.020) and that the beneficial effect was even more evident

during long-term follow-up (fig. 3). The effect was most pronounced among the predefined group (n>272) without previous insulin treatment and at a

low cardiovascular risk (RR>0.49, p>0.004). Fibrinolytic Agents. For many years diabetes represented a relative contra- indication to the use of fibrinolytic agents, based on the fear their use would lead to an unacceptable rate of hemorrhages (cerebral and retinal). However, the relative decrease in mortality of diabetics with fibrinolytic treatment has been at least similar to that observed in nondiabetics: the overview of fibrinolytic trials in acute MI found that fibrinolytic treatment was associated with

a 35-day mortality of 13.6 vs. 17.3% in diabetics (–21.7%) and 8.7 vs. 10.2% in nondiabetics (–14.3%). Of note, the incidence of stroke in diabetics is doubled that of nondiabetics (1.0 vs. 0.6%, respectively); however, this increased risk is by far outweighed by the beneficial effect on mortality. The relative efficacy of newer fibrinolytic treatment regimens in this population remains to be determined.

Aspirin and Other Antiplatelet Agents. Aspirin’s effect in primary prevention trials has been investigated in a subgroup analysis of the Early Treatment

Diabetic Retinopathy Study which showed a nonsignificant reduction in MI but no conclusive impact on all-cause mortality.

The role of aspirin as first-line therapy in the treatment of patients with acute MI has been firmly established. However, the optimal dosage in the diabetic population remains unclear. Interestingly, in ISIS-2 there was no reduction in mortality among diabetic patients receiving aspirin 160 mg daily compared with a 20% reduction in nondiabetic patients. On the other hand, aspirin 325 mg in the GISSI-3 trial (a nonrandomized treatment) was associated to an independent beneficial effect on 6-week mortality. Increased platelet turnover may be one explanation for this disparity, as 300 mg of aspirin may

be necessary to effectively suppress thromboxane A. The antiplatelet trialists collaboration overview on patients with unstable angina, acute MI, prior MI,

stroke or transient ischemic attack indicate a similar benefit (38 vs. 36 vascular events saved/1,000 treated patients) in diabetics vs. nondiabetics. Taken to- gether, these data would suggest that the beneficial effect of aspirin is maintained in diabetics, but the optimal dosage remains speculative.

Attention has recently shifted toward selective antiplatelet agents, such as the glycoprotein IIb/IIIa antagonists. Preliminary data from subgroup analysis of the several trials in acute coronary syndromes recently completed suggest that these agents are as effective in diabetic as in nondiabetic patients.

b -Blockers. b-Blockers are able to reduce mortality post-MI in diabetic patients, with an absolute and relative beneficial effect in most cases larger than that observed in nondiabetics. The pooled data indicate a 37% mortality reduction during the acute phase (13% in nondiabetics) and a 48% mortality reduction postdischarge (33% in nondiabetics). Since all these studies have

been performed before the advent of fibrinolytic therapy, they would need confirmation with current therapy. Data from a subgroup analysis of the DIGAMI study showed a relative risk of dying for patients on b-blockers of

0.62 (95% CI 0.39–0.98). Also, data from the GISSI-3 trial in a total of 2,553 diabetic patients discharged alive from the hospital (25% of them on b-blockers) showed a survival benefit in diabetic patients taking b-blockers at discharge (3.6 vs. 7.6% mortality). These data point to a protective effect of b-blocker treatment even in the fibrinolytic era.

ACE Inhibitors. Recent trials used ACE inhibitors as a new therapeutic strategy in an attempt to reduce mortality and morbidity after acute MI. In the GISSI-3 study, treatment with lisinopril was associated with a decreased 6-week mortality in both type 1 (11.8 vs. 21.1%, p=0.05, n>496) and type 2 (8.0 vs. 10.6%, p=0.05, n>2294) patients corresponding to a 44.1 and 24.5% reduction, respectively. The beneficial effect of the early use of an ACE inhibitor was mostly maintained at 6 months and after 4 years despite with- drawal of the treatment at 6 weeks. The metaanalysis by the ‘ACE inhibitor in MI Collaborative Group’ including data from GISSI-3, CCS-1 and CON- SENSUS-II trials, confirmed that the subgroup of diabetic patients experi- ACE Inhibitors. Recent trials used ACE inhibitors as a new therapeutic strategy in an attempt to reduce mortality and morbidity after acute MI. In the GISSI-3 study, treatment with lisinopril was associated with a decreased 6-week mortality in both type 1 (11.8 vs. 21.1%, p=0.05, n>496) and type 2 (8.0 vs. 10.6%, p=0.05, n>2294) patients corresponding to a 44.1 and 24.5% reduction, respectively. The beneficial effect of the early use of an ACE inhibitor was mostly maintained at 6 months and after 4 years despite with- drawal of the treatment at 6 weeks. The metaanalysis by the ‘ACE inhibitor in MI Collaborative Group’ including data from GISSI-3, CCS-1 and CON- SENSUS-II trials, confirmed that the subgroup of diabetic patients experi-

Calcium Antagonists. Calcium antagonists have always been considered as a rather homogeneous class, despite the well-known pharmacodynamic and pharmacokinetic differences, particularly between nondihydropiridines and dihydropiridines. These differences are most apparent in terms of the relative action of these agents at myocardial vs. vascular level, but may include effects also at renal level that can be important particularly for the diabetic patient. For example, a recent study has shown that diltiazem, but not nifedipine, is able to reduce microalbuminuria in diabetic patients. Several trials have been performed with calcium antagonists in acute MI and, in general, nondihydropi- ridine (‘heart rate lowering’) calcium antagonists proved to be neutral or effective in patients recovering from acute MI, short-acting dihydropiridines were detrimental in the acute MI setting and long-acting dihydropiridines were neutral in patients with congestive heart failure. Data in the diabetic subpopulation seem to mirror those obtained in nondiabetics.

Statins. Three recent studies, the 4S, CARE and LIPID trials, evaluated the effect of statins in reducing morbidity and mortality in patients with a

history of ischemic heart disease (mainly previous MI). The main difference between these trials lies in the cut-off cholesterol level for enrollment, that was much tighter for 4S than for CARE or LIPID. In all the trials diabetics had a worsened outcome compared to nondiabetics; also the reduction in mortality was proportionally at least similar to that observed in nondiabetics. In the 4S study a 42% reduction in the incidence of death was observed in diabetic patients compared to 27% in nondiabetics; in the CARE study mortality reductions were –25% nondiabetics and –23% diabetics. Despite the obvious limitations of this post-hoc analyses, these data suggest that statins confer long-term protection from cardiovascular events in diabetic patients recovering from MI at least to the same extent as in nondiabetics.

In summary, there appears to be compelling evidence for the use of statin therapy post-MI in diabetic subjects. There is also growing evidence for lipid- lowering therapy in the primary prevention of CVD, although we are restricted to drawing conclusions from subgroup analyses of large trials.

Treatment of Diabetic Patients with Chronic Ischemic Heart Disease As discussed earlier, diabetic patients with ischemic heart disease have a

higher prevalence of silent ischemia and a more diffuse pattern of atheroscle- higher prevalence of silent ischemia and a more diffuse pattern of atheroscle-

Drugs commonly used in the treatment of chronic myocardial ischemia include b-blockers, nitrates and calcium antagonists. Surprisingly, data on morbidity and mortality in diabetic patients are available only for b-blockers:

a post-hoc analysis of the BIP Study showed their usefulness in patients with diabetes and coronary artery disease. Total mortality during a 3-year follow- up was 14% in patients who were not on b-blockers and 7.8% in those patients receiving b-blockers (a 44% reduction). After multiple adjustment, RR of b- blocking treated patients were 0.58 (95% CI 0.46–0.74). Overall, the striking beneficial effect of b-blockers in diabetic patients with ischemic heart disease challenges the view that these drugs are not a first choice in these patients because of their ‘detrimental’ effect on the glycolipidic metabolism and the risk of masking hypoglycemic episodes

Data on the effect of calcium antagonists on ‘hard endpoints’ in diabetic patients with ischemic heart disease are still missing; however, very recent data from trials performed in hypertensive type 2 diabetics such as ABCD and

FACET raised an alarm bell concerning morbidity due to ischemic heart disease in patients treated with dihydropiridines since in several instances the incidence of cardiac events such as acute MI was documented to be significantly higher than that observed in patients treated with other cardiovascular drugs such as ACE inhibitors or diuretics. On the other hand, data with nitrendipine obtained in the SYST-EUR trial lead to a major protective effect in diabetic elderly with isolated systolic hypertension.

Treatment of Diabetic Patients Undergoing PTCA or CABG So far, no conclusive data are available to indicate the best pharmaco-

logical treatment to prevent restenosis in these settings. Studies with ACE inhibitors, calcium antagonists or statins usually failed to show any consistent effect of these agents in reducing the incidence of restenosis or morbidity during long-term follow-up. Recent data from the EPILOG study indicate that the antithrombotic agent abciximab is effective in preventing restenosis in nondiabetic, but not in diabetic patients. All other available data do suggest that the efficacy (or lack of efficacy) of different agents is similar irrespective of the diabetic status of patients. Thus, currently the treatment of diabetic patients undergoing PTCA and also CABG mirrors that of nondiabetic patients. In particular, no data are available to indicate whether a careful control of blood glucose during the peri-intervention period would decrease morbidity and mortality.

Treatment of Diabetic Patients with Heart Failure As for data after MI, all available data on diabetic patients with heart

failure are available from post-hoc subgroup analyses. The main data are reviewed here.

ACE Inhibitors. The landmark ramdomized studies in the evaluation of the efficacy of ACE inhibitors were performed in the eighties and early nineties,

when the CONSENSUS, SOLVD treatment and SOLVD prevention trials were completed. A subanalysis of the SOLVD trial and registry showed that ACE inhibitors are as effective in diabetics as in nondiabetics in reducing mortality and hospitalization rates. The attention of researchers then shifted toward testing ACE inhibitors in patients with left ventricular dysfunction resulting from acute MI. All the studies have shown a significant benefit of ACE inhibitor therapy, with a risk reduction in mortality of 19–27% over a

2.5- to 4-year follow-up. The meta-analysis of the major trials in this setting, including SAVE, AIRE and TRACE studies, indicate that the beneficial effect

of ACE inhibitors documented in the overall population is present also when limiting the analysis to patients with a history of diabetes. Mortality was 36.4% in control and 31.6% in ACE inhibitor-treated patients, respectively, corresponding to an RR of 0.81; 95% CI 0.68–0.97.

b -Blockers. For many years b-blockers have been contraindicated in chronic heart failure (CHF) patients, and even more so in diabetic patients; however, the pioneering work performed in the seventies and eighties, particularly by Scandinavian groups, led the way to their targeted use in patients with asymptomatic or overt CHF. A retrospective analysis performed by Kjekshus et al. showed that diabetic patients with CHF post-MI benefited even more than those with preserved left ventricular function. The MOCHA trial, a randomized study comparing different doses of carvedilol with placebo, reported that the treatment was associated to a dramatic decrease in mortality, that was most evident in diabetic patients, with a 6.1% mortality after a median of 6 months, compared to a 30% mortality in the control group. These data would suggest that diabetic patients with CHF are among the ones who benefit most from a treatment with b-blockers.

Natural History of Coronary Artery Disease in Diabetes