Efficacy of treatment

Intensive glucose control

Data from the pivotal DIGAMI trial [8] demonstrated that an intensive treatment with insulin-glucose infusion, targeted to achieve a tight control of blood glucose in patients with acute myocardial infarction, is associated with a lower long term morbidity and mortality.

However, control of glucose metabolism does not appear as the sole strategy to follow to prevent the progression of cardiovascular disease and its consequences in diabetic patients: in large prevention studies such as UGPD, DCCT and UKPDS, although tight glucose control was associated with a reduction of microvascular complications in both type 1 (DCCT) and type 2 (UKPDS) diabetes, the reduction of macrovascular complications did not always reach statistical significance, or was limited to specific patients or treatment groups (overweight patients treated with metformin in UKPDS), indicating that targeting abnormalities other than glucose metabolism is a key step in attempting to ameliorate prognosis of diabetics with cardiovascular diseases [9].

Table 1. Significance of acronyms of trials quoted


The Acute Infarction Ramipril Efficacy


Assessment of the Safety and Efficacy of a New Thrombolytic


Angina with Extremely Serious Operative Mortality Evaluation


Bypass Angioplasty Revascularization Investigation


Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction


Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events


Cholesterol and Recurrent Events


Chinese Cardiac Study Collaborative Groups


Cardiac Insufficiency Bisoprolol Study


Cooperative New Scandinavian Enalapril Survival Study


Carvedilol Prospective Randomised Cumulative Survival


Clopidogrel in Unstable Angina to Prevent Recurrent Events


Diabetes Control and Complication Trial


Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction


Evaluation of c7E3 for the Prevention of Ischemic Complications


Evaluation of PTCA to Improve Long-Term Outcome by c7E3 GP IIb/IIIa

Receptor Blockade


Evaluation of Platelet IIb/IIIa Inihibitor for Stenting Trial


Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin



Scandinavian Simvastatin Survival Study


Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico


Global Utilization of Streptokinase and Tissue Plasminogen Activator for

Occluded Coronary Arteries


Heart Protection Study


Long-term Intervention with Pravastatin in Ischemic Disease


Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart


MITRA plus

Maximal Individual Optimized Therapy for Acute Myocardial Infarction


Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist



Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome

Events in a Global Organization Network


Prospective Pravastatin Pooling Project


Platelet Receptor Inhibition in Ischemic Syndrome Management


Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients

Limited by Unstable Signs and Symptoms


Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin



Survival and Ventricular Enlargement


Studies of Left Ventricular Dysfunction


Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial


Trandolapril Cardiac Evaluation


University Group Diabetes Program


United Kingdom Perspective Diabetes Study


Valsartan Heart Failure Trial

Fibrinolytic agents

Fibrinolytic treatment is similarly effective in diabetic and non-diabetic patients. The overview of fibrinolytic trials in acute MI [10] found that fibrinolytic treatment was associated with a 35 days mortality of 13.6% vs. 17.3% in diabetics (-21.7%, or 37 lives saved per 1000 treated patients) and 8.7% vs. 10.2% in non-diabetics (-14.3% or 15 lives saved per 1000 treated patients). The incidence of stroke in diabetics (1.9% in fibrinolytic treated patients vs. 1.3% in control subjects) was higher than in non-diabetics (1.0% vs. 0.6% respectively); however, this increased risk was by far outweighed by the beneficial effect on mortality. On the basis of the available data, in February 2003 the European Committee of Proprietary Medicinal Products (CPMP) issued a position statement highlighting that the increased chance of survival and reduced cardiac morbidity in diabetic patients treated with fibrinolytics outweighs the risk of intraocular haemorrhage. The relative efficacy of newer fibrinolytic treatment regimens has been determined in several trials, such as GUSTO-IV ASSENT-2 and others, all showing that there was no specific clinical advantage of newer fibrinolytics such as reteplase or tecneteplase over standard thrombolytic treatment.

Aspirin, glycoprotein Ilb/IIIa antagonists and clopidogrel The role of aspirin as first-line therapy in the treatment of ACS patients with diabetes has been firmly established. The antiplatelet trialists' collaboration overview on patients with unstable angina, acute MI, prior MI, stroke or transient ischemic attack indicated a similar benefit (38 vs. 36 vascular events saved /1000 treated patients) in diabetics vs. non-diabetics [11]. However, the optimal dosage in the diabetic population remains unclear, since these patients tend to have a higher platelet aggregability. In the last years research has focussed on selective antiplatelet agents, such as the glycoprotein (GP) Ilb/IIIa antagonists, particularly in patients with non-STEMI. A meta-analysis [12], including data on a total of 6458 diabetic patients (22% of the enrolled population) from the 6 large-scale platelet GP IIb/IIIa inhibitor non-STEMI ACS trials (i.e. PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT and GUSTO-IV) demonstrated that these agents may significantly reduce mortality at 30 days among diabetic patients. Platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days in diabetic (from 6.2 to 4.6%, p = 0.007), but not in non-diabetic patients (3.0 vs. 3.0%). The most marked benefit from active therapy was documented in 1279 diabetic patients undergoing percutaneous interventions (PCI) during hospitalisation (20% of the diabetic population), with a significant mortality reduction at 30 days in patients treated with these agents (from 4.0 to 1.2%). These observations confirm and expand the results of previous studies, showing a mortality reduction with abciximab, eptifibatide and tirofiban in diabetic patients undergoing coronary stenting. A pooled analysis of EPIC, EPILOG and EPISTENT showed a mortality reduction from 4.5% to 2.5% (p = 0.031) at 1 year in diabetic patients undergoing PCI [13]. Results from the ESPRIT trial [6] suggest that selective GP IIb/IIIa inhibition with eptifibatide is equally effective in ACS patients with or without diabetes undergoing coronary stenting in reducing the composite endpoint of death, MI, urgent target vessel revascularisation or thrombotic bailout at 48 hours.

Data from comparative trials indicate that there are no major differences among GP IIb/IIIa antagonists: results from the TARGET trial [14] suggest that tirofiban and abciximab are equally effective and well-tolerated in patients with coronary disorders and diabetes undergoing PCI, with comparable 1-year mortality rates.

Other antiplatelet agents, like the thienopyridine derivatives ticlopidine and clopidogrel, have been shown to reduce the recurrence of ischemic events in ACS patients: the CAPRIE study [15] demonstrated that clopidogrel reduced the combined risk of ischemic stroke, myocardial infarction, and vascular death to a greater extent than aspirin in patients with recent ischaemic stroke, recent myocardial infarction or peripheral arterial disorders (RR = 19%, p < 0.01). A subgroup analysis of the CAPRIE results, limited to patients with diabetes (n = 3866), confirmed the superiority of clopidogrel in reducing ischemic events in this high-risk population (RR = 13%, p < 0.05) [16].

In patients undergoing percutaneous coronary angioplasty (PTCA) with stenting (see also paragraph below), short-term aspirin treatment plus clopidogrel resulted in a substantial lower rate of myocardial infarction than did either aspirin alone or warfarin [17]. The role of long term combined therapy with aspirin and an antiplatelet agent like clopidogrel in ACS patients with non-STEMI has been investigated by the CURE trial [18]: the first primary outcome, death from cardiovascular causes, non-fatal myocardial infarction or stroke, was significantly reduced in the clopidogrel group as compared with the placebo group (RR = 0.80, p < 0.001). The benefits of adding clopidogrel to the standard treatment regimen for ACS patients were in addition to those of aspirin and were consistent in a number of patient subgroups, including that of patients with diabetes.

Percutaneous Coronary Angioplasty and Coronary Artery Bypass Grafting A history of diabetes is associated with a higher incidence of complications during PTCA and to increased morbidity and mortality during follow-up. Interestingly, in the BARI trial [19] in patients with multivessel disease, diabetic patients treated with PTCA had a higher incidence of 5-year mortality as compared with patients undergoing coronary artery bypass grafting (CABG) (34.5 vs. 19.4%, RR = 1.87, p < 0.01), whereas no difference was observed in non-diabetic patients using the two different approaches. Based on these results, current guidelines favour CABG over percutaneous interventions (PCI) for the treatment of diabetics with multivessel coronary artery disease. However, the recent findings of the AWESOME randomised trial and registry [20] challenge this approach, showing that diabetic patients with medically refractory unstable angina and risk factors for adverse outcomes with bypass have a similar short- and long-term survival whether they undergo PCI or CABG (97 vs. 92% at 30 days; 81 vs. 72% at 36 months). The difference between the results of the BARI and AWESOME trials likely resides in the fact that the BARI study compared CABG with baloon angioplasty rather than contemporary PCI (including stenting and GP IIb/IIIa receptor blockers), and excluded patients who were at higher risk of adverse outcomes with bypass surgery. In light of the AWESOME results, PCI appears as a relatively safe alternative to CABG for diabetic patients with medically refractory unstable angina who are at high risk for CABG.


Beta-blockers are able to reduce post-MI mortality in diabetic patients, with an absolute and relative beneficial effect in most cases larger than that observed in non-diabetics. Current evidence is based on subgroup analysis of several trials performed during the eighties and on non-randomized studies [21], in which the population of patients with diabetes was scarcely represented. However, the pooled data indicate a 37% mortality reduction during the acute phase (13% in non-diabetics) and a 48% mortality reduction post-discharge (33% in non-diabetics). Since all these studies were performed before the advent of fibrinolytic therapy, the question remains whether this marked beneficial effect is still present in more "updated" populations. In a recent observational study conducted on 613 MI survivors with diabetes [22], use of beta-blockers (recorded in 53% of patients with diabetes) was associated with a 27% risk reduction in the incidence of a new coronary event, adjusted for age, sex, history of hypertension, body mass index (BMI) and blood lipids (p = 0.0001).

The use of beta-blockers in diabetic patients post-MI also decreases the risk for the development of heart failure, as documented by a large observational study of more than 13,600 patients with a mean age of 76 years and a high comorbidity index (including diabetes), documenting a 43% reduction of 1-year hospital admissions for heart failure in patients given beta-blockers compared with those not receiving these agents [23]. The results of the CAPRICORN trial [24] recently provided further evidence of the benefits of beta-blockers in patients post-MI with high risk of heart failure and left ventricular systolic dysfunction. Treatment with carvedilol 6.25-25 mg/day, started 3-21 days after the onset of MI, significantly decreased all-cause mortality (RR = 0.77, p = 0.03) as well as cardiovascular mortality and recurrence of non-fatal MI. Although 22% of patients in this study had diabetes, no subgroup analysis on diabetic patients has been published so far.

Agents acting on renin-angiotensin system

The studies in which ACE-inhibitors have been started within 24 to 36 hrs after the onset of acute MI symptoms showed an overall reduction of about 5 deaths for 1000 treated patients. In the GISSI-3 study [25], treatment with lisinopril was associated with a decreased 6-week mortality both in type 1 (11.8% vs. 21.1%, p < 0.05) and in type 2 diabetes (8.0% vs. 10.6%, p < 0.05), corresponding to a 44.1 and 24.5% reduction, respectively. The meta-analysis by the "ACE-inhibitor in MI Collaborative Group" [26], including data from GISSI-3, CCS-1 and CONSENSUS-2, confirmed that the subgroup of patients with diabetes experienced a 30 days lower mortality (10.3 vs. 12.0%, or 17.3 lives saved per 1000 patients) when treated early with an ACE-inhibitor.

The one and only head to head trial of ACE-inihbibitors vs. angiotensin II receptor antagonists (AIIRA) currently available in the post-MI setting is OPTIMAAL [27], a multicentre study comparing the treatment effects of losartan 50 mg once daily and of captopril 50 mg three times daily on mortality and morbidity in patients with evidence of heart failure or left ventricular dysfunction after acute myocardial infarction. A non significant trend toward lower total mortality (the primary endpoint) was seen in favour of captopril; however, in the subgroup of diabetic patients risk ratio was very close to one, suggesting a substantial equivalence of the two therapeutic options in this subgroup of patients.


Three studies, the 4S [28], CARE [29] and LIPID [30] trials, evaluated the effect of statins in reducing morbidity and mortality in patients with an history of ischemic heart disease (mainly previous MI). The main difference among these trials lies in the cut-off of cholesterol level for enrolment, that was much tighter for 4S than for CARE or LIPID. In all trials diabetics had a worse outcome compared to non-diabetics; also, in all trials, the reduction in mortality was proportionally at least similar to that observed in non-diabetics. A subsequent pooled analysis of data from CARE and LIPID, prospectively combined in the PPP Project [31], showed a significant reduction of coronary events in patients treated with pravastatin irrespective of diabetes status, with relative risk reductions ranging from 17 to 25%.

Finally, in the HPS trial [32], comparing simvastatin 40 mg daily to placebo in high risk patients irrespective of their cholesterol levels, the rate of first occurence of any major vascular event (non-fatal myocardial infarction or coronary death, non-fatal or fatal stroke, coronary or non-coronary revascularisation) was significantly reduced by simvastatin. The beneficial effect was maintained also in the different subgroups of high risk patients and particularly in diabetics with prior MI or other CHD (33.4% vs. 37.8%).

CONGESTIVE HEART FAILURE Pathophysiology and Prognosis

The interest toward this clinical condition has grown recently mainly due to the increasing prevalence of this disease as a consequence of chronic ischemic heart disease, to the better understanding of pathophysiological mechanisms responsible for its evolution and to the availability of drugs that appear to markedly improve prognosis.

Again, data obtained in diabetic patients with CHF have been gathered mainly through the post-hoc analysis of clinical trials in patients with overt or silent CHF. There is strong evidence indicating that ischemic heart disease in diabetics, particularly in the post-MI setting, is associated with an increased incidence of CHF, which is not explained by a greater propensity for left ventricular remodelling, as shown by the echocardiographic substudy of the SAVE trial [33]: among post-MI patients, left ventricular enlargement between baseline and 2 years was lower in diabetic than non-diabetic patients (p < 0.05), although CHF developed in 30% of diabetic and in 17% of non-diabetic patients during follow-up (p<0.001). Moreover, in patients who developed CHF, left ventricular diastolic and systolic dilatation were greater in non-diabetic than in diabetic patients. These data suggest that the diabetic heart may be less capable of adapting to the loss of stroke volume by dilating than non-diabetic heart and thus may be less able to restore stroke volume after MI, leading to increased filling pressures with the same degree of contractile loss.

Analysis of crude mortality and morbidity rates in diabetics vs. non-diabetics with CHF indicates that diabetics have a worse outcome. For example, a metaanalysis of the major trials in this setting [34], including about 13,000 patients from SAVE, AIRE, TRACE, and a subpopulation of SOLVD trials, showed mortality of 36.4% in diabetics and 24.7% in non-diabetics. The relative role of concomitant risk factors in this setting remains undefined.

Efficacy of treatment

Together with diuretics, two classes of drugs are critical in the management of patients with heart failure: agents acting on renin-angiotensin system (ACE-inhibitors and AIIRA), which are now indicated in all classes of CHF patients, and beta-blockers, whose efficacy in reducing morbidity and mortality has rapidly emerged from the latest trials.

Agents acting on renin-angiotensin system

The landmark 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 sub-analysis of the SOLVD trial showed that ACE-inhibitors are as effective in diabetics as in non-diabetics in reducing mortality and hospitalisation rates [35]. More recently, the attention of researchers shifted toward patients with overt CHF and/or left ventricular dysfunction resulting from acute MI. All the "long-term" studies enrolling patients with left ventricular dysfunction some time after MI have shown a significant benefit of ACE-inhibitor therapy, with a risk reduction in mortality of 19 to 27% over a 2.5-4 years follow-up. The meta-analysis of the major trials in this setting mentioned earlier [34] indicates 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. More in detail, the benefit per 1000 patients was 36 in the 10,501 non-diabetics and 48 in the 2282 diabetics.

The recently published VaAlL-HeEFT trial [36] evaluated the long-term effects of the addition of the AIIRA valsartan to standard therapy for heart failure in a total of 5010 patients with CHF (NYHA class II-IV), randomly assigned to receive 160 mg of valsartan or placebo twice daily. The primary outcomes were overall mortality and the combined endpoint of mortality and morbidity. Overall mortality was similar in the two groups, whereas the incidence of the combined endpoint was 13.2% lower in the valsartan than in the placebo group (RR= 0.87, p = 0.009), predominantly because of a lower number of patients hospitalised for heart failure (13.8 vs. 18.2%, p < 0.0001). The beneficial effect of valsartan on the combined mortality-morbidity endpoint was generally consistent among predefined subgroups of patients, although the effect in diabetics seemed less pronounced than in non-diabetics.


For many years beta-blockers have been contraindicated in CHF patients, and even more so in diabetic patients, where the accentuation of altered lipid levels induced by these drugs and the fear of masking hypoglycaemic episodes have been considered strong contraindications to their use; however, the pioneering work performed in the seventies and the eighties particularly by Scandinavian groups led the way to their targeted use in patients with asymptomatic or overt CHF. A variety of large randomized trials on beta-blockers have included diabetic patients groups. In the MERIT-HF study [37], the proportional effect of the beta-blocker metoprolol was similar in diabetics as in non-diabetics. Consistent results were obtained with bisoprolol in CIBIS II [38] and carvedilol in COPERNICUS [39]. In this latter trial, enrolling patients with severe CHF, the risk reduction of total mortality was identical (35%) in both non-diabetic and diabetic patients. Therefore, it seems that the effect of beta-blockers is prominent irrespective of the diabetic status.

Table 2. Pharmacological agents in diabetic patients with ACS, post-MI, and overt CHF

Prevention of

Treatment of

Treatment of

Treatment of

ACS in high-


MI post-

overt CHF

risk patients













GP IIb/IIIa antagonists






























* efficacy evaluated only in patients with left ventricular dysfunction +++ efficacy higher than that in non-diabetics

++ efficacy similar to that in non-diabetics + efficacy lower than that in non-diabetics NA not applicable

* efficacy evaluated only in patients with left ventricular dysfunction +++ efficacy higher than that in non-diabetics

++ efficacy similar to that in non-diabetics + efficacy lower than that in non-diabetics NA not applicable

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