1-s2.0-S1521690X09000049-main

Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 305–316

Contents lists available at ScienceDirect

Best Practice & Research ClinicalEndocrinology & Metabolism

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2

Diabetes and acute coronary syndromes

Marco Roffi, MD, Director *, Franz R. Eberli, MD, Professor,Chairman of CardiologyUniversity Hospital, Geneva, Switzerland

Keywords:Diabetesacute coronary syndromesanti-platelet therapycoronary re-vascularisation

* Corresponding author. Interventional Cardiolog1211 Geneva, Switzerland. Tel.: þ41 22 37 27 208;

E-mail address: [email protected] (M. Roffi)

1521-690X/$ – see front matter � 2009 Elsevier Ldoi:10.1016/j.beem.2009.01.003

Diabetic patients with acute coronary syndromes (ACSs) are ata high risk for subsequent cardiovascular events but derive, at thesame time, greater benefit from evidence-based therapy than non-diabetic individuals. State-of-the-art anti-thrombotic therapyincludes a triple anti-platelet combination – aspirin, clopidogreland glycoprotein (GP) IIb/IIIa receptor inhibitors – and unfractio-nated heparin or enoxaparin. For low- or medium-risk individuals,a treatment based on aspirin, clopidogrel and bivalirudin isa valuable alternative. Prasugrel, a new and more potent inhibitorof the platelet P2Y12 receptor, has to be regarded as the mostpromising anti-thrombotic agent for diabetic patients with ACS.This agent may replace clopidogrel – and possibly GP IIb/IIIainhibitors – in the future. In addition to aggressive anti-thrombotictherapy, diabetic patients should undergo systematic early invasiveangiography if presenting with non-ST-segment elevation ACS, andimmediate percutaneous coronary intervention if presenting withST-segment elevation myocardial infarction. Indeed, the benefitderived from these strategies appears to be more pronounced inthe diabetic population than in non-diabetic individuals. Despitethe benefit, multiple surveys have demonstrated that, in thesetting of ACS, diabetic patients receive evidence-based therapyless frequently than non-diabetic counterparts.

� 2009 Elsevier Ltd. All rights reserved.

Prevalence and outcomes

The high prevalence of disturbances in glucose metabolism in patients with acute manifestationsof coronary artery disease (CAD) has been confirmed in large-scale surveys. In the Euro Heart Survey,

y Unit, Division of Cardiology, University Hospital, Rue Micheli-du-Crest 24,Fax: þ44 22 37 27 229..

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glucose metabolism was assessed in 2854 patients with stable CAD and 2107 patients with acutecoronary syndromes (ACSs).1 The overall prevalence of diabetes was approximately 30% both in thestable and the unstable CAD group. Among patients with ACS and no known diabetes, oral glucosetolerance test detected impaired glucose tolerance and diabetes in 36% and 22% of cases, respectively(in the stable disease group those proportions were 37% and 14%, respectively (Fig. 1)).1 In theCRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes withEarly implementation of the ACC/AHA guidelines) registry, enrolling 46,410 patients with non-ST-elevation ACS, the prevalence of diabetes was 33%.2 In the US-based National Registry of MyocardialInfarction (NRMI), the prevalence of diabetes among patients presenting with ST-elevationmyocardial infarction (STEMI) and non-ST-elevation myocardial infarction (MI) was 27% and 34%,respectively.3

The prevalence of characteristics and comorbidities that may negatively impact the outcomes ofACS are higher among diabetic than among non-diabetic individuals.4 However, after accounting forsuch differences, several studies have demonstrated that diabetes remains an independent predictor ofmorbidity and mortality. With regard to non-ST-elevation ACS, these findings were recently replicatedin the CRUSADE registry (Table 1).4 Diabetic patients, not only during the acute phase but also duringlong-term follow-up, remain at significantly higher risk of death, MI, stroke and heart failure comparedwith non-diabetics.5 Data from the Euro Heart Survey suggest that the mortality is particularly high indiabetic women.6 Importantly, in the setting of ACS, the cardiovascular (CV) risk increase associatedwith glucose metabolism abnormality begins at the stage of pre-diabetes (i.e., fasting glucose levelsbetween 100 and 126 mg dl�1).7

Paralleling the observations for the non-ST-elevation ACS setting, diabetic STEMI patients sufferworse acute and long-term outcomes compared with non-diabetic individuals. Within the GlobalUtilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO 1)trial, which enrolled almost 40,000 patients (5944 with diabetes) undergoing fibrinolytic therapy, the30-day mortality rates among patients with no diabetes, diabetic individuals not treated with insulinand insulin-requiring diabetic patients were 6.2%, 9.7% and 12.5%, respectively (p< 0.001).8 Aftercorrecting for imbalances in baseline characteristics, diabetes remained an independent predictor formortality at 1 year (odds ratio [OR]: 1.6). In addition, heart failure, shock, atrioventricular block andatrial fibrillation were all more common among diabetic patients. Similar findings were reported inanother large-scale thrombolytic trial, the Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto

Fig. 1. Prevalence of abnormal glucose regulation in the Euro Heart Survey assessed by oral glucose tolerance test (OGTT) or fastingplasma glucose (FPG). Reprinted with permission from Bartnik M et al.1

Table 1In-hospital clinical outcomes in diabetic patients with non-ST-elevation ACS in the crusade registry. Reprinted with permissionfrom Brogan GX et al.4

AOR (95% CI)

Clinical outcome Nondiabetic NIDDM IDDM NIDDMa IDDMb

N 31,049 9,773 5,588Death (%) 4.4 5.4 6.8 1.14 (1.02–1.29) 1.29 (1.12–1.49)Reinfarction (%) 3.2 3.5 3.8 1.07 (0.96–1.19) 1.07 (0.93–1.24)Congestive heart failure (%) 8.0 12.4 13.7 1.25 (1.16–1.34) 1.19 (1.09–1.31)Shock (%) 2.5 3.2 3.5 1.22 (1.05–1.41) 1.18 (0.97–1.44)Red blood cell transfusion (%) 12.9 17.4 20.8 1.31 (1.23–1.40) 1.51 (1.40–1.63)

ACS¼ acute coronary syndromes; NIDDM¼ non-insulin-dependent diabetes; IDDM¼ insulin-dependent diabetes; AOR¼ adjustedodds ratio.

a Nondiabetic vs. Type 2 diabetic patients.b Nondiabetic vs. insulin-dependent diabetic patients.

M. Roffi, F.R. Eberli / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 305–316 307

Miocardico (GISSI)-2 study, with an age-adjusted risk ratio (RR) for in-hospital mortality ranging from1.4 for diabetic men not treated with insulin to 1.9 for women with insulin-requiring diabetes.9

Worse outcomes of diabetic patients in the setting of acute MI have also been documented inregistries. The Register of Information and Knowledge about Swedish Heart Intensive care Admission(RIKS-HIA) enrolled all patients admitted with the diagnosis of acute MI to coronary care units at 58hospitals during 1995–1998 in Sweden.10 A total of 5193 patients had diabetes while 20,440 were non-diabetics. The 1-year mortality was substantially higher among diabetic patients compared with thosewithout diabetes mellitus in all age groups (OR 2.6 for patients <65 years of age; 1.8 for patients 65–74years; and 1.7 for patients >75 years). A large retrospective study evaluating admission glucose of141,680 patients presenting with acute MI demonstrated a linear correlation between glucose level andmortality (Fig. 2).11 Compared with individuals with admission glucose�110 mg dl�1, individuals withglucose >140–170, >170–240 and >240 mg dl�1 had an HR for mortality of 1.1, 1.3, 1.5 and 1.8 at 30days, respectively; and of 1.1, 1.2, 1.3 and 1.5 at 1 year, respectively.

The impact of diabetes on outcomes following discharge for acute MI was addressed in a contem-porary large-scale study, the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.12 The studyenrolled 3400 patients with known diabetes, 580 patients with newly diagnosed diabetes and 10,719patients with no diabetes. At 1 year, patients with previously known and newly diagnosed diabetes hadsimilarly increased adjusted risks of mortality (HR: 1.4 and 1.5, respectively) and of CV events (HR: 1.4and 1.3) compared with those without diabetes. The GISSI-Prevenzione trial enrolled a total of 10,384

Fig. 2. Relationship between admission plasma glucose values and 30-day and 1-year mortality rates among patients presentingwith acute myocardial infarction. Reprinted with permission from Kosiborod M et al.11


patients post-MI and followed them for a mean of 3.5 years; of which 3047 patients had metabolicsyndrome and 2139 had diabetes.13 Compared with controls, the RR for mortality, CV events andhospitalisation for heart failure in patients with metabolic syndrome were 1.3, 1.2 and 1.2, respectively;and among patients with diabetes 1.7, 1.5 and 1.9, respectively.13

The gap between the prognosis of diabetic and non-diabetic individuals is observed even in cohortsundergoing state-of-the-art treatment for ACS, such as early invasive strategy in non-ST ACS and primarypercutaneous coronary intervention (PCI) for STEMI. The Acute Catheterization and Urgent InterventionTriage strategY (ACUITY) trial enrolled 13,819 patients with moderate-risk non-ST ACS undergoing earlyinvasive strategy. Compared with non-diabetic patients, diabetic patients (N¼ 3,852) had higher 30-dayrates of net adverse clinical outcomes (12.9% vs. 10.6%; p< 0.001), composite ischaemia (8.7% vs. 7.2%;p¼ 0.003) and major bleeding (5.7% vs. 4.2%; p< 0.001).14 In the Controlled Abciximab and DeviceInvestigation to Lower Late Angioplasty Complications (CADILLAC) trial, which enrolled lower-risk STEMIpatients undergoing primary PCI, the 1-year incidence of death, disabling stroke, re-infarction andischaemic target-vessel re-vascularisation (TVR) at 1 year occurred in 21.9% of diabetic patients (N¼ 346)vs. 16.8% of non-diabetic individuals (N¼ 1736) (p< 0.02).15 The difference was driven by increased ratesof death (6.1% vs. 3.9%, p¼ 0.04) and TVR (16.4% vs. 12.7%, p¼ 0.07) among diabetic patients.

Anti-platelet agents

Clopidogrel

Aspirin remains a cornerstone of therapy for ACS, though specific data focussing on diabetic patientsare lacking. The value of adding clopidogrel in the medical management of non-ST ACS was addressedin the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial.16 Diabetic patients(N¼ 2840) derived only a modest benefit from the combination of aspirin and clopidogrel adminis-tered for 3–12 months (death, MI or stroke rate 14.2% the dual anti-platelet group vs. 16.7% in theaspirin-only group; p¼NS). Among the subgroup of patients undergoing PCI, the benefit of thecombined anti-platelet therapy was somehow less marked (RR: 0.77) among diabetic patientscompared with non-diabetic ones (RR: 0.66).17

Following the results of the ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)18

and The CLopidogrel as Adjunctive Reperfusion TherapY (CLARITY-TIMI 28) trials19, the Food and DrugAdministration has expanded the indications of clopidogrel for STEMI in August 2006. In this setting,the benefit of adding clopidogrel to aspirin as a standard treatment is less well documented in diabeticthan in non-diabetic patients. The COMMIT trial randomised 45,852 patients with suspected acute MIto clopidogrel 75 mg day�1 in addition to aspirin 162 mg day�1 or aspirin alone for the duration of thehospitalisation (mean of 15 days).18 The allocation to clopidogrel led to a significant reduction in death,re-infarction or stroke during the treatment period (relative risk reduction (RRR) 9% and 7%, respec-tively). Limitations of the study included the lack of systematic reperfusion therapy (approximately50% received fibrinolysis, while primary PCI was performed only in isolated cases). Since in the mainmanuscript the prevalence of diabetes, as of other CV risk factors, is not described, no information ondiabetes can be derived from the study.

The CLARITY-TIMI 28 trial randomised patients receiving fibrinolytic therapy for acute MI to clo-pidogrel loading dose of 300 mg, followed by 75 mg day�1 or placebo. At 30 days, the incidence of CVdeath, recurrent MI or recurrent ischaemia leading to urgent re-vascularisation was reduced by 20%.19

No subgroup analysis addressing the diabetic patients enrolled in the main trial (N¼ 575) is currentlyavailable. Nevertheless, among the 282 diabetic patients who underwent subsequent PCI during indexhospitalisation, pre-treatment with clopidogrel resulted in a 39% reduction of subsequent 30-dayevents, albeit not statistically significant due to the small sample size.20

Overall, clopidogrel in addition to aspirin remains important drug regimen for the treatment andprevention of atherothrombotic complications in diabetic patients in the setting of elective PCI or astreatment for ACS, though no preferential benefit of the drug has been observed in this patient pop-ulation. The efficacy of current anti-platelet agents may be limited by an impaired responsiveness –also called resistance – which has been described in the diabetic population for both aspirin21 andclopidogrel.22


Prasugrel

Prasugrel inhibits the P2Y12 receptor more consistently and with smaller individual variation thanclopidogrel. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhi-bition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) randomised 13,608subjects with ACS (both non-ST ACS and STEMI) to clopidogrel or prasugrel for 6–15 months. Amongthem, 3146 subjects had diabetes and 776 were treated with insulin on admission. The primary end-point (death from CV causes, MI or stroke) was reduced significantly with prasugrel among subjectswithout diabetes (9.2% vs. 10.6%; HR 0.86; p¼ 0.02) and with diabetes (12.2% vs. 17.0%; HR 0.70;p< 0.001) (Fig. 3).45 A benefit for prasugrel was observed among diabetic subjects receiving insulin(14.3% vs. 22.2%; HR 0.63; p¼ 0.009) and those not on insulin (11.5% vs. 15.3%; HR: 0.74; p¼ 0.009). MIwas reduced with prasugrel by 18% among subjects without diabetes (7.2% vs. 8.7%; HR: 0.82;p¼ 0.006) and by 40% among subjects with diabetes (8.2% vs. 13.2%; HR: 0.60; p< 0.001). The inter-action analyses for treatment benefit–diabetic status showed a trend (p¼ 0.09) for the primary end-point and were significant (p¼ 0.02) for MI, suggesting a preferential benefit of prasugrel in thediabetic population. Although TIMI major haemorrhage was increased among subjects without dia-betes on prasugrel (1.6% vs. 2.4%; HR, 1.43; p¼ 0.02), the rates were similar among subjects withdiabetes for clopidogrel and prasugrel (2.6% vs. 2.5%; HR, 1.06; p¼ 0.81, p(interaction)¼ 0.29). Netclinical benefit with prasugrel was greater for diabetic patients (14.6% vs. 19.2%; HR, 0.74; p¼ 0.001)than for non-diabetic individuals (11.5% vs. 12.3%; HR, 0.92; p¼ 0.16, p(interaction)¼ 0.05). Animportant observation is that the overall rate of stent thrombosis in the overall population (0.9% vs.2.0%) and in the diabetic population (2.0% vs. 3.5%) was significantly reduced by the treatment withprasugrel.

GP IIb/IIIa antagonists

In the setting of non-ST-segment elevation ACS, while the overall impact of GP IIb/IIIa receptorinhibitors used in a conservative approach has been modest23, a mortality benefit has been detectedamong diabetic patients. Accordingly, the meta-analysis of the diabetic populations (N¼ 6458)enrolled in the six large-scale platelet GP IIb/IIIa inhibitor ACS trials detected a 26% mortality reductionassociated with the use of these agents at 30 days compared with placebo, from 6.2% to 4.6% (p¼ 0.007)(Fig. 4).24 These findings were reinforced by a statistically significant interaction between treatment

Fig. 3. Kaplan-Meier curves for prasugrel vs. clopidogrel stratified for diabetic status in the TRITON-TIMI 38 trial. The primaryendpoint consisted of cardiovascular death, myocardial infarction, or stroke. DM¼ diabetes mellitus, HR¼Hazard Ration.Reproduced with permission from Wiviott et al.45


and diabetic status. The use of these potent platelet inhibitors was associated with similar propor-tionate reduction in mortality for patients treated with insulin and those on diet or oral hypoglycaemicdrugs. Even more striking was the benefit among diabetic patients undergoing PCI, with a 70% 30-daymortality reduction, from 4.0% to 1.2% (p¼ 0.002) (Fig. 4). However, these results were obtained in theabsence of additional clopidogrel therapy. Nevertheless, the 2007 Guidelines of the European Society ofCardiology (ESC) recommend that diabetic patients with non-ST-elevation ACS should receive intra-venous GP IIb/IIIa inhibitors as part of the initial medical management and be continued through thecompletion of PCI (class IIa-B).25

The value of GP IIb/IIIa inhibitors for diabetic patients at the time of mechanical re-vascularisationfor STEMI cannot be adequately assessed since little data are available. In a small placebo-controlledrandomised trial with abciximab for stent-based primary PCI, the use of the GP IIb/IIIa antagonistsamong diabetic patients (N¼ 53) led to a significant lower mortality at 6 months (0% vs. 16.7%, p¼ 0.02)as well as to reduced rates of re-infarction.26 In the CADILLAC trial, no benefit of abciximab in terms ofmorbidity or mortality was observed among 346 low-risk diabetic patients for acute MI treated witheither percutaneous transluminal coronary angioplasty (PTCA) or stents.15

Anticoagulants

Enoxaparin

The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIainhibitors (SYNERGY) trial compared the low-molecular-weight heparin enoxaparin with unfractio-nated heparin in 9978 patients with ACS treated with early invasive strategy and found no difference inoutcomes at 30 days and 6 months in the overall study population as well as in the diabetic cohort(N¼ 2926).27 In the trial, in-hospital coronary angiography was performed in over 90% of the cases and,at the time of PCI, GP IIb/IIIa inhibitors were administered in approximately one-third of the cases. TheAggrastat-to Zocor (A-to-Z) trial randomised 3987 patients with non-ST-ACS to enoxaparin orunfractionated heparin on top of aspirin and tirofiban and found no additional benefit of enoxaparin inthe overall cohort, although among diabetic patients (N¼ 751) the composite of death, MI or refractoryischaemia at 30 days was non-significantly lowered with enoxaparin (8.4% vs. 10.7%).28 Accordingly,unfractionated heparin and enoxaparin are both recommended as equal treatments for diabeticpatients in the setting of ACS and elective PCI.

Bivalirudin

The value of a bivalirudin-based anti-thrombotic strategy for PCI in non-ST ACS has been studied inthe in the ACUITY trial which included 13,819 moderate-risk patients who were randomised toheparins (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI

Fig. 4. Meta-analysis of 6 randomized placebo controlled trials demonstrating the effect of platelet glycoprotein IIb/IIIa inhibitors(IIb/IIIa) on 30-day mortality among diabetic patients with acute coronary syndromes (ACS). Panel A demonstrate the overall benefitwhile Panel B shows the efficacy among patients who underwent in-hospital percutaneous coronary intervention (PCI). The data arereported as odds ratio with 95% confidence intervals (CI) and corresponding p-values. Values to left of 1.0 indicate a survival benefitof IIb/IIIa. Reprinted with permission from Roffi M et al.24


or bivalirudin monotherapy. The primary end-point of the study was the 30-day net adverse clinicaloutcomes (composite ischaemia [death, MI or unplanned ischaemic re-vascularisation] or majorbleeding). Among the 3852 diabetic patients, compared with heparin plus GPI, bivalirudin plus GPIresulted in similar rates of net adverse clinical outcomes (14.0% vs. 13.8%), while bivalirudin mono-therapy resulted in a similar rate of composite ischaemia (7.9% vs. 8.9%; p¼ 0.39) and less majorbleeding (3.7% vs. 7.1%; p< 0.001), yielding fewer net adverse clinical outcomes (10.9% vs. 13.8%;p¼ 0.02).14 Therefore, bivalirudin may be seen as valuable option in low-medium-risk diabeticpatients presenting with non-ST-elevation ACS. The use of bivalirudin in the setting of primary PCI forSTEMI has been addressed in the Harmonizing Outcomes with Revascularization and Stents in AcuteMyocardial Infraction (HORIZONS-AMI).29 While in the overall study population (N¼ 3,602) anti-coagulation with bivalirudin alone, as compared with heparin plus GP IIb/IIIa inhibitors, resulted insignificantly reduced 30-day rates of major bleeding and net adverse clinical events, no data are yetavailable for the diabetic patient population.

Early invasive strategy in non-ST-ACS

In diabetic patients with non-ST-segment elevation ACS, the positive impact of an early invasivestrategy can be derived from subgroup analyses of large-scale randomised studies. The Fragmin andFast Revascularisation during InStability in Coronary artery disease (FRISC II) study randomised 2457patients to an invasive or conservative strategy and detected a significant survival benefit associatedwith the invasive strategy at 1 year.30 The benefit from an early coronary angiography, and if needed,a re-vascularisation in terms of 1-year death or MI was dramatic among diabetic patients (N¼ 299),both in terms of relative and absolute risk reduction (39% and 9.3%, respectively) (Fig. 5).31 Among non-diabetic individuals the effect was less pronounced (28% and 3.1%, respectively). Due to differences insample size the benefit observed did not reach statistical significance among diabetics (p¼ 0.07), whileit did among non-diabetics (p¼ 0.02). In addition, diabetic patients undergoing early invasive therapyhad a 38% reduction in the relative risk of 1-year death (7.7% vs. 12.5%), again not reaching statisticalsignificance due to the small sample size.30

In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or ConservativeStrategy (TACTICS)-TIMI 18 trial32, an early invasive strategy was associated with a significant 22%reduction in the relative risk of death, MI or re-hospitalisation for ACS at 6 months compared with anearly conservative strategy.32 All patients were treated with aspirin, clopidogrel and tirofiban. Diabeticpatients derived a greater benefit than individuals not affected by diabetes from an early invasivestrategy both in terms of absolute (7.6% and 1.8%, respectively) and relative 6-month event reduction

Fig. 5. Outcomes according to diabetic status in the FRISC II (Panel A) and TACTICS (Panel B) trials of invasive vs. conservativestrategy in non-ST-elevation acute coronary syndromes (ACS). MI¼myocardial infarction. Panel A is reprinted with permission fromNorhammar A et al.31 Panel B is created based on data from Cannon CP et al.32


(27% and 13%, respectively) (Fig. 5). Accordingly, the 2007 ESC guidelines recommend an early invasivestrategy for all diabetic patients with non-ST-elevation ACS (class I–A).25

Reperfusion therapy in STEMI

With respect to fibrinolytic therapy, the meta-analysis of the Fibrinolytic Therapy Trialists’Collaborative Group involving all the large randomised trials of fibrinolytic therapy versus placebo inSTEMI demonstrated a greater than twofold survival benefit at 35 days among diabetic patients(N¼ 2236) compared with non-diabetic individuals (N¼ 19,423), corresponding to 3.7 lives and 1.5lives saved per 100 patients treated, respectively.33 While coronary artery bypass surgery in the settingof STEMI is typically reserved for cases of failed PCI or for MI-related mechanical complications,primary PCI may be preferred over thrombolytic therapy in diabetic patients. However, the data tosupport this notion are limited. In a pooled analysis on a total of 367 diabetic patients enrolled in 11randomised trials, allocation to primary PCI led to a reduction in death or non-fatal MI rates at 30 dayscompared with fibrinolytic therapy (9.2% vs. 19.3%, p< 0.05).34 Overall, the benefit of primary PCI overthrombolytic therapy was greater in diabetic patients compared with non-diabetic patients (number-needed-to-treat [NNT] 10 and 16, respectively).

Within the Comparison of Angioplasty and Prehospital Thrombolysis In acute Myocardial infarction(CAPTIM) trial, a small group of diabetic patients with acute MI (N¼ 103) were randomised to pre-hospital thrombolysis or a more contemporary primary PCI (stents and GP IIb/IIIa inhibitors used in83% and 27% of cases, respectively).35 The 30-day incidence of death, recurrent MI or stroke tended tobe higher in individuals receiving fibrinolysis than in those undergoing mechanical reperfusion (21.0%vs. 8.8%; p¼ 0.09). The difference was driven by the higher, though not statistically significant,mortality rate in the fibrinolysis group (13.0% vs. 5.3%). A single-centre retrospective analysis includinga limited number of diabetic patients (N¼ 202) treated with reperfusion therapy for STEMI detecteda significant lower 1-year incidence of death or re-infarction in patients (N¼ 103) treated with primaryPCI compared with those undergoing fibrinolysis (19.4% vs. 36.4%, respectively).36

No dedicated trials have specifically addressed the use of drug-eluting stents in diabetic patientspresenting with ACS. Stent placement in the setting of ACS is known to be associated with an increasedrisk of stent thrombosis. Potentially, the rate of stent thrombosis in acute MI could be further increasedin the presence of drug-eluting stents. Accordingly, the inflammatory state contributing to plaquerupture may be enhanced by the drug or the polymer present on the surface of the stent. In addition,the presence of thrombus in the vessel might result in incomplete stent apposition at the time ofimplantation. Finally, due to generalised vasoconstriction the real vessel size may be underestimatedand the implanted stent might be undersized.37 Although diabetic patients may be at an increased riskof stent thrombosis following implantation of a drug-eluting stent, a recent collaborative networkmeta-analysis of trials showed that in diabetic patients the use of these devices was associated withsuperior effectiveness and similar safety compared to bare-metal stents.38 However, current rando-mised and registry experience does not support the notion that drug-eluting stents may be associatedwith increased complications in the setting of acute MI.39,40 Therefore, drug-eluting stents can be safelyused in ACS and in primary PCI when prolonged double anti-platelet therapy is part of the treatment.

Glucose-lowering therapy

The Diabetes mellitus, Insulin Glucose infusion in Acute Myocardial Infarction (DIGAMI) study wasdesigned to test the hypothesis that intensive glucose-lowering therapy in patients with diabetes andacute MI improved the prognosis. A total of 620 patients were randomised for standard treatment plusinsulin–glucose infusion titrated according to glucose levels for at least 24 h, followed by subcutaneousinsulin treatment for approximately 3 months after discharge or standard treatment (controls). Aftera mean follow up of 3.5 years, the overall mortality was 33% in the active treatment group and 44% inthe control group (RR 0.72; p¼ 0.011).41 This translated into an impressive NNT of 9 to save one life. Inaddition, a reduction in recurrent MI and heart failure rates at follow-up was observed in the activetreatment group. In the DIGAMI 2 study, three glucose-lowering strategies were compared among1253 diabetic patients with suspected acute MI: group 1, acute insulin-glucose infusion titrated to


glucose levels for 24 h, followed by insulin-based long-term glucose control; group 2, insulin–glucoseinfusion for 24 h, followed by standard glucose control; and group 3, routine metabolic managementaccording to local practice.42 At 2 years, the mortality rates between group 1 (23.4%), group 2 (22.6%) orgroup 3 (19.3%) were comparable (Fig. 6) and no significant differences in non-fatal MI or stroke weredetected. Contrary to the expectations, the levels of blood glucose lowering were identical in the threegroups. One limitation of the trial is that it had to be stopped prematurely due to slow enrolment andlack of funding.

Taken together, the results of the DIGAMI trials may be reconciled by affirming that the mostimportant action is to aggressively lower blood glucose levels in diabetic patients with acute MI,independently from how these goals are achieved. On the management with ACS, the 2007 ESCguidelines suggest a tight glycaemic control to achieve normoglycaemia as soon as possible, which isrecommended in all diabetic patients within the acute phase (recommendation class I-C).25 In addition,they state that insulin infusion may be needed to achieve normoglycaemia in selected patients withhigh blood glucose levels at admission (IIa-C).

However, the optimal level of glucose lowering for diabetic patients with established CV disease orwith additional CV risk factors still needs to be defined. The Action to Control CardiOvascular Risk inDiabetes (ACCORD) study randomised over 10,000 diabetic patients to an intensive glucose-loweringregime (target glycated haemoglobin level below 6.0%) or to a standard regimen (target glycatedhaemoglobin level of 7.0–7.9%). The mean levels of glycated haemoglobin achieved in the study were6.4% and 7.5%, respectively. The intensive therapy arm was discontinued after a mean follow-up of 3.5years because of an increased mortality.43 Although the reasons for these findings are still unclear, ithas been hypothesised that these may be related to the observed increased incidence of hypoglycaemiaand heart failure, the latter possibly due to fluid retention associated with insulin or glitazone therapy.

Adherence to evidence-based therapy

Despite the preferential benefit for diabetic patients from GP IIb/IIIa antagonists in the setting ofnon-ST ACS, data from the NRMI registry including over 60,000 patients in the United States showedthat, even after adjusting for baseline characteristics, diabetic patients had a significantly lesser chanceto get these potent platelet inhibitors compared with non-diabetic individuals.44 The same is true forthe under-usage of an early invasive strategy. Despite that diabetes has repeatedly been recognised asa high-risk feature in the setting of ACS for which the American and European guidelines recommend

Fig. 6. 3-year mortality curves in diabetic patients with acute myocardial infarction randomized in the DIGAMI 2 trial according to 3different glucose-lowering strategies (for details see the text). Reproduced with permission from Malmberg K et al.42


an early coronary angiography and, if needed a re-vascularisation, this patient population hada statistically significant lesser chance to get early coronary angiography compared with the non-diabetic individuals in the CRUSADE registry.2 Furthermore, in the management of acute MI, diabeticpatients are less frequently exposed to evidence-based therapy. According to the Swedish RIKS-HIAregistry, after adjustments for differences in baseline characteristics between the diabetic and non-diabetic patients, patients with diabetes were significantly less likely to be treated with reperfusiontherapy, heparins, statins or to be re-vascularised than non-diabetic patients.10 This is despite the factthat the same analysis documented a mortality benefit from several of these therapies in the diabeticpopulation.10

Practical points and research agenda

� Diabetic patients with ACS are at a high risk for subsequent CV events but derive, at the sametime, greater benefit from evidence-based therapy than non-diabetic individuals.� State-of-the-art anti-thrombotic for diabetic patients with ACS therapy includes a triple anti-

platelet combination – aspirin, clopidogrel and GP IIb/IIIa receptor inhibitors – and unfrac-tionated heparin or enoxaparin. For low- or medium-risk individuals, a treatment based onaspirin, clopidogrel and bivalirudin is a valuable alternative.� Prasugrel, a new and more potent inhibitor of the platelet P2Y12 receptor, is currently the

most promising anti-thrombotic agent for this patient population. This drug may replaceclopidogrel and GP IIb/IIIa receptor inhibitors in the future.� Diabetic patients should undergo early invasive angiography if presenting with non-ST-

segment elevation ACS and immediate PCI if presenting with STEMI.� Despite the documented benefit, diabetic patients with ACS receive evidence-based treat-

ments less frequently than non-diabetic individuals.� Current research efforts, for both diabetic and non-diabetic individuals, focus on the devel-

opment of agents targeting platelet receptors other than the COX-1 and the P2Y12 receptorsand of newer-generation drug-eluting stents with improved long-term safety profile.� Clinical studies are needed to define the impact of glucose lowering agents on the prognosis

of ACS and the optimal level of glucose control in this setting.

References

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