Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 305316

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Diabetes and acute coronary syndromes

Marco Rof, MD, Director *, Franz R. Eberli, MD, Professor,
Chairman of Cardiology
University Hospital, Geneva, Switzerland

Keywords:
Diabetes
acute coronary syndromes
anti-platelet therapy
coronary re-vascularisation

Diabetic patients with acute coronary syndromes (ACSs) are at

a high risk for subsequent cardiovascular events but derive, at the
same time, greater benet from evidence-based therapy than nondiabetic individuals. State-of-the-art anti-thrombotic therapy
includes a triple anti-platelet combination aspirin, clopidogrel
and glycoprotein (GP) IIb/IIIa receptor inhibitors and unfractionated heparin or enoxaparin. For low- or medium-risk individuals,
a treatment based on aspirin, clopidogrel and bivalirudin is
a valuable alternative. Prasugrel, a new and more potent inhibitor
of the platelet P2Y12 receptor, has to be regarded as the most
promising anti-thrombotic agent for diabetic patients with ACS.
This agent may replace clopidogrel and possibly GP IIb/IIIa
inhibitors in the future. In addition to aggressive anti-thrombotic
therapy, diabetic patients should undergo systematic early invasive
angiography if presenting with non-ST-segment elevation ACS, and
immediate percutaneous coronary intervention if presenting with
ST-segment elevation myocardial infarction. Indeed, the benet
derived from these strategies appears to be more pronounced in
the diabetic population than in non-diabetic individuals. Despite
the benet, multiple surveys have demonstrated that, in the
setting of ACS, diabetic patients receive evidence-based therapy
less 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 manifestations
of coronary artery disease (CAD) has been conrmed in large-scale surveys. In the Euro Heart Survey,

* Corresponding author. Interventional Cardiology Unit, Division of Cardiology, University Hospital, Rue Micheli-du-Crest 24,
1211 Geneva, Switzerland. Tel.: 41 22 37 27 208; Fax: 44 22 37 27 229.
E-mail address: marco.rof@hcuge.ch (M. Rof).
1521-690X/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.beem.2009.01.003

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glucose metabolism was assessed in 2854 patients with stable CAD and 2107 patients with acute
coronary syndromes (ACSs).1 The overall prevalence of diabetes was approximately 30% both in the
stable and the unstable CAD group. Among patients with ACS and no known diabetes, oral glucose
tolerance 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 the
CRUSADE (Can Rapid risk stratication of Unstable angina patients Suppress ADverse outcomes with
Early implementation of the ACC/AHA guidelines) registry, enrolling 46,410 patients with non-STelevation ACS, the prevalence of diabetes was 33%.2 In the US-based National Registry of Myocardial
Infarction (NRMI), the prevalence of diabetes among patients presenting with ST-elevation
myocardial 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 of
ACS are higher among diabetic than among non-diabetic individuals.4 However, after accounting for
such differences, several studies have demonstrated that diabetes remains an independent predictor of
morbidity and mortality. With regard to non-ST-elevation ACS, these ndings were recently replicated
in the CRUSADE registry (Table 1).4 Diabetic patients, not only during the acute phase but also during
long-term follow-up, remain at signicantly higher risk of death, MI, stroke and heart failure compared
with non-diabetics.5 Data from the Euro Heart Survey suggest that the mortality is particularly high in
diabetic women.6 Importantly, in the setting of ACS, the cardiovascular (CV) risk increase associated
with glucose metabolism abnormality begins at the stage of pre-diabetes (i.e., fasting glucose levels
between 100 and 126 mg dl1).7
Paralleling the observations for the non-ST-elevation ACS setting, diabetic STEMI patients suffer
worse acute and long-term outcomes compared with non-diabetic individuals. Within the Global
Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO 1)
trial, which enrolled almost 40,000 patients (5944 with diabetes) undergoing brinolytic therapy, the
30-day mortality rates among patients with no diabetes, diabetic individuals not treated with insulin
and insulin-requiring diabetic patients were 6.2%, 9.7% and 12.5%, respectively (p < 0.001).8 After
correcting for imbalances in baseline characteristics, diabetes remained an independent predictor for
mortality at 1 year (odds ratio [OR]: 1.6). In addition, heart failure, shock, atrioventricular block and
atrial brillation were all more common among diabetic patients. Similar ndings were reported in
another large-scale thrombolytic trial, the Gruppo Italiano per lo Studio della Streptochinasi nellInfarto

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

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Table 1
In-hospital clinical outcomes in diabetic patients with non-ST-elevation ACS in the crusade registry. Reprinted with permission
from Brogan GX et al.4
AOR (95% CI)
Clinical outcome

Nondiabetic

NIDDM

IDDM

NIDDMa

IDDMb

N
Death (%)
Reinfarction (%)
Congestive heart failure (%)
Shock (%)
Red blood cell transfusion (%)

31,049
4.4
3.2
8.0
2.5
12.9

9,773
5.4
3.5
12.4
3.2
17.4

5,588
6.8
3.8
13.7
3.5
20.8

1.14 (1.021.29)
1.07 (0.961.19)
1.25 (1.161.34)
1.22 (1.051.41)
1.31 (1.231.40)

1.29 (1.121.49)
1.07 (0.931.24)
1.19 (1.091.31)
1.18 (0.971.44)
1.51 (1.401.63)

ACS acute coronary syndromes; NIDDM non-insulin-dependent diabetes; IDDM insulin-dependent diabetes; AOR adjusted
odds ratio.
a
Nondiabetic vs. Type 2 diabetic patients.
b
Nondiabetic vs. insulin-dependent diabetic patients.

Miocardico (GISSI)-2 study, with an age-adjusted risk ratio (RR) for in-hospital mortality ranging from
1.4 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 in
registries. 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 58
hospitals during 19951998 in Sweden.10 A total of 5193 patients had diabetes while 20,440 were nondiabetics. The 1-year mortality was substantially higher among diabetic patients compared with those
without diabetes mellitus in all age groups (OR 2.6 for patients <65 years of age; 1.8 for patients 6574
years; and 1.7 for patients >75 years). A large retrospective study evaluating admission glucose of
141,680 patients presenting with acute MI demonstrated a linear correlation between glucose level and
mortality (Fig. 2).11 Compared with individuals with admission glucose 110 mg dl1, individuals with
glucose >140170, >170240 and >240 mg dl1 had an HR for mortality of 1.1, 1.3, 1.5 and 1.8 at 30
days, 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 contemporary large-scale study, the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.12 The study
enrolled 3400 patients with known diabetes, 580 patients with newly diagnosed diabetes and 10,719
patients with no diabetes. At 1 year, patients with previously known and newly diagnosed diabetes had
similarly increased adjusted risks of mortality (HR: 1.4 and 1.5, respectively) and of CV events (HR: 1.4
and 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 presenting
with acute myocardial infarction. Reprinted with permission from Kosiborod M et al.11

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patients post-MI and followed them for a mean of 3.5 years; of which 3047 patients had metabolic
syndrome and 2139 had diabetes.13 Compared with controls, the RR for mortality, CV events and
hospitalisation 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 cohorts
undergoing state-of-the-art treatment for ACS, such as early invasive strategy in non-ST ACS and primary
percutaneous coronary intervention (PCI) for STEMI. The Acute Catheterization and Urgent Intervention
Triage strategY (ACUITY) trial enrolled 13,819 patients with moderate-risk non-ST ACS undergoing early
invasive strategy. Compared with non-diabetic patients, diabetic patients (N 3,852) had higher 30-day
rates of net adverse clinical outcomes (12.9% vs. 10.6%; p < 0.001), composite ischaemia (8.7% vs. 7.2%;
p 0.003) and major bleeding (5.7% vs. 4.2%; p < 0.001).14 In the Controlled Abciximab and Device
Investigation to Lower Late Angioplasty Complications (CADILLAC) trial, which enrolled lower-risk STEMI
patients undergoing primary PCI, the 1-year incidence of death, disabling stroke, re-infarction and
ischaemic target-vessel re-vascularisation (TVR) at 1 year occurred in 21.9% of diabetic patients (N 346)
vs. 16.8% of non-diabetic individuals (N 1736) (p < 0.02).15 The difference was driven by increased rates
of death (6.1% vs. 3.9%, p 0.04) and TVR (16.4% vs. 12.7%, p 0.07) among diabetic patients.
Anti-platelet agents
Clopidogrel
Aspirin remains a cornerstone of therapy for ACS, though specic data focussing on diabetic patients
are lacking. The value of adding clopidogrel in the medical management of non-ST ACS was addressed
in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial.16 Diabetic patients
(N 2840) derived only a modest benet from the combination of aspirin and clopidogrel administered for 312 months (death, MI or stroke rate 14.2% the dual anti-platelet group vs. 16.7% in the
aspirin-only group; p NS). Among the subgroup of patients undergoing PCI, the benet of the
combined anti-platelet therapy was somehow less marked (RR: 0.77) among diabetic patients
compared 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 Drug
Administration has expanded the indications of clopidogrel for STEMI in August 2006. In this setting,
the benet of adding clopidogrel to aspirin as a standard treatment is less well documented in diabetic
than in non-diabetic patients. The COMMIT trial randomised 45,852 patients with suspected acute MI
to clopidogrel 75 mg day1 in addition to aspirin 162 mg day1 or aspirin alone for the duration of the
hospitalisation (mean of 15 days).18 The allocation to clopidogrel led to a signicant reduction in death,
re-infarction or stroke during the treatment period (relative risk reduction (RRR) 9% and 7%, respectively). Limitations of the study included the lack of systematic reperfusion therapy (approximately
50% received brinolysis, while primary PCI was performed only in isolated cases). Since in the main
manuscript the prevalence of diabetes, as of other CV risk factors, is not described, no information on
diabetes can be derived from the study.
The CLARITY-TIMI 28 trial randomised patients receiving brinolytic therapy for acute MI to clopidogrel loading dose of 300 mg, followed by 75 mg day1 or placebo. At 30 days, the incidence of CV
death, 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 (N 575) is currently
available. Nevertheless, among the 282 diabetic patients who underwent subsequent PCI during index
hospitalisation, pre-treatment with clopidogrel resulted in a 39% reduction of subsequent 30-day
events, albeit not statistically signicant due to the small sample size.20
Overall, clopidogrel in addition to aspirin remains important drug regimen for the treatment and
prevention of atherothrombotic complications in diabetic patients in the setting of elective PCI or as
treatment for ACS, though no preferential benet of the drug has been observed in this patient population. The efcacy 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 and
clopidogrel.22

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Prasugrel
Prasugrel inhibits the P2Y12 receptor more consistently and with smaller individual variation than
clopidogrel. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) randomised 13,608
subjects with ACS (both non-ST ACS and STEMI) to clopidogrel or prasugrel for 615 months. Among
them, 3146 subjects had diabetes and 776 were treated with insulin on admission. The primary endpoint (death from CV causes, MI or stroke) was reduced signicantly with prasugrel among subjects
without diabetes (9.2% vs. 10.6%; HR 0.86; p 0.02) and with diabetes (12.2% vs. 17.0%; HR 0.70;
p < 0.001) (Fig. 3).45 A benet for prasugrel was observed among diabetic subjects receiving insulin
(14.3% vs. 22.2%; HR 0.63; p 0.009) and those not on insulin (11.5% vs. 15.3%; HR: 0.74; p 0.009). MI
was reduced with prasugrel by 18% among subjects without diabetes (7.2% vs. 8.7%; HR: 0.82;
p 0.006) and by 40% among subjects with diabetes (8.2% vs. 13.2%; HR: 0.60; p < 0.001). The interaction analyses for treatment benetdiabetic status showed a trend (p 0.09) for the primary endpoint and were signicant (p 0.02) for MI, suggesting a preferential benet of prasugrel in the
diabetic population. Although TIMI major haemorrhage was increased among subjects without diabetes on prasugrel (1.6% vs. 2.4%; HR, 1.43; p 0.02), the rates were similar among subjects with
diabetes for clopidogrel and prasugrel (2.6% vs. 2.5%; HR, 1.06; p 0.81, p(interaction) 0.29). Net
clinical benet with prasugrel was greater for diabetic patients (14.6% vs. 19.2%; HR, 0.74; p 0.001)
than for non-diabetic individuals (11.5% vs. 12.3%; HR, 0.92; p 0.16, p(interaction) 0.05). An
important 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 signicantly reduced by the treatment with
prasugrel.
GP IIb/IIIa antagonists
In the setting of non-ST-segment elevation ACS, while the overall impact of GP IIb/IIIa receptor
inhibitors used in a conservative approach has been modest23, a mortality benet has been detected
among diabetic patients. Accordingly, the meta-analysis of the diabetic populations (N 6458)
enrolled in the six large-scale platelet GP IIb/IIIa inhibitor ACS trials detected a 26% mortality reduction
associated with the use of these agents at 30 days compared with placebo, from 6.2% to 4.6% (p 0.007)
(Fig. 4).24 These ndings were reinforced by a statistically signicant interaction between treatment

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

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and diabetic status. The use of these potent platelet inhibitors was associated with similar proportionate reduction in mortality for patients treated with insulin and those on diet or oral hypoglycaemic
drugs. Even more striking was the benet among diabetic patients undergoing PCI, with a 70% 30-day
mortality reduction, from 4.0% to 1.2% (p 0.002) (Fig. 4). However, these results were obtained in the
absence of additional clopidogrel therapy. Nevertheless, the 2007 Guidelines of the European Society of
Cardiology (ESC) recommend that diabetic patients with non-ST-elevation ACS should receive intravenous GP IIb/IIIa inhibitors as part of the initial medical management and be continued through the
completion of PCI (class IIa-B).25
The value of GP IIb/IIIa inhibitors for diabetic patients at the time of mechanical re-vascularisation
for STEMI cannot be adequately assessed since little data are available. In a small placebo-controlled
randomised trial with abciximab for stent-based primary PCI, the use of the GP IIb/IIIa antagonists
among diabetic patients (N 53) led to a signicant lower mortality at 6 months (0% vs. 16.7%, p 0.02)
as well as to reduced rates of re-infarction.26 In the CADILLAC trial, no benet of abciximab in terms of
morbidity or mortality was observed among 346 low-risk diabetic patients for acute MI treated with
either percutaneous transluminal coronary angioplasty (PTCA) or stents.15
Anticoagulants
Enoxaparin
The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa
inhibitors (SYNERGY) trial compared the low-molecular-weight heparin enoxaparin with unfractionated heparin in 9978 patients with ACS treated with early invasive strategy and found no difference in
outcomes at 30 days and 6 months in the overall study population as well as in the diabetic cohort
(N 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. The
Aggrastat-to Zocor (A-to-Z) trial randomised 3987 patients with non-ST-ACS to enoxaparin or
unfractionated heparin on top of aspirin and tiroban and found no additional benet of enoxaparin in
the overall cohort, although among diabetic patients (N 751) the composite of death, MI or refractory
ischaemia at 30 days was non-signicantly lowered with enoxaparin (8.4% vs. 10.7%).28 Accordingly,
unfractionated heparin and enoxaparin are both recommended as equal treatments for diabetic
patients 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 in
the in the ACUITY trial which included 13,819 moderate-risk patients who were randomised to
heparins (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 benet
while Panel B shows the efcacy among patients who underwent in-hospital percutaneous coronary intervention (PCI). The data are
reported as odds ratio with 95% condence intervals (CI) and corresponding p-values. Values to left of 1.0 indicate a survival benet
of IIb/IIIa. Reprinted with permission from Rof M et al.24

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or bivalirudin monotherapy. The primary end-point of the study was the 30-day net adverse clinical
outcomes (composite ischaemia [death, MI or unplanned ischaemic re-vascularisation] or major
bleeding). Among the 3852 diabetic patients, compared with heparin plus GPI, bivalirudin plus GPI
resulted in similar rates of net adverse clinical outcomes (14.0% vs. 13.8%), while bivalirudin monotherapy resulted in a similar rate of composite ischaemia (7.9% vs. 8.9%; p 0.39) and less major
bleeding (3.7% vs. 7.1%; p < 0.001), yielding fewer net adverse clinical outcomes (10.9% vs. 13.8%;
p 0.02).14 Therefore, bivalirudin may be seen as valuable option in low-medium-risk diabetic
patients presenting with non-ST-elevation ACS. The use of bivalirudin in the setting of primary PCI for
STEMI has been addressed in the Harmonizing Outcomes with Revascularization and Stents in Acute
Myocardial Infraction (HORIZONS-AMI).29 While in the overall study population (N 3,602) anticoagulation with bivalirudin alone, as compared with heparin plus GP IIb/IIIa inhibitors, resulted in
signicantly reduced 30-day rates of major bleeding and net adverse clinical events, no data are yet
available 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 invasive
strategy can be derived from subgroup analyses of large-scale randomised studies. The Fragmin and
Fast Revascularisation during InStability in Coronary artery disease (FRISC II) study randomised 2457
patients to an invasive or conservative strategy and detected a signicant survival benet associated
with the invasive strategy at 1 year.30 The benet from an early coronary angiography, and if needed,
a re-vascularisation in terms of 1-year death or MI was dramatic among diabetic patients (N 299),
both in terms of relative and absolute risk reduction (39% and 9.3%, respectively) (Fig. 5).31 Among nondiabetic individuals the effect was less pronounced (28% and 3.1%, respectively). Due to differences in
sample size the benet observed did not reach statistical signicance among diabetics (p 0.07), while
it did among non-diabetics (p 0.02). In addition, diabetic patients undergoing early invasive therapy
had a 38% reduction in the relative risk of 1-year death (7.7% vs. 12.5%), again not reaching statistical
signicance due to the small sample size.30
In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative
Strategy (TACTICS)-TIMI 18 trial32, an early invasive strategy was associated with a signicant 22%
reduction in the relative risk of death, MI or re-hospitalisation for ACS at 6 months compared with an
early conservative strategy.32 All patients were treated with aspirin, clopidogrel and tiroban. Diabetic
patients derived a greater benet than individuals not affected by diabetes from an early invasive
strategy 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. conservative
strategy in non-ST-elevation acute coronary syndromes (ACS). MI myocardial infarction. Panel A is reprinted with permission from
Norhammar A et al.31 Panel B is created based on data from Cannon CP et al.32

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(27% and 13%, respectively) (Fig. 5). Accordingly, the 2007 ESC guidelines recommend an early invasive
strategy for all diabetic patients with non-ST-elevation ACS (class IA).25
Reperfusion therapy in STEMI
With respect to brinolytic therapy, the meta-analysis of the Fibrinolytic Therapy Trialists
Collaborative Group involving all the large randomised trials of brinolytic therapy versus placebo in
STEMI demonstrated a greater than twofold survival benet at 35 days among diabetic patients
(N 2236) compared with non-diabetic individuals (N 19,423), corresponding to 3.7 lives and 1.5
lives saved per 100 patients treated, respectively.33 While coronary artery bypass surgery in the setting
of 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 to
support this notion are limited. In a pooled analysis on a total of 367 diabetic patients enrolled in 11
randomised trials, allocation to primary PCI led to a reduction in death or non-fatal MI rates at 30 days
compared with brinolytic therapy (9.2% vs. 19.3%, p < 0.05).34 Overall, the benet of primary PCI over
thrombolytic therapy was greater in diabetic patients compared with non-diabetic patients (numberneeded-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 (N 103) were randomised to prehospital thrombolysis or a more contemporary primary PCI (stents and GP IIb/IIIa inhibitors used in
83% and 27% of cases, respectively).35 The 30-day incidence of death, recurrent MI or stroke tended to
be higher in individuals receiving brinolysis than in those undergoing mechanical reperfusion (21.0%
vs. 8.8%; p 0.09). The difference was driven by the higher, though not statistically signicant,
mortality rate in the brinolysis group (13.0% vs. 5.3%). A single-centre retrospective analysis including
a limited number of diabetic patients (N 202) treated with reperfusion therapy for STEMI detected
a signicant lower 1-year incidence of death or re-infarction in patients (N 103) treated with primary
PCI compared with those undergoing brinolysis (19.4% vs. 36.4%, respectively).36
No dedicated trials have specically addressed the use of drug-eluting stents in diabetic patients
presenting with ACS. Stent placement in the setting of ACS is known to be associated with an increased
risk of stent thrombosis. Potentially, the rate of stent thrombosis in acute MI could be further increased
in the presence of drug-eluting stents. Accordingly, the inammatory state contributing to plaque
rupture 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 of
implantation. Finally, due to generalised vasoconstriction the real vessel size may be underestimated
and the implanted stent might be undersized.37 Although diabetic patients may be at an increased risk
of stent thrombosis following implantation of a drug-eluting stent, a recent collaborative network
meta-analysis of trials showed that in diabetic patients the use of these devices was associated with
superior effectiveness and similar safety compared to bare-metal stents.38 However, current randomised and registry experience does not support the notion that drug-eluting stents may be associated
with increased complications in the setting of acute MI.39,40 Therefore, drug-eluting stents can be safely
used 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 was
designed to test the hypothesis that intensive glucose-lowering therapy in patients with diabetes and
acute MI improved the prognosis. A total of 620 patients were randomised for standard treatment plus
insulinglucose infusion titrated according to glucose levels for at least 24 h, followed by subcutaneous
insulin treatment for approximately 3 months after discharge or standard treatment (controls). After
a mean follow up of 3.5 years, the overall mortality was 33% in the active treatment group and 44% in
the control group (RR 0.72; p 0.011).41 This translated into an impressive NNT of 9 to save one life. In
addition, a reduction in recurrent MI and heart failure rates at follow-up was observed in the active
treatment group. In the DIGAMI 2 study, three glucose-lowering strategies were compared among
1253 diabetic patients with suspected acute MI: group 1, acute insulin-glucose infusion titrated to

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glucose levels for 24 h, followed by insulin-based long-term glucose control; group 2, insulinglucose
infusion for 24 h, followed by standard glucose control; and group 3, routine metabolic management
according to local practice.42 At 2 years, the mortality rates between group 1 (23.4%), group 2 (22.6%) or
group 3 (19.3%) were comparable (Fig. 6) and no signicant differences in non-fatal MI or stroke were
detected. Contrary to the expectations, the levels of blood glucose lowering were identical in the three
groups. One limitation of the trial is that it had to be stopped prematurely due to slow enrolment and
lack of funding.
Taken together, the results of the DIGAMI trials may be reconciled by afrming that the most
important 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 ESC
guidelines suggest a tight glycaemic control to achieve normoglycaemia as soon as possible, which is
recommended 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 with
high blood glucose levels at admission (IIa-C).
However, the optimal level of glucose lowering for diabetic patients with established CV disease or
with additional CV risk factors still needs to be dened. The Action to Control CardiOvascular Risk in
Diabetes (ACCORD) study randomised over 10,000 diabetic patients to an intensive glucose-lowering
regime (target glycated haemoglobin level below 6.0%) or to a standard regimen (target glycated
haemoglobin level of 7.07.9%). The mean levels of glycated haemoglobin achieved in the study were
6.4% and 7.5%, respectively. The intensive therapy arm was discontinued after a mean follow-up of 3.5
years because of an increased mortality.43 Although the reasons for these ndings are still unclear, it
has been hypothesised that these may be related to the observed increased incidence of hypoglycaemia
and heart failure, the latter possibly due to uid retention associated with insulin or glitazone therapy.
Adherence to evidence-based therapy
Despite the preferential benet for diabetic patients from GP IIb/IIIa antagonists in the setting of
non-ST ACS, data from the NRMI registry including over 60,000 patients in the United States showed
that, even after adjusting for baseline characteristics, diabetic patients had a signicantly lesser chance
to get these potent platelet inhibitors compared with non-diabetic individuals.44 The same is true for
the under-usage of an early invasive strategy. Despite that diabetes has repeatedly been recognised as
a 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 3
different glucose-lowering strategies (for details see the text). Reproduced with permission from Malmberg K et al.42

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

Practical points and research agenda

 Diabetic patients with ACS are at a high risk for subsequent CV events but derive, at the same
time, greater benet from evidence-based therapy than non-diabetic individuals.
 State-of-the-art anti-thrombotic for diabetic patients with ACS therapy includes a triple antiplatelet combination aspirin, clopidogrel and GP IIb/IIIa receptor inhibitors and unfractionated heparin or enoxaparin. For low- or medium-risk individuals, a treatment based on
aspirin, 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 replace
clopidogrel and GP IIb/IIIa receptor inhibitors in the future.
 Diabetic patients should undergo early invasive angiography if presenting with non-STsegment elevation ACS and immediate PCI if presenting with STEMI.
 Despite the documented benet, diabetic patients with ACS receive evidence-based treatments less frequently than non-diabetic individuals.
 Current research efforts, for both diabetic and non-diabetic individuals, focus on the development of agents targeting platelet receptors other than the COX-1 and the P2Y12 receptors
and of newer-generation drug-eluting stents with improved long-term safety prole.
 Clinical studies are needed to dene the impact of glucose lowering agents on the prognosis
of ACS and the optimal level of glucose control in this setting.

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