Acute myocardial infarction: Patients with

diabetes mellitus
Authors: Richard W Nesto, MD, Matthew A Cavender, MD, MPH
Section Editors: Christopher P Cannon, MD, David M Nathan, MD
Deputy Editor: Todd F Dardas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Aug 19, 2022.

INTRODUCTION

Cardiovascular events related to atherosclerotic cardiovascular disease are a major

cause of morbidity and mortality among patients with diabetes mellitus.
Compared with patients without diabetes, those with diabetes are more likely to
have coronary heart disease and more severe multivessel coronary artery disease
when it occurs. As a result of these and other factors, patients with diabetes and
coronary heart disease have worse outcomes, including lower rates of long-term
survival when compared with patients without diabetes who have coronary heart
disease. (See "Prevalence of and risk factors for coronary heart disease in patients
with diabetes mellitus".)

With respect to acute myocardial infarction (MI), including ST-elevation MI (STEMI)

and non-ST-elevation MI (NSTEMI), in patients with diabetes, its treatment is
broadly similar to that in those without diabetes. (See "Overview of the acute
management of ST-elevation myocardial infarction" and "Overview of the acute
management of non-ST-elevation acute coronary syndromes".)

This topic will focus on a number of specific issues that should be considered in
diabetic patients. The majority of data discussed in this review are related to those
patients with type 2 diabetes mellitus. However, despite a paucity of data in type 1
diabetes, the general principles of care appear to also be applicable to them.
RELATIONSHIP BETWEEN DIABETES AND MYOCARDIAL
INFARCTION

Diabetes is increasing in prevalence across the world and has increased from 108
million in 1980 to 422 million in 2014 [1]. Diabetes is underrecognized and it is
estimated that approximately 5 percent of the population has undiagnosed
diabetes [2]. While there have been overall reductions in the absolute number of
acute myocardial infarctions in patients with diabetes given advances in medical
therapy, these gains are threatened by the continued increase in the prevalence of
diabetes [3].

It is not uncommon for the first diagnosis of diabetes to be made at the time of a
MI. The incidence of newly diagnosed diabetes varies and has been found in
approximately 5 percent of patients [4,5]. Other studies have found even higher
prevalence of undiagnosed diabetes [6].

Similar to smoking, hypertension, and dyslipidemia, the high prevalence of

diabetes in patients with acute MI relates to the fact that it is an independent risk
factor for atherosclerotic heart disease. Diabetes has continued to be a significant
independent risk factor for atherosclerotic heart disease. The importance of
diabetes as a risk factor was illustrated in a 1998 study of the Finnish population
that compared the seven-year incidence of MI in 1373 nondiabetics and 1059
patients with type 2 diabetes [7].

Patients with diabetes but no prior infarction had a similar risk of subsequent MI
(20 and 19 percent, respectively) and coronary mortality (15 versus 16 percent) as
nondiabetic patients with a prior MI. The risk of infarction was greatest in diabetics
with a prior MI and lowest in nondiabetics without a prior MI (45 and 4 percent,
respectively). While these data have led some to conclude that having diabetes
increases a patient's risk of CHD events to a similar magnitude as patients with
prior MI who do not have type 2 diabetes mellitus, the totality of and newer
evidence does not support diabetes as a CHD equivalent. A 2009 meta-analysis
found that those with diabetes but no history MI had a lower risk of cardiovascular
events when compared with patients without diabetes who have had a prior MI
(OR 0.56, 95% CI 0.53-0.60) [8,9].
 In patients with acute MI, those with diabetes have significantly higher risk of
subsequent mortality and future cardiovascular events [10]. Furthermore, there
appears to be a graded rise in cardiovascular risk with increasing degree of
hyperglycemia. In a community-based sample of elderly patients hospitalized with
acute MI from 1994 to 1996, higher glucose levels were associated with higher risk
of 30-day mortality in patients without known diabetes (glucose ≤110 mg/dL;
range from glucose >110 to 140 mg/dL: hazard ratio [HR] 1.17; 95% CI 1.11-1.24; to
glucose ≥240 mg/dL: HR 1.87; 95% CI 1.75-2.00) [11]. (See "Prevalence of and risk
factors for coronary heart disease in patients with diabetes mellitus", section on
'CHD before diabetes'.)

Outcomes after myocardial infarction — Outcomes after acute MI in patients

with diabetes are worse than in patients without diabetes, particularly in women
( figure 1) [12-14]. In the TIMI ACS trials from 1997 to 2006, 10,613 patients had
diabetes (17 percent of the overall population). Diabetes was independently
associated with higher mortality at 30 days after unstable angina/non-ST elevation
MI (2.1 versus 1.1 percent; odds ratio [OR] 1.78; 95% CI 1.24-2.56) or STEMI (8.5
versus 5.4 percent; OR 1.40; 95% CI 1.24-1.57) [15].

Similar observations have been seen in other cohorts [4,12,13,16-18]. The reason
for these associations are likely multifactorial and include higher burden of
coronary artery disease, increased comorbidities such as renal disease, and
increased acuity at the time of presentation.

In the TAMI trial, patients with diabetes were more likely to present in acute
pulmonary edema than patients without diabetes (11 versus 4 percent in TAMI)
[12]. The increased incidence of heart failure frequently occurs despite similar
infarct sizes and left ventricular ejection fractions [12,13,19].

One or more of the following may contribute to the higher incidence of heart
failure at the time of MI in diabetics:

● A greater extent of coronary disease (ie, more multivessel disease) which

affects myocardial performance by limiting blood flow to noninfarcted
myocardium [12,20,21]

● Intrinsic myocardial dysfunction (see "Heart failure in patients with diabetes

:
 mellitus: Epidemiology, pathophysiology, and management")

● An increased incidence of prior MI [19,20]

Diabetic patients also may have a higher risk of other complications, including
arrhythmias, cardiogenic shock, heart failure, renal failure, and recurrent MI
[4,13,14,16,17].

REPERFUSION

Many patients with acute MI benefit from early reperfusion.

ST-elevation myocardial infarction — Immediate coronary reperfusion is, in the

absence of a contraindication, recommended in all patients with an acute ST-
elevation MI (STEMI). This is usually achieved by primary percutaneous coronary
intervention (PCI) or fibrinolytic therapy. Primary PCI is the preferred method for
reperfusion after an acute ST-elevation MI since it produces better outcomes than
thrombolysis. (See "Primary percutaneous coronary intervention in acute ST
elevation myocardial infarction: Determinants of outcome" and "Acute ST-elevation
myocardial infarction: Selecting a reperfusion strategy".)

Primary percutaneous coronary intervention — Patients with diabetes have

better outcomes with primary PCI (percutaneous transluminal coronary
angioplasty [PTCA] or stenting) than with fibrinolysis. The best data come from a
meta-analysis of pooled patient data from 19 randomized trials that enrolled 6315
patients, 14 percent of whom had diabetes [22]. The following statistically
significant findings were noted at 30 days:

● Mortality was lower after primary PCI than fibrinolysis (6.6 versus 12.4
percent; unadjusted OR 0.49, 95% CI 0.31-0.79).

● Death or recurrent MI was reduced after primary PCI (9.6 versus 17.1
percent; unadjusted OR 0.52; 95% CI 0.35-0.77).

● Stroke was reduced after primary PCI (1.5 versus 3.7 percent; unadjusted OR
0.40; 95% CI 0.16-0.99).
:
 The value of primary PCI with stenting compared to PTCA alone was evaluated in
the CADILLAC trial in which 2082 patients with acute STEMI (almost 17 percent
diabetic) were randomly assigned to PTCA alone, PTCA and abciximab, stenting
alone, or stenting and abciximab; clopidogrel or ticlopidine was given to all
patients initially and then continued in those who received a stent [23]. The
outcomes were significantly better with stenting and the relative benefit was
similar in patients with or without diabetes (OR 0.56 and 0.52, respectively). In the
cohort with diabetes, the rate of target vessel revascularization at one year was
higher in patients treated with PTCA when compared with coronary stenting (10.3
versus 22.4 percent, p = 0.004). There were no significant differences in the other
endpoints including death, reinfarction, or stroke [24].

One possible contributor to the worse outcomes in diabetics is microvascular

disease. This issue was addressed in a report of two substudies from the CADILLAC
trial [25]. Two markers of tissue perfusion were evaluated: TIMI myocardial
perfusion (blush) grade on angiography and ST segment resolution. (See
"Diagnosis and management of failed fibrinolysis or threatened reocclusion in
acute ST-elevation myocardial infarction", section on 'Primary failure'.)

The following findings were noted:

● Postprocedural TIMI flow grade 3 (normal flow) was attained in more than 95
percent of patients (including those with and without diabetes).

● Patients with diabetes were significantly more likely to have a TIMI

myocardial perfusion (or blush) grade of 0/1 after PCI (56 versus 47 percent
in nondiabetics), indicating little or no tissue perfusion.

● Patients with diabetes were significantly more likely to have persistent ST-
segment elevation (20 versus 8 percent), indicating a larger area with
endangered perfusion.

These persistent abnormalities were associated with a trend toward increased

mortality in patients with diabetes. Similar findings in diabetics (reduced
myocardial blush grade and impaired ST-segment resolution after primary PCI)
have also been noted in other studies [26].
:
 Fibrinolytic therapy — Patients with diabetes and ST-elevation myocardial
infarction (STEMI) appear to derive the same or greater benefit (including
mortality) from fibrinolytic therapy as patients without diabetes [27]. For patients
who cannot receive timely PCI, fibrinolytic therapy should be considered.

While there has been a specific concern about the use of fibrinolytics with regard
to the potential risk of intraocular hemorrhage in patients with diabetic
retinopathy, we do not believe it is a major contraindication. Among 6011 patients
with diabetes in the GUSTO-I trial, it was estimated that about 2000 had
nonproliferative retinopathy and about 300 had proliferative retinopathy [28]. Only
one patient had an ocular hemorrhage, which was an eyelid hematoma. Although
the risk of ocular hemorrhage was not as completely evaluated in other major
thrombolytic trials, an appreciable number of diabetics were included without
reports of major intraocular bleeding [29].

Non-ST-elevation myocardial infarction — In patients with an acute NSTEMI, an

early invasive strategy in which patients go for coronary angiography with plans to
proceed with revascularization (if amenable) within 48 hours of the index event
has been shown to reduce cardiovascular events [30]. This benefit appears
proportional to the risk of the patient. Given the increased risk associated with
diabetes, this cohort warrants an early invasive strategy when presenting with
NSTEMI. Coronary angiography, performed in the acute period following NSTEMI,
demonstrates that the infarct-related artery is not occluded in 60 to 85 percent of
cases.

However, because of improved long-term outcomes with revascularization, almost

all patients with a NSTEMI are candidates for early angiography (performed within
4 to 48 hours after presentation) followed by revascularization with either
percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery
(CABG) if appropriate. Given the higher prevalence of multivessel coronary artery
disease in patients with diabetes, they are more likely to need CABG [31]. This topic
will not be discussed further here since the presence or absence of diabetes does
not influence decision making other than denoting the cohort of patients with
diabetes as high risk in nature. (See "Coronary artery revascularization in stable
patients with diabetes mellitus".)
:
 ANTICOAGULANT THERAPY

Early anticoagulation remains a cornerstone of treatment for patients hospitalized

with acute MI. The choice of anticoagulants is similar irrespective of the presence
or absence of diabetes. Intravenous heparin is the preferred agent in patients
undergoing PCI [32]. (See "Acute ST-elevation myocardial infarction: Management
of anticoagulation" and "Anticoagulant therapy in non-ST elevation acute coronary
syndromes".)

ANTIPLATELET THERAPY

All MI patients, including those with diabetes, should receive aspirin (see "Aspirin
for the secondary prevention of atherosclerotic cardiovascular disease", section on
'Summary and recommendations') and a P2Y12 receptor blocker as soon as
possible after the diagnosis has been made. The choice of the P2Y12 receptor
blocker depends on the reperfusion strategy. (See "Acute ST-elevation myocardial
infarction: Antiplatelet therapy", section on 'Our approach to early DAPT'.)

In every major trial which compared clopidogrel to placebo or prasugrel or

ticagrelor to clopidogrel, outcomes in the subgroup of patients with diabetes were
similar to the broad population of patients enrolled [33-38].

Patients with diabetes mellitus have increased platelet reactivity, with intensified
adhesion, activation, and aggregation. This appears to be due to dysregulation of
several signaling pathways secondary to changes at the receptor level (eg,
increased expression) and abnormalities in intracellular downstream signaling
[39,40]. These abnormalities may partially explain the higher risk of developing an
acute coronary syndrome, as well as in the larger proportion of diabetes patients
with inadequate response to antiplatelet agents (eg, clopidogrel, aspirin)
compared to patients without diabetes. (See "Clopidogrel resistance and
clopidogrel treatment failure", section on 'Diabetes mellitus'.)

Since clopidogrel is a pro-drug that may be metabolized into its active form via the
liver, there is patient-level variation in platelet reactivity [39,40]. Patients with
diabetes are more likely to have high platelet reactivity during treatment with
:
 clopidogrel. These patients are at increased risk of major adverse cardiovascular
events [41]. Patients with diabetes benefit from more intensive antiplatelet
therapy, and we choose ticagrelor in most cases. (See "Clopidogrel resistance and
clopidogrel treatment failure", section on 'Diabetes mellitus'.)

Intravenous glycoprotein IIb/IIIa inhibitors — For patients with diabetes and

MI who receive early antiplatelet therapy with aspirin and a P2Y12 inhibitor, we
recommend not routinely using a GP IIb/IIIa inhibitor. In those patients
undergoing PCI who have not been treated with a P2Y12 inhibitor, intravenous
cangrelor can be considered. GP IIb/IIIa inhibitor should be reserved for patients
with thrombotic complications of PCI. (See "Acute ST-elevation myocardial
infarction: Antiplatelet therapy", section on 'Intravenous agents'.)

SECONDARY PREVENTION

Similar to the broad group of patients with acute MI, we employ multiple
secondary preventive interventions in those with diabetes. (See "Prevention of
cardiovascular disease events in those with established disease (secondary
prevention) or at very high risk".)

Lipid lowering — Patients with diabetes mellitus are considered to be at very high

risk for subsequent coronary artery disease events. Aggressive low density
lipoprotein cholesterol (LDL-C) lowering is beneficial in all patients with a prior MI.
Patients should be started on high-intensity lipid-lowering therapy, such as with
atorvastatin 80 mg daily, while in the hospital. (See "Low density lipoprotein-
cholesterol (LDL-C) lowering after an acute coronary syndrome".)

Beta blockers — Beta blocker therapy after MI reduces infarct size, the incidence
of infarct extension, recurrent ischemia, reinfarction, and cardiac and sudden
death mortality. The concern about the possibility of masking hypoglycemic
symptoms or worsening glycemic control has made some physicians reluctant to
prescribe beta blockers to patients with diabetes. However, these concerns have
been overstated, and analysis of outcomes of diabetic subgroups in several
postinfarction beta blocker trials has shown an overall benefit from the use of beta
blockers that is at least equivalent to and may be greater than that seen in
:
 patients without diabetes [42,43]. (See "Acute myocardial infarction: Role of beta
blocker therapy".)

The National Cooperative Cardiovascular Project reviewed the records of 45,308

patients 65 years of age or older, 26 percent of whom had diabetes [44]. After
adjusting for potential confounders, use of beta blockers was associated with a
lower one-year mortality rate for patients with both insulin and non-insulin-treated
diabetes. The association between use of beta blockers and outcomes was similar
to that seen in patients without diabetes. There was no association with an
increased risk of readmission for diabetes-related complications. Despite these
data, patients with diabetes were less likely to receive beta blockers when
compared with patients without diabetes.

ACE inhibitors — All patients with diabetes should be considered for an

angiotensin converting enzyme (ACE) inhibitor or, if not tolerated, an angiotensin
II receptor blocker early after the diagnosis of an MI. When given after an acute
MI, ACE inhibitors reduce infarct size, limit ventricular remodeling, and reduce
mortality.

They may be of particular benefit in patients with diabetes. Many patients with
type 1 and 2 diabetes will be treated with an ACE inhibitor or angiotensin II
receptor blocker for blood pressure control and risk mitigation even before their
myocardial event. (See "Angiotensin converting enzyme inhibitors and receptor
blockers in acute myocardial infarction: Recommendations for use" and
"Angiotensin converting enzyme inhibitors and receptor blockers in acute
myocardial infarction: Clinical trials", section on 'Effects in all patients'.)

The GISSI-3 trial of patients with acute MI, which included 2790 patients with
diabetes, found that six weeks of treatment with lisinopril reduced mortality (odds
ratio 0.88; 95% CI 0.79-0.99) [45]. In the cohort with diabetes, six-month mortality
was reduced (12.9 versus 16.1 percent) ( figure 2) [46]. The benefit of ACE
inhibition translated into 37 lives saved per 1000 treated patients, an effect that
was higher than that observed in patients without diabetes.

Aldosterone antagonists — We recommend an aldosterone receptor blocker to

all patients with diabetes who meet the following criteria, which were derived from
:
 the EPHESUS trial of patients 3 to 14 days after acute MI [47,48]:

● Are receiving an ACE inhibitor and a beta blocker

● Have a left ventricular ejection fraction ≤40 percent
● Have a serum creatinine ≤2.5 mg/dL (221 micromol/L) in men and ≤2.0 mg/dL
(177 micromol/L) in women
● Have a serum potassium ≤5.0 mEq/L

The serum potassium must be monitored closely during treatment. Although

uncommon, life-threatening hyperkalemia can occur due to the combination of
aldosterone inhibition and reduced aldosterone secretion associated with ACE
inhibitor therapy, and, in some patients, renal insufficiency. (See "Initial
pharmacologic therapy of heart failure with reduced ejection fraction in adults".)

Glycemic control — The optimal blood glucose target in hyperglycemic critically ill

patients is uncertain, but we believe a range of 140 to 180 mg/dL (7.8 to 10.0
mmol/L) is reasonable. This issue is discussed in detail elsewhere. (See "Glycemic
control for acute myocardial infarction in patients with and without diabetes
mellitus".)

Efforts to reduce long-term cardiovascular risk in patients with diabetes should

include glycemic control after discharge. The goal HbA1c should depend upon the
individual characteristics of each patient. In general, the goal HbA1c should be less
than 7 percent, although more lenient control can be accepted in patients with
limited life-span, comorbidities, or those at high risk of hypoglycemia. In contrast,
more strict control should be considered in patients at low risk of hypoglycemia.
(See "Glycemic control for acute myocardial infarction in patients with and without
diabetes mellitus" and "Initial management of hyperglycemia in adults with type 2
diabetes mellitus", section on 'Glycemic management'.)

Other drugs

Sodium glucose-like co-transporter-2 inhibitors — Sodium glucose-like co-

transporter-2 (SGLT2) inhibitors including empagliflozin, canagliflozin and
dapagliflozin reduce cardiovascular events by approximately 15 percent, largely in
patients with prior cardiovascular events. The role of SGLT2 inhibitors in patients
with diabetes is discussed elsewhere. (See "Sodium-glucose co-transporter 2
:
 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section
on 'Patient selection' and "Sodium-glucose co-transporter 2 inhibitors for the
treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular
effects'.)

SGLT2 inhibitors should be utilized in patients with diabetes following a myocardial

infarction. There are no data available to support use during the acute event. Thus,
these agents should be considered once patients are stabilized from their acute
event, particularly in those patients in whom the risk of heart failure is elevated.

GLP-1 receptor agonists — Randomized clinical trials to establish cardiovascular

safety have found that some glucagon-like peptide 1 receptor (GLP-1) agonists
decrease cardiovascular events in patients with diabetes (see "Glucagon-like
peptide 1-based therapies for the treatment of type 2 diabetes mellitus"). In a
meta-analysis of seven trials, GLP-1 receptor agonists reduced cardiovascular
death, MI, or stroke in patients with established coronary artery disease by 14
percent (HR 0.86, 95% CI 0.79-0.94). However, there are differences across the class
with regard to the effects of an agent on cardiovascular events. GLP-1 receptor
agonists have been shown to decrease cardiovascular events in the cohort of
patients with established cardiovascular disease [49]. Similar to SGL2i, these
agents should be considered once patients are stabilized from their acute event.

Metformin — While metformin is first-line therapy for patients with diabetes,

there have been no adequately powered randomized clinical trials to assess its
benefit following an MI. In the GIPS III trial, there was no difference in left
ventricular function at four months [50].

Regulators of gene transcription — Small molecule regulators of gene

transcription, such as bromodomain and extraterminal (BET) proteins, may be
involved in the pathogenesis of atherosclerosis (see "Pathogenesis of
atherosclerosis", section on 'Pathogenesis'). The ability of apabetalone, a selective
inhibitor of these proteins, to improve cardiovascular outcomes after ACS has been
evaluated. In the BETonMACE randomized trial of 2425 ACS patients with diabetes
and low high-density lipoprotein cholesterol, apabetalone did not significantly
lower the rate of a composite of adverse cardiovascular outcomes during more
than two years of follow-up (hazard ratio 0.82, 95% CI 0.645-1.04) [51].
:
 Blood pressure control — Hypertension should be aggressively treated in
patients who have diabetes mellitus. The optimal goal blood pressure and choice
of antihypertensive drugs in such patients are discussed in detail separately. (See
"Treatment of hypertension in patients with diabetes mellitus".)

Multifactorial risk factor reduction — The benefits associated with multifactorial

risk factor reduction (eg, aspirin, blood pressure and glycemic control, and
cessation of smoking) in patients with diabetes have been demonstrated in
multiple studies [52,53]. Cardiac rehabilitation is indicated for patients with ACS
and can be helpful in initiating lifestyle changes. The details of the protocol and
overall results of this study are discussed elsewhere. (See "Overview of general
medical care in nonpregnant adults with diabetes mellitus", section on
'Multifactorial risk factor reduction' and "Cardiac rehabilitation: Indications,
efficacy, and safety in patients with coronary heart disease", section on 'Summary
and recommendations'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries

and regions around the world are provided separately. (See "Society guideline
links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial
infarction)" and "Society guideline links: ST-elevation myocardial infarction
(STEMI)".)

SUMMARY AND RECOMMENDATIONS

● Coronary heart disease patients with diabetes have worse long-term survival
than those without diabetes. (See 'Introduction' above.)

● The treatment of myocardial infarction (MI) in patients with diabetes mellitus

is largely similar to that in those without diabetes.

• Patients with acute coronary syndrome (ACS) and diabetes should

undergo early reperfusion. (See 'Reperfusion' above.)
:
 In patients with ST-elevation MI (STEMI), immediate percutaneous
coronary intervention (PCI) is recommended. (See 'ST-elevation myocardial
infarction' above.)

In patients with NSTE-ACS, an early invasive strategy is recommended.

The mode of revascularization, PCI or coronary artery bypass graft
surgery, is dependent upon clinical variables including severity/burden of
disease, anatomy, and patient characteristics. (See 'Non-ST-elevation
myocardial infarction' above.)

• Following ACS, patients should be treated with aggressive secondary

prevention strategies. (See 'Secondary prevention' above.)

This includes (but is not limited to) aspirin, high-dose statin therapy, beta
blockers, renin-angiotensin-aldosterone system inhibitors, sodium-
glucose co-transporter 2 inhibitors, and glucagon-like peptide-1 agonists
in appropriate patients.

• The optimal blood glucose target in hyperglycemic critically ill patients is

uncertain, but we believe a range of 140 to 180 mg/dL (7.8 to 10.0
mmol/L) is reasonable. (See 'Glycemic control' above.)

Use of UpToDate is subject to the Terms of Use.

REFERENCES
1. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since
1980: a pooled analysis of 751 population-based studies with 4.4 million
participants. Lancet 2016; 387:1513.

2. Cheng YJ, Kanaya AM, Araneta MRG, et al. Prevalence of Diabetes by Race and
Ethnicity in the United States, 2011-2016. JAMA 2019; 322:2389.

3. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the

United States, 1990-2010. N Engl J Med 2014; 370:1514.

4. Aguilar D, Solomon SD, Køber L, et al. Newly diagnosed and previously known
:
 diabetes mellitus and 1-year outcomes of acute myocardial infarction: the
VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Circulation 2004;
110:1572.

5. Shore S, Borgerding JA, Gylys-Colwell I, et al. Association between

hyperglycemia at admission during hospitalization for acute myocardial
infarction and subsequent diabetes: insights from the veterans
administration cardiac care follow-up clinical study. Diabetes Care 2014;
37:409.

6. Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with

acute myocardial infarction and no previous diagnosis of diabetes mellitus: a
prospective study. Lancet 2002; 359:2140.

7. Haffner SM, Lehto S, Rönnemaa T, et al. Mortality from coronary heart

disease in subjects with type 2 diabetes and in nondiabetic subjects with and
without prior myocardial infarction. N Engl J Med 1998; 339:229.

8. Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary

risk equivalent? Systematic review and meta-analysis. Diabet Med 2009;
26:142.

9. Cavender MA, Steg PG, Smith SC Jr, et al. Impact of Diabetes Mellitus on
Hospitalization for Heart Failure, Cardiovascular Events, and Death:
Outcomes at 4 Years From the Reduction of Atherothrombosis for Continued
Health (REACH) Registry. Circulation 2015; 132:923.

10. Cavender MA, Scirica BM, Bonaca MP, et al. Vorapaxar in patients with
diabetes mellitus and previous myocardial infarction: findings from the
thrombin receptor antagonist in secondary prevention of atherothrombotic
ischemic events-TIMI 50 trial. Circulation 2015; 131:1047.

11. Kosiborod M, Rathore SS, Inzucchi SE, et al. Admission glucose and mortality
in elderly patients hospitalized with acute myocardial infarction: implications
for patients with and without recognized diabetes. Circulation 2005;
111:3078.

12. Granger CB, Califf RM, Young S, et al. Outcome of patients with diabetes
:
 mellitus and acute myocardial infarction treated with thrombolytic agents.
The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study
Group. J Am Coll Cardiol 1993; 21:920.

13. Stone PH, Muller JE, Hartwell T, et al. The effect of diabetes mellitus on
prognosis and serial left ventricular function after acute myocardial
infarction: contribution of both coronary disease and diastolic left ventricular
dysfunction to the adverse prognosis. The MILIS Study Group. J Am Coll
Cardiol 1989; 14:49.

14. Savage MP, Krolewski AS, Kenien GG, et al. Acute myocardial infarction in
diabetes mellitus and significance of congestive heart failure as a prognostic
factor. Am J Cardiol 1988; 62:665.

15. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following
acute coronary syndromes. JAMA 2007; 298:765.

16. Yudkin JS, Oswald GA. Determinants of hospital admission and case fatality in
diabetic patients with myocardial infarction. Diabetes Care 1988; 11:351.

17. Franklin K, Goldberg RJ, Spencer F, et al. Implications of diabetes in patients

with acute coronary syndromes. The Global Registry of Acute Coronary
Events. Arch Intern Med 2004; 164:1457.

18. Zuanetti G, Latini R, Maggioni AP, et al. Influence of diabetes on mortality in

acute myocardial infarction: data from the GISSI-2 study. J Am Coll Cardiol
1993; 22:1788.

19. Jaffe AS, Spadaro JJ, Schechtman K, et al. Increased congestive heart failure
after myocardial infarction of modest extent in patients with diabetes
mellitus. Am Heart J 1984; 108:31.

20. Mak KH, Moliterno DJ, Granger CB, et al. Influence of diabetes mellitus on
clinical outcome in the thrombolytic era of acute myocardial infarction.
GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol
1997; 30:171.
:
 21. Stein B, Weintraub WS, Gebhart SP, et al. Influence of diabetes mellitus on
early and late outcome after percutaneous transluminal coronary
angioplasty. Circulation 1995; 91:979.

22. Timmer JR, Ottervanger JP, de Boer MJ, et al. Primary percutaneous coronary
intervention compared with fibrinolysis for myocardial infarction in diabetes
mellitus: results from the Primary Coronary Angioplasty vs Thrombolysis-2
trial. Arch Intern Med 2007; 167:1353.

23. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting,
with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;
346:957.

24. Stuckey TD, Stone GW, Cox DA, et al. Impact of stenting and abciximab in
patients with diabetes mellitus undergoing primary angioplasty in acute
myocardial infarction (the CADILLAC trial). Am J Cardiol 2005; 95:1.

25. Prasad A, Stone GW, Stuckey TD, et al. Impact of diabetes mellitus on
myocardial perfusion after primary angioplasty in patients with acute
myocardial infarction. J Am Coll Cardiol 2005; 45:508.

26. Timmer JR, van der Horst IC, de Luca G, et al. Comparison of myocardial
perfusion after successful primary percutaneous coronary intervention in
patients with ST-elevation myocardial infarction with versus without diabetes
mellitus. Am J Cardiol 2005; 95:1375.

27. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither

among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2
(Second International Study of Infarct Survival) Collaborative Group. Lancet
1988; 2:349.

28. Mahaffey KW, Granger CB, Toth CA, et al. Diabetic retinopathy should not be
a contraindication to thrombolytic therapy for acute myocardial infarction:
review of ocular hemorrhage incidence and location in the GUSTO-I trial.
Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries. J
Am Coll Cardiol 1997; 30:1606.

29. Ward H, Yudkin JS. Thrombolysis in patients with diabetes. BMJ 1995; 310:3.
:
 30. Bavry AA, Kumbhani DJ, Rassi AN, et al. Benefit of early invasive therapy in
acute coronary syndromes: a meta-analysis of contemporary randomized
clinical trials. J Am Coll Cardiol 2006; 48:1319.

31. O'Donoghue ML, Vaidya A, Afsal R, et al. An invasive or conservative strategy

in patients with diabetes mellitus and non-ST-segment elevation acute
coronary syndromes: a collaborative meta-analysis of randomized trials. J Am
Coll Cardiol 2012; 60:106.

32. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for
percutaneous coronary intervention: a meta-analysis of randomised
controlled trials. Lancet 2014; 384:599.

33. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in
patients with acute coronary syndromes without ST-segment elevation. N
Engl J Med 2001; 345:494.

34. Franchi F, Rollini F, Aggarwal N, et al. Pharmacodynamic Comparison of

Prasugrel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and
Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in
Diabetes Mellitus)-4 Study. Circulation 2016; 134:780.

35. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in

patients with acute coronary syndromes. N Engl J Med 2009; 361:1045.

36. James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients
with acute coronary syndromes and diabetes: a substudy from the PLATelet
inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010; 31:3006.

37. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in
patients with acute coronary syndromes. N Engl J Med 2007; 357:2001.

38. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute
coronary syndromes without revascularization. N Engl J Med 2012; 367:1297.

39. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary
syndrome. Circulation 2011; 123:798.
:
 40. Ferroni P, Basili S, Falco A, Davì G. Platelet activation in type 2 diabetes
mellitus. J Thromb Haemost 2004; 2:1282.

41. Angiolillo DJ, Bernardo E, Sabaté M, et al. Impact of platelet reactivity on

cardiovascular outcomes in patients with type 2 diabetes mellitus and
coronary artery disease. J Am Coll Cardiol 2007; 50:1541.

42. Gundersen T, Kjekshus J. Timolol treatment after myocardial infarction in

diabetic patients. Diabetes Care 1983; 6:285.

43. Malmberg K, Herlitz J, Hjalmarson A, Rydén L. Effects of metoprolol on

mortality and late infarction in diabetics with suspected acute myocardial
infarction. Retrospective data from two large studies. Eur Heart J 1989;
10:423.

44. Chen J, Marciniak TA, Radford MJ, et al. Beta-blocker therapy for secondary
prevention of myocardial infarction in elderly diabetic patients. Results from
the National Cooperative Cardiovascular Project. J Am Coll Cardiol 1999;
34:1388.

45. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and
together on 6-week mortality and ventricular function after acute myocardial
infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto
Miocardico. Lancet 1994; 343:1115.

46. Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on
mortality in diabetic patients with acute myocardial infarction: data from the
GISSI-3 study. Circulation 1997; 96:4239.

47. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker,

in patients with left ventricular dysfunction after myocardial infarction. N
Engl J Med 2003; 348:1309.

48. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the
management of patients with non-ST-elevation acute coronary syndromes:
executive summary: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. Circulation 2014;
130:2354.
:
 49. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney
outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a
systematic review and meta-analysis of cardiovascular outcome trials. Lancet
Diabetes Endocrinol 2019; 7:776.

50. Lexis CP, van der Horst IC, Lipsic E, et al. Effect of metformin on left
ventricular function after acute myocardial infarction in patients without
diabetes: the GIPS-III randomized clinical trial. JAMA 2014; 311:1526.

51. Ray KK, Nicholls SJ, Buhr KA, et al. Effect of Apabetalone Added to Standard
Therapy on Major Adverse Cardiovascular Events in Patients With Recent
Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.
JAMA 2020; 323:1565.

52. Gæde P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial

intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358:580.

53. Bittner V, Bertolet M, Barraza Felix R, et al. Comprehensive Cardiovascular

Risk Factor Control Improves Survival: The BARI 2D Trial. J Am Coll Cardiol
2015; 66:765.

Topic 84 Version 31.0

:
: