REVIEW PAPER doi: 10.1111/j.1559-4572.2008.00040.x

Screening Guidelines for Coronary Heart Disease in Diabetes:Current Recommendations

Diabetes mellitus (DM) is a com-plex metabolic disorder character-

ized by complete lack of endogenouspancreatic insulin production in type 1and by the progressive insulin secretorydefect on the background of insulinresistance in type 2. The spectrum ofcoronary heart disease (CHD), whichcan include angina, congestive heartfailure, myocardial infarction (MI), andsudden cardiac death, is a major com-plication of both type 1 and type 2 DM.In type 1 DM, which does not usuallyhave the traditional cardiovascular riskfactors, duration of DM becomes themost important predictor of prematureCHD. CHD can present as early asbetween the 3rd and 4th decade of lifein type 1 DM. Persons with type 2 DMusually have concomitant traditionalCHD risk factors and often presentwith CHD between the fifth or sixthdecade of life or later. They frequentlypresent soon after DM is diagnosed oreven at the time of diagnosis.1

DM is associated with developmentof specific complications that are micro-vascular and macrovascular dependingon the organ damage. The macrovascu-lar complications refer to the high riskof cardiovascular, cerebrovascular, andperipheral arterial disease. The increasein cardiovascular risk is due to bothDM and the frequent presence of otherrisk factors (eg, dyslipidemia and hyper-tension). Cardiovascular disease, whichincludes CHD, cerebrovascular disease,and peripheral vascular disease, is theleading cause of mortality in personswith DM. Most of these deaths are dueto complications of coronary artery dis-ease. Diabetic persons have at least twicethe risk of cardiovascular complicationscompared with age-matched individualswithout DM. Subsequent to MI, dia-betics have 2- to 3-fold greater morbid-ity and mortality.1

This review addresses the currentscreening and diagnosis recommen-

dations for coronary artery disease inpatients with DM.

MethodologyThis manuscript is based primarily on areview of recent recommendations fromthe American Diabetes Association, theThird Report of the National Choles-terol Education Program Adult Treat-ment Panel (NCEP ATP III), theEuropean Society of Cardiology, andthe European Association for the Studyof Diabetes.

Definition of DM and Prediabe-tes. Before type 2 DM develops,patients almost always have ‘‘prediabe-tes,’’ classified as blood glucose levelsthat are higher than normal but not yethigh enough for DM to be diagnosed.There are 54 million individuals in theUnited States with prediabetes. Recent

data suggest that a few long-term com-plications, especially involving the heartand circulatory system, may alreadybe occurring during the prediabeticstage.2,3

There are 2 different tests used todetermine whether prediabetes or DMis present: the fasting plasma glucosetest and the oral glucose tolerance test.The blood glucose levels measured afterthese tests determine whether a patienthas a normal metabolism there is predi-abetes or DM. If the blood glucose levelis abnormal following the fastingplasma glucose test, it is consideredimpaired fasting glucose; an abnormalblood glucose level on the oral glucosetolerance test falls under the category ofimpaired glucose tolerance. Fastingblood glucose levels >126 mg/dL aredefined as diabetic (see the criteria out-lined in Table I).

Diabetes and cardiovascular disease are so intertwined with one another that the

presence of one prompts a search for the other. Diabetes has been considered to be

equivalent to coronary heart disease (CHD), and conversely many patients with known

CHD have concomitant diabetes or its pre-states. This review has been compiled based

on the guidelines of the American Diabetes Association, the Third Report of the

National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), the

European Society of Cardiology, and the European Association for the Study of

Diabetes. A systematic approach was developed by the European Society of Cardiology

and the European Association for the Study of Diabetes recently to help detect CHD

in patients with diabetes and to detect metabolic diseases in patients with CHD.This

article is intended for the clinician in everyday practice focusing on the impact of recent

advances in the prevention and management of CHD in diabetic patients and the

background behind it. J Cardiometab Syndr. 2009;4:107–112. �2009 Wiley

Periodicals, Inc.

Sarabjeet Singh, MD; Jasleen Duggal, MD; Natalia Khosla, MD; Rohit Arora, MD

From the Division of Cardiology, Department of Medicine, Chicago Medical School,

Chicago, IL

Address for correspondence:

Sarabjeet Singh, MD, Division of Cardiology, Department of Medicine, Chicago Medical

School, 3001 Green Bay Road, North Chicago, IL 60064

E-mail: singh60660@yahoo.com

Manuscript received December 21, 2007; revised February 8, 2008;

accepted April 28, 2008

heart disease in diabetes JCMS spring 2009 107

DiscussionCardiovascular Risk With DM andPrediabetes. The NCEP ATP III fromthe United States and guidelines fromEurope consider type 2 DM to be aCHD equivalent.4,5 This was based onthe observation that individuals withtype 2 DM without a prior history ofCHD were at equivalent risk for MIand cardiac mortality compared withindividuals without DM who had priorMI.6 Further support of the relationbetween DM and MI was obtainedfrom the INTERHEART study.7

The association between abnormalglucose tolerance and increased CHDrisk has been provided by theDECODE study,8 a collaborative anal-ysis of diagnostic criteria in Europe.This study included approximately18,000 men and 7000 women. Thecumulative mortality curves suggestedthat the individuals with impaired glu-cose tolerance defined as prediabetichad significantly increased mortalitycompared with those who had normalglucose levels. All-cause mortality andcoronary artery disease rates were alsohigher in persons with DM diagnosedby 2-hour postload plasma glucoseassessment.8

In addition to an increase in cardio-vascular events, patients with type 2DM also have a high rate of asymptom-atic coronary artery disease comparedwith the general population. Further-more, asymptomatic patients with �2cardiovascular risk factors may have cor-onary arteries that do not permit opti-mal outcomes with revascularizationprocedures.9 These observations sup-port the practice of screening patientswith asymptomatic DM for CHD.

Screening for CHD in Patients WithDM. Many therapies have been shownto be beneficial in reducing the inci-dence of cardiovascular events in per-sons with DM. These therapies includetreatment of hypertension and dyslipi-demia and the use of aspirin, b-block-ers, and angiotensin-converting enzyme(ACE) inhibitors. Hence, recognitionof a previously undiagnosed MI orknowledge of the presence of CHD willhave an impact on the type and aggres-siveness of therapy.

In the patient with DM who has noclear evidence of CHD, clinicians mustdecide when to test for CHD and,equally important, which testing strat-egy is appropriate. To further assist phy-sicians faced with these problems, theAmerican Diabetes Association and theAmerican College of Cardiology con-vened a Consensus Development Con-ference in February 1998 calledDiagnosis of Coronary Heart Disease inPeople with Diabetes.1

Objective. The objective of screeningis to initiate anti-ischemic pharmaco-therapy and identify those who willpotentially benefit from revasculariza-tion procedures such as fibrinolyticadministration, percutaneous coronaryintervention (PCI), or coronary arterybypass grafting (CABG). There areenough data to support that early andaggressive intervention in diabetics withknown CHD is beneficial in reducingrates of major adverse cardiovascularevents.

Another advantage of screening maybe to implement preventive programsto reduce the risk of future coronaryevents. Early diagnosis of asymptomatic

CHD should encourage aggressivelipid-lowering therapy.1

The NCEP ATP III guidelines4 dif-ferentiate goals of therapy according tothe absence or presence of coronary dis-ease. This distinction suggests that diag-nosis of presymptomatic CHD shouldinfluence therapeutic decisions. It iswell established that control of hyper-tension in patients with DM is impor-tant to reduce the onset or progressionof diabetic nephropathy. Demonstra-tion of the presence of coronary diseaseor abnormal left ventricular functionmight have an impact on the choice ofantihypertensive agent prescribed, inparticular, ACE inhibitors.

Studies using conventional echocar-diography have shown global diastolicdysfunction with a prevalence ofabout 60% in patients with type II DMwho have no clinically detectableCHD.10,11

Who Should Be Tested. The role ofscreening for CHD in patients withDM has been addressed by the Ameri-can Diabetes Association and the Amer-ican College of Cardiology/AmericanHeart Association and is indicated inthe following settings:

(1) Typical or atypical cardiac symp-toms

(2) Resting electrocardiography (ECG)results suggestive of ischemia orinfarction

(3) Peripheral or carotid occlusive arte-rial disease

(4) Sedentary lifestyle, age of 35 yearsor older, and plans to begin a vigor-ous exercise program

It has previously been proposed toscreen those with �2 additional cardiacrisk factors. However, this likelyincludes the vast majority of patientswith type 2 DM (given that the risk fac-tors frequently cluster). The Detectionof Silent Myocardial Ischemia inAsymptomatic Diabetic Subjects(DIAD) study suggested that conven-tional cardiac risk factors did not helpto identify patients with abnormal per-fusion imaging findings.12 The 2006American Diabetes Association guide-lines no longer recommended screening

Table I. Criteria Established by the American Diabetes Association

Glucose Control Criteria, mg/dL

Normal glucose regulation FPG<100

IFG FPG>100 and<126IGT 2-Hour postload plasma

glucose>140 and<200Diabetes mellitus FPG�126

Abbreviations: FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impairedglucose tolerance. IGT can only be diagnosed via oral glucose tolerance test. It isperformed in the morning after 12 hours’ fasting; one blood sample is taken before andone 120 minutes after intake of 75 g of glucose dissolved in 250 mL water for 5 minutes.

heart disease in diabetes JCMS spring 2009108

‘‘high-risk’’ diabetic patients with car-diac stress testing, a revision from previ-ous recommendations.13 The 2002American College of Cardiology/Amer-ican Heart Association guidelines forexercise testing concluded that the cur-rent evidence favors evaluation only inasymptomatic patients with DM whoplan to begin a vigorous exercise pro-gram (class IIa [level of evidence: C])14

(classes and evidence grading men-tioned in Table II).

Stress Testing for DiagnosingCHD. Standard exercise ECG is rec-ommended if baseline ECG findings arenormal, since the exercise response willbe an important factor in determiningprognosis. If baseline ECG findingsshow abnormalities that will interferewith interpretation during exercise or iflocalization of ischemia is an importantconsideration, exercise testing withimaging can be recommended (eg, echo-cardiography or myocardial perfusionimaging [MPI]). For patients who can-not exercise, pharmacologic stress test-ing should be done. Diabetic patientshave an increased frequency of silent STsegment depression and coronary perfu-sion abnormalities during stress testing.9

For stress test screening to be recom-mended in asymptomatic diabeticpatients, the prevalence of CHD shouldbe sufficiently high. However, only onelarge prospective study conducted sofar—the DIAD study—identified silentischemia in only 22% of 1123 asymp-tomatic patients with type 2 DM (aged50–75 years) who underwent adenosinestress MPI.12 Large defects were foundin an even lower percentage (5%). Datafrom large retrospective studies in pop-ulations with asymptomatic DM reporta higher prevalence.9,15,16

More information is required con-cerning prognosis and the significanceof early intervention (invasive or nonin-vasive) before widespread screening isrecommended. At present, there are noprospective studies showing that inter-vention in asymptomatic diabeticpatients with high-risk findings on stresstesting improves outcomes.

The possible benefit of routinescreening is being directly addressed in

the ongoing Bypass Angioplasty Revas-cularization Investigation 2 Diabetes(BARI 2D) trial, which is comparingrevascularization (with PCI or CABG)plus aggressive pharmacologic therapyto aggressive pharmacologic therapyalone in patients with type 2 DM whohave either mild stable coronary diseaseor are asymptomatic and have positivestress test findings and at least 1 majorcoronary artery with �50% stenosis oncoronary angiography.17 The screeningtest should accurately differentiatebetween low- and high-risk patients andshould be helpful in guiding the prog-nosis. High-risk patients would requirefurther evaluation. However, low-riskstress test results appear to predict lowrisk for only 2 years. The ability ofstress testing to determine prognosiswas evaluated in a study including 4755patients (929 with DM) who under-went stress MPI. In patients with nor-mal stress MPI findings, cardiacmortality was low and equivalent in dia-betic and nondiabetic patients for thefirst 2 years. However, after 2 years,there was a sharp increase in cardiacevents in the diabetic patients, with thehighest risk in diabetic women.18 Theworse outcomes in patients with DMcould be related to accelerated progres-sion of atherosclerosis. In high-riskpatients (such as those with DM) suchobservations have suggested that the‘‘warranty period’’ of normal stress MPIresults may be limited to 2 years.19

All patients with CHD status shouldhave aggressive cardiovascular risk fac-tor modification. Patients with abnor-mal exercise ECG findings and patientsunable to undergo exercise ECG requireadditional or alternative testing. Cur-rently, stress nuclear perfusion andstress echocardiography are valuablenext-level diagnostic procedures. A con-sultation with a cardiologist is recom-mended regarding further work-up.

At present, the optimal therapeuticapproach to the diabetic patient withsilent myocardial ischemia is unknown.However, if obstructed coronary arterydisease is recognized, aggressive inter-vention is suggested. If nonobstructedcoronary artery disease is detected, it isunknown whether there is any benefitto further therapy. There are no well-conducted prospective trials with ade-quate control groups to shed light onthis subject. Accordingly, there are noevidence-based guidelines or recom-mendations for screening asymptomaticdiabetics for coronary artery disease.The American College of Cardiology/American Heart Association establishedroutine screening of asymptomatic indi-viduals as a class III recommendation,thus favoring against an aggressive diag-nostic approach in nondiabetic persons.

Management. Anti-Ischemic Medica-tions. Initiating early treatment afterdetecting coronary artery disease isappropriate to prevent further ischemia.

Table II. American College of Cardiology/American Heart Association Classification forIndications and Level of Evidence

ClassificationClass I: Conditions for which there is evidence and/or general agreement that agiven procedure or treatment is useful and effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence ofopinion about the usefulness/efficacy of a procedure or treatment.

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Class IIb: Usefulness/efficacy is less well established by evidence/opinion.Class III: Conditions for which there is evidence and/or general agreement thatthe procedure/treatment is not useful/effective and in some cases may be harmful.

Level of evidenceHighest (A) if the data were derived from multiple randomized clinical trials thatinvolved large numbers of patients.

Intermediate (B) if the data were derived from a limited number of randomized

trials that involved small numbers of patients or from careful analyses ofnonrandomized studies or observational registries.

Lower rank (C) when expert consensus was the primary basis for the recommendation.

heart disease in diabetes JCMS spring 2009 109

b-Blocker therapy plays a vital role inthe setting of DM post-MI. Thus, estab-lishing the diagnosis of a previouslyunrecognized MI is essential in thesepatients.1 Patients treated with b-block-ers have a 50% reduction in mortalitycompared with patients not receivingthem.20 b-Blocker therapy was alsoshown to be effective in the Diabetesand Insulin-Glucose Infusion in AcuteMyocardial Infarction (DIGAMI)study.21 Also, use of cardioselective b-blockers (eg, carvedilol) might be partic-ularly beneficial in diabetic patients withreduced heart rate variability. However,b-blockers should be used with cautionparticularly in diabetic patients as it canpotentiate hypoglycemia. Epinephrineacts via the b-adrenergic receptors andenhances glucose release by stimulatingboth glycogenolysis and gluconeogene-sis, inhibits glucose utilization by severaltissues, and via the a2-receptors, inhib-

its insulin secretion. All of these aredefensive mechanisms to protect againstthe development of hypoglycemia.Besides, epinephrine induces earlywarning symptoms of neuroglycopenia,such as sweating and anxiety. The non-selective b-blockers can delay recoveryfrom insulin-induced hypoglycemia,and the reactions can be severe. The lat-ter effect is presumably due to dimin-ished or absent early warning signs.However, the effects on glucose metabo-lism may be less marked with b1-selec-tive drugs and those with intrinsicsympathomimetic activity. Further-more, carvedilol appears to promoteglucose utilization and lower insulin lev-els in patients with type 2 DM.22

Revascularization. Patients with sev-ere coronary obstruction shouldbe considered for revascularization,although the benefit of percutaneous

transluminal coronary angioplasty orCABG in those with asymptomaticCHD and DM is not clear. The previousBypass Angioplasty RevascularizationInvestigation (BARI) trial23 indicatedexcellent 5-year survival in symptomaticdiabetic patients with advanced mul-tivessel coronary disease treated withCABG. As mentioned above, the resultsof BARI 2D are awaited to assess thebenefits of the revascularization proce-dure (PCI or CABG) compared withmedical therapy alone.

Cardiovascular Risk Reduction. Atleast annually, cardiovascular riskfactors should be assessed. These riskfactors include dyslipidemia, hyper-tension, smoking, a positive familyhistory of premature coronary disease,and the presence of microalbuminuriaor macroalbuminuria. Aspirin therapyis recommended for primary preven-

Table III. ADA and European Guidelines (ESC and EASD) for Cardiovascular Disease Prevention: Treatment Goals in Diabetes andCardiovascular Disease (ABCDE)

A1c ADA A1c goal of<7% (B)A1c as close to normal (<6%) as possible without significant hypoglycemia (E)

ESC/EASD A1c�6.5%

BP ADA Systolic BP<130 mm Hg (C)Diastolic BP<80 mm Hg (B)

ESC/EASD BP <130/80 mm Hg

BP <125/75 mm Hg in renal impairment, proteinuria>1 g/24 hCholesterol/lipid profile ADA Without overt CVD: LDL-C<100 g/dL (A)

With overt CVD: LDL-C<70 mg/dL (B)

Triglycerides to<150 mg/dL (C)HDL-C to>40 mg/dL in men (C) and>50 mg/dL in women (C)

ESC/EASD LDL-C�70 mg/dLTriglycerides<150 mg/dL

HDL-C>40 mg/dL in men and>46 mg/dL in womenDiet ADA Weight loss for all overweight or obese individuals

who have or are at risk for diabetes (A)

Individualized medical nutrition (B): Therapy as neededto achieve treatment goals, preferably provided by a registereddietitian familiar with the components of diabetes MNT (B)

Saturated fat intake should be<7% of total calories (A)ESC/EASD Body mass index<25 kg/m2

Overweight 10% weight reductionSaturated fat<10% of dietary energy

Exercise ADA At least 150 min/wk of moderate-intensity aerobic physical activityAt least 90 min/wk of vigorous aerobic exercise

ESC/EASD 30–45 Min/d of physical activity

Smoking ADA Advise all patients not to smoke (A)ESC/EASD Obligatory

Abbreviations: A1c, hemoglobin A1c; ADA, American Diabetes Association; CVD, cardiovascular disease; ESC, European Society ofCardiology; EASD, European Association for the Study of Diabetes; HDL-C, high-density lipoprotein-C; LDL-C, low-density

lipoprotein cholesterol; MNT, medical nutrition therapy.

heart disease in diabetes JCMS spring 2009110

tion in high-risk men and women.1

The use of ACE inhibitors is alsorecommended as first-line treatment ofhypertension in patients with DM andthose with proteinuria.1 CHD screen-ing and treatment are reviewed indetail in the American Diabetes Associ-ation consensus statement on CHDin persons with DM.1 Emphasisshould be placed on reducing cardio-vascular risk factors when possible,and clinicians should be alert for signsand symptoms of atherosclerosis.(Target goals can be remembered asABCDE, as in Table III).

Benefits and Limitations of Screen-ing. The decision to perform a screen-ing test is driven by the utility of thetest, cost-effectiveness, and the benefitsand risks of treating a disease that mightbe identified by that test.

Regarding noninvasive testing inasymptomatic diabetic patients, the useof standard ECG stress testing has arelatively low sensitivity for detectingsingle-vessel disease, particularly whenit does not involve the proximal leftanterior descending artery. Consider-

ation should be given when conductingdiagnostic testing in individuals withlow pretest probability (screening)because of false-positive results. Suchfalse-positive results often impact thecost more than the economic burden ofthe initial test itself.1

In diabetic patients in whom CHDhas not clinically manifested, the identi-fication of occult disease might providebenefit in several ways. Patients inwhom very severe disease is identifiedmight benefit from some form of myo-cardial revascularization. A largercohort of patients with mild disease willlikely benefit from pharmacologic andlifestyle interventions, which couldretard the development of more severedisease and its complications, such asdeath, MI, disabling angina, and con-gestive heart failure.

Some patients are motivated for bet-ter compliance after learning the prog-nostic information that testing mightprovide.

ConclusionsThe diagnostic and therapeutic pro-gram for CHD in diabetic individuals

should be individualized, based on thepatient’s specific characteristics. Thosewho meet the eligibility criteria forscreening should be advised toundergo it. Achievement of the targetgoal of cardiovascular risk factors isimportant.

Physicians can carefully weigh thebenefits and risks of revascularizationand select patients with disease that ismost critical and most amenable torevascularization.

Disclaimer: This guideline has been com-posed primarily as an educational resourcefor busy physicians to provide them with asummary of recommendations from differ-ent organizations. In determining the pro-priety of any specific procedure or test, theclinician should apply his or her own pro-fessional judgment to the specific circum-stances presented by the individualpatient. The American Diabetes Associa-tion guidelines that were published10 years ago are taken into account, butthe recent updates are incorporated in anattempt to present the current standard ofpractice.

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