European Heart Journal Cardiovascular Imaging (2015) 16, 10651073

doi:10.1093/ehjci/jev106

Impact of diabetes duration on the extent

and severity of coronary atheroma burden
and long-term clinical outcome in asymptomatic
type 2 diabetic patients: evaluation by Coronary
CT angiography
Jin-Jin Kim 1, Byung-Hee Hwang 1, Ik Jun Choi 2, Eun-Ho Choo 3, Sungmin Lim 4,
Jae-Kyung Kim 3, Yoon-Seok Koh 5, Dong-Bin Kim 1, Sung-Won Jang 1, Eun Joo Cho 1,
Jong Min Lee 3, Pum-Joon Kim 5, Jae-Hyoung Cho 6, Jung Im Jung 7, Ki-Bae Seung 5,
James K. Min 8, and Kiyuk Chang 5*
1
Cardiovascular Center and Cardiology Division, St Pauls Hospital, The Catholic University of Korea, Seoul, Republic of Korea; 2Cardiovascular Center and Cardiology Division, Incheon
St Marys Hospital, The Catholic University of Korea, Incheon, Republic of Korea; 3Cardiovascular Center and Cardiology Division, Uijeongbu St Marys Hospital, The Catholic University
of Korea, Uijeongbu, Republic of Korea; 4Cardiovascular Center and Cardiology Division, Bucheon St Marys Hospital, The Catholic University of Korea, Bucheon, Republic of Korea;
5
Cardiovascular Center and Cardiology Division, Seoul St Marys Hospital, The Catholic University of Korea, 505 Banpodong, Seochogu, Seoul 137-701, Republic of Korea; 6Division of
Endocrinology, Department of Internal Medicine, Seoul St Marys Hospital, The Catholic University of Korea, Seoul, Republic of Korea; 7Department of Radiology, Seoul St Marys Hospital,
The Catholic University of Korea, Seoul, Republic of Korea; and 8Department of Radiology, Weill Cornell Medical College and the New York Presbyterian Hospital, New York, NY, USA

Received 7 October 2014; accepted after revision 2 April 2015; online publish-ahead-of-print 11 June 2015

Aims We investigated the association between diabetes duration and the extent and severity of coronary artery disease
(CAD) as well as long-term clinical outcomes using coronary computed tomography angiography (CCTA) in asymptom-
atic type 2 diabetic patients.
.....................................................................................................................................................................................
Methods We analysed 933 asymptomatic type 2 diabetic patients without known CAD who underwent CCTA. Patients were
and results divided into three groups according to the duration of diabetes: ,5 years, 510 years, and 10 years. Stenosis by
CCTA was scored as none (0%), non-obstructive (1 49%), or obstructive (50%) for each coronary artery segment.
For these patients, we compared the prevalence, extent, and severity of CAD, including coronary artery calcium
score (CACS), atheroma burden obstructive score (ABOS), segment involvement score (SIS), and segment stenosis
score (SSS). Major adverse cardiac and cerebrovascular events (MACCE), including all-cause mortality, non-fatal myocar-
dial infarction, and stroke, within a follow-up period were also compared.
Patients with longer duration of diabetes possessed higher rates of obstructive CAD (P , 0.001). Patients with longer
duration of diabetes also manifested greater degree of CACS, ABOS, SIS, and SSS (P , 0.001 for all) with associated
higher rate of MACCE (P 0.025). Presence of obstructive CAD as assessed by CCTA was an independent predictor
of MACCE after adjusting for confounding risk factors (hazard ratio: 1.979, confidence interval: 1.178 3.327, P 0.010).
.....................................................................................................................................................................................
Conclusion In asymptomatic diabetic patients, longer diabetes duration is associated with a higher prevalence, extent, and severity of
CAD as well as risk of MACCE. Moreover, greater CAD burden increases the risk of MACCE independent of co-existing
CAD risk factors.
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Keywords diabetes coronary artery disease coronary CT angiography

* Corresponding author. Tel: +82 2 2258 1139; Fax: +82 2 2258 1142, E-mail: kiyuk@catholic.ac.kr

Co-corresponding author.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.

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 1066
Introduction
Diabetes mellitus is associated with an increased risk of coronary artery
disease (CAD) and CAD events. Population-based studies have
demonstrated that type 2 diabetic patients experience a two- to four-
fold increase in the number of cardiovascular events compared with
non-diabetics.1 3 Recently, coronary computed tomography angiog-
raphy (CCTA) has emerged as a non-invasive imaging modality for
the detection or exclusion of CAD,4 with prior studies observing a
high prevalence of CAD in asymptomatic type 2 diabetic patients
using CCTA that is associated with worsened outcomes.5 7 While
several studies have investigated the association of diabetes duration
and CAD prognosis in the pre-CCTA era,8 10 these outcome-based
analyses lacked information regarding the prevalence, extent, and se-
verity of CAD. Prior CCTA studies have examined CAD findings and
prognosis in type 2 diabetic patients but have limitations of single-centre
study and small cohorts of diabetic patients.11,12 The CONFIRM regis-
try clearly demonstrated that diabetic patients had a higher prevalence,
extent, and severity of CAD compared with matched non-diabetics, but
also had a limitation of the lack of information on the longitudinal nature
of the diabetic process on CAD burden and prognosis.13
Thus, the aim of the present study was to evaluate the relationship
between diabetes duration and the presence, extent, and severity of
CAD by CCTA, as well as to determine its association with long-term
clinical outcomes in asymptomatic type 2 diabetic patients.
Methods
Study population
The CRONOS-ADM (CoROnary CT aNgiography evaluation for clinical
OutcomeS in Asymptomatic patients with type 2 Diabetes Mellitus)
registry is a large, prospective observational registry of demographic, clin-
ical, laboratory, and coronary CT angiographic data, with long-term clin-
ical outcome of asymptomatic type 2 diabetic patients without a history
of CAD. Since the primary objective of the CRONOS-ADM registry was
to assess whether screening for coronary atherosclerosis with the use of
CCTA would beneficially affect clinical outcome in asymptomatic type 2
diabetic patients, the registry was composed of two separate populations:
a CCTA group vs. a non-CCTA group.
Consecutive asymptomatic patients of .30 years of age with type 2
diabetes undergoing CCTA were prospectively enrolled into a CCTA
group from the division of endocrinology and cardiology at two affiliated
hospitals of The Catholic University of Korea between January 2006 and
December 2010: Seoul St Marys Hospital, Seoul, Korea and St. Vincents
Hospital, Suwon, Korea. Within 3 months of enrollment, two age- and
sex-matched asymptomatic type 2 diabetic patients were simultaneously
enrolled into a non-CCTA group. The present study only analysed the
CCTA group to evaluate the presence, extent, and severity of CAD
according to diabetes duration.
Patients were excluded if they had type 1 diabetes, angina, or
angina-equivalent symptoms by the Rose questionnaire,14 or if already
taking anti-angina medication, history of myocardial infarction (MI), cor-
onary revascularization (either by percutaneous coronary intervention
or bypass), cardiac transplantation, absence of stable sinus rhythm
during investigation, life-threatening conditions, or contraindications
for the use of iodinated contrast media. Patients with estimated glomeru-
lar filtration rate (eGFR) , 30 mL/min/1.73 m2 were also excluded.
There was no industry involvement in the design, conduct, or analysis
of the study. This prospective observational study was approved by the
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J.-J. Kim et al.
institutional review board of our institution and performed in accordance
with Strengthening the Reporting of Observational Studies in Epidemi-
ology guidelines.15 All patients provided written informed consent.
Before the CCTA examination, the patients underwent a structured
interview with a physician or allied health professional to ascertain the
demographic and clinical data, and to obtain additional anthropometric
data, including the height, weight, and waist-to-hip ratio. Patients under-
went blood and urine laboratory testing. The blood samples were col-
lected in the morning after an overnight fast to measure the serum
haemoglobin A1C, fasting plasma glucose, and lipid profiles. All labora-
tory tests were performed using standard methods.
The diagnosis of type 2 diabetes mellitus was made using the 2010
criteria of the American Diabetes Association. According to this defin-
ition, subjects with fasting glucose 126 mg/dL, glycated haemoglobin
(HbA1C) 6.5% or 48 mmol/mol, and/or post-challenge glucose
(glucose at 2 h after a 75 g oral glucose load) 200 mg/dL are diagnosed
with diabetes.16 Patients with a self-reported or documented history of
type 2 diabetes, or treatment with oral hypoglycemic agents or insulin
were also considered to be diabetic. Diabetes onset was defined as the
point in time when any of the above criteria were first met. The informa-
tion on diabetes onset in patients with known type 2 diabetes was pro-
spectively obtained at the time of the patient interview and, if unknown
to the patient, by direct medical record query. Diabetes duration was
calculated as the difference between the current age of the patients
and the age at diabetes onset.
Systemic arterial hypertension was diagnosed if the systolic and/or dia-
stolic blood pressure exceeded 140 and/or 90 mmHg, or if there was a
history of hypertension, which was evident through the use of antihyperten-
sive medications. A current smoker was defined as current smoking or ces-
sation of smoking within 6 months before the study enrollment. An
ex-smoker was defined as a person who was formerly a daily smoker but
currently did not smoke at all for .6 months. Whether or not there was
a family history of premature coronary heart disease was determined by
asking the patients. Information about the presence of previous stroke or
transient ischaemic attack (TIA) was also collected by asking the patients.
Scan protocol and image reconstruction
CCTA was performed with a 64-slice MDCT (LightSpeed VCT 64; GE
Healthcare, Milwaukee, WI, USA) or a dual-source CT (DSCT)
(Somatom definition, Siemens Healthcare, Forchheim, Germany). Scan
protocols for each CT scanner were as follows: for the 64-slice MDCT
scan protocol, slice collimation of 64 0.625 mm; gantry rotation time
of 350 ms; pitch of 0.2; tube voltage of 100 120 kV (depending on
BMI); tube current of 600 mAs. The ECG-triggered tube current modu-
lation was switched on to reduce the radiation dose. Heart rates of all
patients were determined 1 h before examinations. If heart rate was
.65 bpm, the patient was orally administered 40 80 mg of oral beta-
blocker propranolol hydrochloride (indenol at 40 mg/tablet) except
those with contraindications to beta-blockers. A 0.3 mg sublingual
dose of nitroglycerin was administered just before the scan. A two-phase
contrast medium protocol was used for adjusting the scan duration. The
first phase consisted of administration of 80 mL of iodinated contrast
agent (iopromide, Ultravist 370; Schering AG, Berlin, Germany) at a
rate of 5.0 mL/s for 16 s, while the second phase included 50 mL of
15% contrast medium and 85% saline solution at a rate of 5.0 mL/s for
10 s. A test bolus of 15 20 mL at a rate of 4 5 mL/s was administered
with sequential scanning every 2 s at the level of the left main (LM) cor-
onary artery, with the region of interest set as the aortic root to deter-
mine the optimum scan delay for each patient. Next, for the DSCT
scan protocol, slice collimation 2 32 0.6 mm by means of a z-flying
focal spot, gantry rotation time 330 ms, pitch 0.2 0.5, tube voltage
100 120 kVp (depending on BMI), and reference tube current 320
 Association between diabetes duration and the extent and severity of CAD
mAs. Scans were performed with ECG-controlled tube current modula-
tion. In each patient, 80 mL of iodinated contrast (Iomeron 350, Iomeprol,
Bracco, Milano, Italy) was injected at a flow rate of 5 mL/s followed by
50 mL of contrast mixture (15% contrast medium and 85% saline solution)
at the same rate. Contrast material administration was controlled by bolus
tracking in the ascending aorta (signal attenuation threshold 120 HU). The
scan delay was 7 s. In the absence of contraindications, patients with a heart
rate .80 bpm received an intravenous selective beta1-blocker, esmolol
(Jeil Brevibloc, Jeil Phama Co., Ltd., Seoul, Korea) 1 h before the scan,
and a 0.3 mg sublingual dose of nitroglycerin was administered just
before the scan. Estimated radiation doses ranged from 5 to 14 mSv.
Images were reconstructed immediately after completing the scan to
identify motion-free coronary artery images. The reconstructed CT
image data were transferred to a computer workstation (MDCT: advan-
tage Windows 4.3, GE Healthcare; DSCT: Syngo Multimodality Work-
place, version 2008, Siemens Healthcare) for post-processing, including
axial, multiplanar reformat, maximum intensity projection, and short-axis,
cross-sectional views. In all individuals, irrespective of the image quality,
every arterial segment was scored in an intent-to-diagnose fashion.
CCTA analysis
All scans were analysed by two radiologists with experience in interpret-
ing over several thousand CCTA scans. In direct accordance with the
Society of Cardiovascular Computed Tomography guidelines, coronary
segments were visually scored for the presence of coronary plaque using
a 16-segment coronary artery model in an intent-to-diagnose fashion.17
Only segments with a diameter .1.5 mm were included for analysis.
Coronary plaques came into consideration when structures .1 mm2
were detected within or adjacent to the coronary artery lumen, which
could be clearly distinguished from the vessel lumen and the surrounding
pericardial tissue.
The severity of luminal diameter stenosis was scored as none (0%
luminal stenosis), non-obstructive (plaques with a lumen narrowing
,50%), or obstructive (plaques with maximum stenosis 50%). Diagno-
sis of CAD was made based on the maximum intra-luminal stenosis in any
of the segments of the major epicardial coronary arteries at the 50%
stenosis threshold. Obstructive CAD in the diagonal branches, obtuse
marginal branches, and posterolateral branches was considered to be
part of the left anterior descending (LAD) artery, left circumflex (LCX)
artery, and right coronary artery (RCA) system, respectively. Depending
on the coronary artery dominance, the posterior descending artery was
considered to be part of the RCA or LCX system. For each patient, the
number of diseased vessels was calculated through the assignation of
one, two, three, or LM coronary artery vessels.
The extent and severity of CAD burden were measured by several
coronary CT angiographic scores,12,18 including coronary artery
calcium score (CACS), atheroma burden obstructive score (ABOS),
segment involvement score (SIS), and segment stenosis score (SSS).
The CACS was assessed with the application of dedicated software
(Smartscore version 3.5, GE Healthcare; Aquarius 3D Workstation, Ter-
aRecon, San Mateo, CA, USA). Coronary artery calcium was identified as
a dense area in the coronary artery exceeding the threshold of 130 HU.19
An overall Agatston score was recorded for each patient. The ABOS
was defined as the number of plaques with .50% stenosis in the entire
coronary artery tree. The SIS was calculated as the total number of cor-
onary artery segments exhibiting plaque, irrespective of the degree of
luminal stenosis within each segment (minimum 0; maximum 16).
The SSS was used as a measure of the overall coronary artery plaque
extent. To determine the SSS, each individual coronary segment was
graded as having no to severe plaque (i.e. scores from 0 to 3) based on
the extent of the obstruction of the coronary luminal diameter. Then,
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1067
the extent scores of all 16 individual segments were summed to yield a
total score ranging from 0 to 48.
Study end point and follow-up
The primary end point was a composite of all-cause mortality, non-fatal
MI, or stroke. The definition of MI was based on the criteria of detection
of a rise and/or fall of cardiac biomarker values with at least one value
above the 99th percentile upper reference limit and with at least one
of the following: symptoms of ischaemia; new or presumed new signifi-
cant ST-segment and T-wave changes or new left bundle branch block;
development of pathological Q-waves on the ECG; imaging evidence
of new loss of viable myocardium or new regional wall motion abnormal-
ity; or identification of an intracoronary thrombus by angiography.20 The
definition of stroke, formulated by the World Health Organization, was
the presence of rapidly developing clinical signs of focal (at times global)
disturbance of cerebral function, lasting .24 h or leading to death with
no apparent cause other than that of vascular origin. All clinical outcomes
of interest were confirmed by source document and were centrally adju-
dicated by a clinical events committee at the Cardiovascular Center of
Seoul St Marys Hospital consisting of an independent group of clinicians
whose members were unaware of the patient status. For the validation of
complete follow-up data, the information on censored survival data
(death or survival) and cause of death (cardiac or non-cardiac death)
was obtained from the Korean Office of Statistics.
Statistical analysis
Baseline and biochemical characteristics were summarized as the mean +
standard deviation (SD) for continuous variables, and as absolute numbers
and percentages for discrete variables. Variables were compared between
groups using ANOVA and post hoc analysis for continuous variables and x 2
or Fishers exact test for categorical variables. Results of the CCTA were
analysed for differences according to the diabetes duration by ANOVA
with contrasts, and post hoc Bonferroni analysis for continuous variables,
and either a x 2 or Fisher exact test for categorical variables, as appropriate.
To assess the independent association of diabetes duration and the extent
and severity of CAD, multivariate ANCOVA with contrasts analysis was
done to adjust confounding cardiovascular risk factors. Cardiovascular
risk stratification was performed according to a simplified version of the
Framingham model (including age, sex, smoking, systolic blood pressure,
and cholesterol). Cumulative event rates as diabetes duration, CCTA-
diagnosed obstructive CAD, and SSS were calculated with the Kaplan
Meier estimator and compared with the log-rank statistic. The Cox
proportional hazards analysis was done to calculate hazard ratios (HR)
with 95% confidence intervals (CI) to describe the relationships
between the various measures of CCTA-diagnosed CAD and the compos-
ite of MACCE, including all-cause mortality, non-fatal MI, or stroke, first
unadjusted and then adjusted for age, sex, hypertension, and eGFR. All
data were analysed using SAS 9.2 (SAS Institute, Cary, NC, USA). Statistical
significance was accepted for bilateral P , 0.05.
We further performed a post hoc power calculation to compare survival
in patients with diabetes duration ,5 years, 510 years, and 10 years
(b 0.80; a 0.05), with our current sample yielding sufficient statistical
power to detect differences in MACCE between these groups with change
in survival rates of 5% or greater.
Results
Characteristics of the study population
Baseline characteristics of the study group are shown in Table 1. From
January 2006 to December 2010, among 955 asymptomatic diabetic
 1068 J.-J. Kim et al.

Table 1 Baseline characteristics

Diabetes duration 5 years diabetes Diabetes P for trend

<5 years duration <10 years duration 10 years
...............................................................................................................................................................................
Number (n 933) 230 186 517
Age, years 58.8 + 9.6a 62.1 + 9.2b 65.9 + 9.0c ,0.001*
Age 65 years (%) 69 (30.0) 78 (41.9) 306 (59.2) ,0.001
Male (%) 152 (66.1) 105 (56.5) 299 (57.8) 0.057
Body mass index, kg/m2 24.9 + 3.1a 25.1 + 3.1a 23.9 + 3.2 0.001*
2
Body mass index, kg/m , ,25 84 (48.6) 57 (49.1) 250 (63.5) ,0.001
Waist hip ratio 0.93 + 0.06 0.94 + 0.09 0.95 + 0.07 0.078*
Hypertension (%) 109 (47.4) 105 (56.5) 296 (57.4) 0.017
Duration of hypertension, years 5.3 + 6.8a 8.1 + 6.5a 12.2 + 8.5 ,0.001*
Current smoker (%) 3.8 (20.2) 25 (17.1) 73 (15.8) 0.188
Chronic kidney disease (%) 12 (6.0) 17 (10.7) 46 (9.4) 0.228
Previous CVA (%) 12 (6.0) 17 (10.7) 46 (9.4) 0.228
Family history of CAD (%) 0 (0.0) 2 (1.5) 4 (0.9) 0.365
Laboratory findings
Haemoglobin, mg/dL 14.3 + 1.7a 13.7 + 1.6b 13.2 + 1.6c ,0.001*
Glucose, mg/dL 144.2 + 64.6 146.3 + 49.9 152.2 + 54.5 0.076*
2-h plasma glucose, mg/dL 208.5 + 79.7 202.9 + 74.1 216.6 + 81.6 0.277*
HbA1C, % 7.8 + 2.3a 7.5 + 1.7a 8.2 + 1.8 0.011*
Creatinine, mg/dL 0.86 + 0.17a 0.86 + 0.17a 0.91 + 0.22 0.001*
eGFR, mL/min/1.73 m2 92.1 + 18.7a 88.0 + 17.8b 83.0 + 20.8c ,0.001*
2
eGFR ,60 mL/min/1.73 m (%) 5 (2.2) 7 (3.8) 61 (11.8) ,0.001
Total cholesterol, mg/dL 176.7 + 43.6a 168.5 + 34.9a,b 165.9 + 35.9b ,0.001*
Triglyceride, mg/dL 155.2 + 123.5a 144.1 + 91.1a,b 127.4 + 79.8b ,0.001*
HDL cholesterol, mg/dL 46.3 + 10.5 47.8 + 12.5 48.0 + 12.2 0.084*
LDL cholesterol, mg/dL 98.8 + 35.5a 91.9 + 31.7a,b 92.5 + 31.6b 0.016*
hs-CRP, mg/L 0.45 + 1.66 1.15 + 4.16 0.96 + 3.12 0.145*
Microalbuminuria, mg/day 36.5 + 72.5 60.9 + 174.4 88.8 + 217.1 0.098*
Medication use
Diabetes management
Life style modification 54 (23.7) 18 (9.7) 26 (5.1) ,0.001
Oral hypoglycemic agents 154 (67.5) 149 (80.1) 316 (61.6) 0.019
Insulin 9 (3.9) 2 (1.1) 52 (10.1) ,0.001
Both OHA and insulin 11 (4.8) 17 (9.1) 119 (23.2) ,0.001
Aspirin 65 (30.5) 88 (50.9) 249 (51.6) ,0.001
Statin 123 (53.5) 106 (57.0) 290 (56.1) 0.565
Hypertensive medication
Beta-blocker 29 (12.6) 20 (10.8) 59 (11.4) 0.695
ACE inhibitor or ARB 91 (39.6) 92 (49.5) 263 (50.9) 0.007
CCB 38 (16.5) 47 (25.3) 143 (27.7) 0.002
Diuretics 23 (10.0) 44 (23.7) 141 (27.3) ,0.001

Data are given as mean + SD or n (%).

CVA, cerebrovascular accident; CAD, coronary artery disease; HbA1C, glycosylated haemoglobin; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL,
low-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; OHA; oral hypoglycemic agent; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

Statistical significances for linear-by-linear association between categorical variables were tested using x 2 test for trend.
*Statistical significances were tested by one-way ANOVA with trend analysis.

The same letters indicate non-significant difference between groups based on Bonferroni multiple comparison test.
a,b,c
Indicate non-significant difference between groups.

patients, 14 (1.5%) patients with CAD and 8 (0.8%) patients without mean duration of diabetes was 11.7 + 9.3 years. When baseline char-
data of diabetes duration were excluded, leaving 933 patients (556 acteristics were examined by 5-year increments of duration, those
males/377 females) available for study analysis. Patients were cate- with a longer duration of diabetes were older, more likely to be
gorized into three groups according to the diabetes duration. The hypertensive, and less likely to be obese. Patients history of previous

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 Association between diabetes duration and the extent and severity of CAD 1069

stroke or TIA and family history of CAD did not differ significantly
between groups (Table 1).
Haemoglobin, total cholesterol, triglyceride, low-density lipopro-
tein (LDL) cholesterol levels, and eGFR were significantly lower in
patients with a longer duration of diabetes. Glycemic control as
reflected by HbA1C levels was worse in patients with long-standing
diabetes compared with those with a shorter duration of diabetes.
However, fasting glucose, 2-h plasma glucose, and high-sensitivity
C-reactive protein levels did not differ significantly between groups.
The proportion of patients with insulin treatment increased in
parallel with the duration of diabetes. Patients with long-standing dia-
betes were more frequently treated with angiotensin-converting
enzyme inhibitors or angiotensin receptor blocker, calcium antago-
nists, diuretics, and acetyl salicylic acid.
CCTA CAD findings
The results of CCTA and CACSs are summarized in Table 2. Of
the study population, 194 patients (20.8%) exhibited no CAD by
CCTA. Non-obstructive CAD was detected in 365 patients (39.1%),
while obstructive CAD was detected in 374 patients (40.1%). Increas-
ing duration of diabetes was associated with lower rates of normal cor-
onary arteries and higher rates of obstructive CAD (P , 0.001 for all).
Higher rates of obstructive two-vessel disease (2VD) and three-vessel
disease (3VD) or LM disease were noted for patients who had long-
standing diabetes (2VD, P , 0.001; 3VD or LM disease, P 0.003).
Patients with diabetes duration of over 10 years had a significantly ele-
vated level of CACS, ABOS, SIS, and SSS in CCTA (P , 0.001 for all),
compared with those with diabetes duration of ,5 years or 510
years (Figure 1). Moreover, patients with long-standing diabetes had
higher SSS compared with patients with a shorter duration of diabetes
for LM artery and for all proximal and mid-coronary segments after
adjustment for Framingham score.
CCTA findings and risk of MACCE
During a median follow-up period (inter-quartile range: 2.0 4.0), 61
MACCE events occurred. Patients with longer duration of diabetes
experienced higher risk of MACCE compared with those with a
shorter duration of diabetes (P 0.025).

Table 2 CCTA CAD findings

Diabetes duration 5 years diabetes Diabetes P for trenda

<5 years duration <10 years duration 10 years
...............................................................................................................................................................................
Number (n 933) 230 186 517
Normal (%) 71 (30.9) 41 (22.4) 81 (15.7) ,0.001
Non-obstructive (1 49%) 94 (40.9) 89 (47.8) 182 (35.2) 0.053
CAD by stenosis 50% (%) 65 (28.3) 55 (29.6) 254 (49.1) ,0.001
Vessels affected
1VD (%) 42 (18.3) 29 (15.6) 113 (21.9) 0.159
2VD (%) 9 (3.9) 14 (7.5) 77 (14.9) ,0.001
3VD or LM disease (%) 14 (6.1) 12 (6.5) 64 (12.4) 0.003
Coronary artery calcium score (Agatston) 134.3 + 425.3 224.4 + 452.0 339.1 + 554.7 ,0.001b
Atheroma burden obstructive score 0.77 + 1.59 0.75 + 1.40 1.48 + 1.95 ,0.001b
Segment involve score 1.51 + 2.24 1.95 + 2.45 2.77 + 2.64 ,0.001b
Segment stenosis score 2.41 + 3.98 2.86 + 3.90 4.70 + 5.00 ,0.001b
LM artery 0.08 + 0.33 0.15 + 0.47 0.19 + 0.48 0.019b
LAD artery
Proximal 0.61 + 0.88 0.70 + 0.89 1.05 + 1.03 ,0.001b
Mid 0.26 + 0.65 0.36 + 0.69 0.51 + 0.93 0.001b
Distal 0.08 + 0.39 0.01 + 0.10 0.11 + 0.42 0.134b
LCX artery
Proximal 0.21 + 0.61 0.33 + 0.77 0.42 + 0.85 0.009b
Mid 0.06 + 034 0.10 + 0.36 0.24 + 0.67 0.003b
Distal 0.20 + 0.61 0.12 + 0.42 0.29 + 0.74 0.240b
RCA
Proximal 0.24 + 0.57 0.30 + 0.68 0.53 + 0.85 ,0.001b
Mid 0.23 + 0.59 0.25 + 0.60 0.41 + 0.79 0.015b
Distal 0.13 + 0.49 0.17 + 0.80 0.30 + 0.70 ,0.001b

Data are given as mean + SD or n (%).

CCTA, coronary computed tomography angiography; CAD, coronary artery disease; VD, vessel disease; LM, left main; LAD, left anterior descending; LCX, left circumflex; RCA, right
coronary artery.
a
Statistical significances for linear-by-linear association between categorical variables were tested using x 2 test for trend.
b
Statistical significances were tested by Framingham score-adjusted ANCOVA with linear trend analysis.
P , 0.05 is significant.

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 1070 J.-J. Kim et al.

Figure 1 Coronary CT angiographic scores. Coronary artery calcium Agatston score, ABOS, SIS, and SSS between groups. Patients with diabetes
duration of 10 years possessed a higher CCTA scores compared with those with a shorter duration of diabetes. CCTA, coronary computed tom-
ography angiography.

Patients with longer duration of diabetes, obstructive CAD, or
higher CACS had a greater rate of MACCE (P 0.0068, P 0.0013,
P 0.0013, respectively). The presence of obstructive CAD and
higher CACS was associated with increased risk of MACCE not only
in patients with diabetes duration ,10 years but also in those with dia-
betes duration 10 years. When patients were subdivided into two
groups according to the presence of obstructive CAD or CACS
,100 vs. 100, risk of MACCE was significantly higher in patients
with longer duration of diabetes and obstructive CAD or CACS
100. Similar rate of MACCE was observed in patients with longer dur-
ation of diabetes without obstructive CAD or CACS , 100 compared
with those with shorter duration of diabetes with obstructive CAD or
CACS 100 (Figure 2).
Cumulative hazard rates of patients with or without obstructive
CAD manifested a linear pattern of increased risk (Figure 3). Patients
with normal coronary arteries experienced a more gradual increase
of cumulative hazards than those with obstructive CAD during
follow-up. Cumulative hazard rates at 2 years in patients with
obstructive CAD were similar to those of 5 years of follow-up in
those with completely normal coronary arteries.
In multivariable Cox regression analyses, age was associated with
increased risk of poor outcome (HR: 4.352, 95% CI: 2.2928.263,
P , 0.001), whereas male sex, hypertension, current smoking, hyper-
cholesterolaemia, decreased renal function, and lower BMI were not
(P . 0.05 for all). After adjustment for confounding risk factors, ob-
structive CAD by CCTA remained an independent predictor of
MACCE (HR: 1.979, 95% CI: 1.1783.327, P 0.010). 2-, 3VD or
LM disease (HR: 1.872, 95% CI: 1.0923.210, P 0.023), increased
ABOS and SSS (HR: 1.140, 95% CI: 1.0201.273, P 0.020 and HR:
1.045, 95% CI: 1.0001.092, P 0.048, respectively) also increase
the risk of MACCE independently of coexisting risk factors.
The sample size of current study provided 81% power to detect
differences in MACCE between patients with diabetes duration
,5 years, 5 10 years, and 10 years.

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 Association between diabetes duration and the extent and severity of CAD 1071

Figure 2 Cumulative survival according to diabetes duration and CAD burden. Graphs show Kaplan Meier survival curves for MACCE stratified
for the presence of obstructive CAD (A) or CACS , 100 vs. 100 (B). (A) Patients with both long-standing diabetes and obstructive CAD have
significantly increased risk of MACCE. Similar rate of MACCE was observed in patients with longer duration of diabetes without obstructive
CAD compared with those with shorter duration of diabetes with obstructive CAD or CACS 100. (B) A significantly higher event rate is observed
in patients with CACS 100 compared with in those with CACS , 100 regardless of diabetes duration. Patients with longer duration of diabetes
without obstructive CAD or CACS , 100 had similar rate of MACCE compared with patients with shorter duration of diabetes with obstructive
CAD or CACS 100. CAD, coronary artery disease; MACCE, major adverse cardiac and cerebral event; DM, diabetes mellitus; CACS, coronary
artery calcium score.

Discussion finding that was associated with the doseresponse relationship of

In this prospective two-centre study, we observed a higher preva-
lence, extent, and severity of CAD burden in asymptomatic type 2
diabetic patients by diabetes duration. Further, we identified a
higher rate of MACCE in patients with longer diabetes duration, a
CAD burden. Interestingly, we observed a similar prevalence,
extent, and severity of CAD by CCTA in patients with diabetes
duration of ,5 years and 5 10 years, which suggests a threshold dur-
ation of diabetes for development of CAD in this asymptomatic
population. To our knowledge, this study represents the first one

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 1072
Figure 3 Cumulative hazard rate in patients with normal CCTA
or obstructive CAD. Cumulative hazard rates of patients with or
without obstructive CAD manifested linear pattern of increase.
Patients with normal coronary arteries showed more gradual in-
crease of cumulative hazard rate than those with obstructive
CAD during follow-up. CCTA, coronary computed tomography
angiography; CAD, coronary artery disease.
to examine not only the presence or absence of diabetes on CAD
extent and severity by CCTA but also the impact of diabetes dur-
ation on CAD extent and severity and its effect on downstream
MACCE in asymptomatic diabetes patients free of prior known
CAD.
The risk of chronic vascular complications of type 2 diabetes
increases as a function of the duration and degree of hyperglycemia.
The duration of diabetes and degree of glycemic control are important
factors for the development of microvascular complications of dia-
betes.21 In case of diabetic nephropathy, up to 40% of patients who
have had diabetes for 510 years begin to excrete small amounts of
albumin in the urine. Over the next 10 years, up to 50% of these
patients progress to macroalbuminuria, a finding that is in direct ac-
cordance with our study results of increased CAD burden and risk
in patients with .10 years of diabetes duration. The results of the
present study indicate a pathogenic worsening of chronic large-vessel
epicardial CAD that appears to be a mirror that reflects microvascular
disease.
Previous studies have suggested that diabetes duration is directly
associated with adverse cardiovascular events. The Framingham
Heart Study reported a 1.38-fold increased risk for CAD and a
1.86-fold higher risk for cardiovascular death for each 10-year in-
crease in diabetes duration.8 In the Verona Diabetes Study, iscaemic
heart disease was the single largest cause of cardiovascular deaths in
men, and the death rate rose with increasing duration of diabetes.9
Moreover, a recent analysis by the British Regional Heart study
showed that only diabetes with duration of .10 years was a coronary
heart disease risk equivalent.22 In line with previous studies, the
present study observed a higher rate of MACCE in asymptomatic
patients with long-standing type 2 diabetes. To demonstrate the addi-
tive value of CCTA-diagnosed CAD and diabetes duration, we sub-
divided patients according to the CAD burden and duration of
diabetes. Patients with long-standing diabetes and obstructive CAD
or higher CACS showed significantly increased risk of MACCE.
Patients with longer duration of diabetes without obstructive CAD
or CACS , 100 had similar rate of MACCE compared with
patients with shorter duration of diabetes with obstructive CAD
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J.-J. Kim et al.
or CACS 100. Interestingly, patients with long-standing diabetes
and lower CAD burden had more favourable outcome compared
with patients with shorter diabetic duration and higher CAD
burden during early follow-up period. Therefore, the current study
strongly supports prior data, as the rates of MACCE were directly
related to the extent and severity of CAD. Further, while an array
of techniques enables determination of coronary luminal stenosis se-
verity, the present study employed the use of CCTA, a non-invasive
technique that lowers the threshold for evaluation of asymptomatic
individuals and that offers the added diagnostic ability to directly visu-
alize coronary stenosis.23 In this regard, our study advances the mech-
anistic understanding of these prior pivotal studies and suggests a
prognostic importance of CAD extent and severity by non-invasive
CCTA to identify asymptomatic diabetic individuals who have
greater cardiovascular risk.
While the current American Diabetes Association consensus guide-
lines recommend CAD screening in diabetic patients with cardiovascu-
lar symptoms,24 no consensus is present for the evaluation of
asymptomatic individuals. Similarly, the use of CCTA has been gener-
ally endorsed only for symptomatic low-to-intermediate-risk patients
by professional societal guidance documents.25 Results of the present
study demonstrated an importance of diabetes duration for the detec-
tion of CAD severity and risk, and suggest the potential benefit of CAD
evaluation in a select group of diabetic individuals with longer duration
of disease. There are extensive evidences suggesting that autonomic
dysfunction is associated with silent myocardial ischaemia in diabetic
patients, a finding that may mask clinical symptoms associated with
the increased CAD extent and severity that we observed in asymp-
tomatic individuals with diabetes of longer duration.26 28 While
these hypothesis generating results are thought provoking, they will
require evaluation in future large-scale controlled trials to determine
any salutary effect of CAD evaluation on asymptomatic diabetic indivi-
duals; particularly, given the prolonged asymptomatic developmental
phase of CAD progression before MACCE occurrence.29
Despite the several important findings and clinical implications for
CAD management in asymptomatic diabetic patients, the present
study has several limitations. First, up to 30% of patients, the diagnosis
and duration of diabetes were either self-reported or obtained by clin-
ical records review. Although the reporting reliability is generally con-
sidered to be high, it is possible that the reported duration of the
disease may have been either over estimated or underestimated.
Second, the sample size was relatively small and thus did not allow
for separate analyses by age or sex. Third, this study had an observa-
tional design and was performed at two centres, which makes it uncer-
tain whether the results can be equally applied to other populations.
Fourth, there were some differences in the baseline characteristics
between groups, which could have contributed to the higher CAD
burden or poorer outcome observed in patients with longer duration
of diabetes. Nevertheless, Framingham score-adjusted ANCOVA ana-
lysis and multivariate Cox proportional hazards analysis were done to
minimize these confounding factors such as age, hypertension, eGFR,
and cholesterol level. However, some residual or undetected confoun-
ders could not be ruled out. Fifth, information about patients medica-
tions and glycemic control as reflected by HbA1C levels in the
pre-CCTA period and during 5 years of follow-up were not available.
Therefore, valid information regarding longitudinal diabetic control or
changes of medication after the investigation was not available.
 Association between diabetes duration and the extent and severity of CAD
Conclusions
In this prospective two-centre study of asymptomatic type 2 diabetic
patients, longer duration of diabetes is associated with greater preva-
lence, extent, and severity of CAD, a finding predictive of future
MACCE.
Acknowledgements
J.J.K., B.H.H., I.J.C., E.H.C., M.C., S.L., U.S.K., S.H.L., J.H.C., and J.I.J. con-
tributed to the design, analyses, data collection, and writing of the
manuscript. J.J.K., S.H.I., J.M.L., P.J.K., H.Y.K., K.D.Y., D.S.J., K.H.Y.,
K.B.S., and J.K.M. contributed to the draft of the manuscript or
revise it critically for important intellectual content. K.C. was involved
in all steps of this study, is the guarantor of this work, and as such
had full access to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the data analysis.
Conflict of interest: None declared.
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