Arora et al.

Cardiovasc Diabetol (2019) 18:26

https://doi.org/10.1186/s12933-019-0832-2 Cardiovascular Diabetology

ORIGINAL INVESTIGATION Open Access

Asymptomatic coronary artery disease

in a Norwegian cohort with type 2
diabetes: a prospective angiographic study
with intravascular ultrasound evaluation
Satish Arora1,6, Anne Pernille Ofstad2*, Geir R. Ulimoen2,3, Kåre I. Birkeland4,5, Knut Endresen1, Lars Gullestad1,5,6
and Odd Erik Johansen2

Abstract
Aims: The prevalence of asymptomatic coronary artery disease (CAD) in type 2 diabetes (T2D) is unclear. We inves-
tigated the extent and prevalence of asymptomatic CAD in T2D patients by utilizing invasive coronary angiography
(ICA) and intravascular ultrasound (IVUS), and whether CAD progression, evaluated by ICA, could be modulated with a
multi-intervention to reduce cardiovascular (CV) risk.
Methods: Fifty-six T2D patients with ≥ 1 additional CV risk factor participated in a 2 year randomized controlled study
comparing hospital-based multi-intervention (multi, n = 30) versus standard care (stand, n = 26), with a pre-planned
follow-up at year seven. They underwent ICA at baseline and both ICA and IVUS at year seven. ICA was described by
conventional CAD severity and extent scores. IVUS was described by maximal intimal thickness (MIT), percent and
total atheroma volume and compared with individuals without T2D and CAD (heart transplant donors who had IVUS
performed 7–11 weeks post-transplant, n = 147).
Results: Despite CV risk reduction in multi after 2 years intervention, there was no between-group difference in
the progression of CAD at year seven. Overall, the prevalence of CAD defined by MIT ≥ 0.5 mm in the T2DM sub-
jects was 84%, and as compared to the non-T2DM controls there was a significantly higher atheroma burden (mean
MIT, PAV and TAV in the T2D population were 0.75 ± 0.27 mm, 33.8 ± 9.8% and 277.0 ± 137.3 mm3 as compared to
0.41 ± 0.19 mm, 17.8 ± 7.3% and 134.9 ± 100.6 mm3 in the reference population).
Conclusion: We demonstrated that a 2 year multi-intervention, despite improvement in CV risk factors, did not
influence angiographic progression of CAD. Further, IVUS revealed that the prevalence of asymptomatic CAD in T2D
patients is high, suggesting a need for a broader residual CV risk management using alternative approaches.
Trial registration Clinical trials.gov id: NCT00133718 (https​://clini​caltr​ials.gov/ct2/show/NCT00​13371​8)
Keywords: Coronary artery disease, Type 2 diabetes mellitus, Invasive coronary angiography, Intravascular
ultrasound, Atheroma burden, Multi-factorial treatment

*Correspondence: [email protected]
2
Department of Medical Research, Bærum Hospital Vestre Viken Hospital
Trust, Gjettum, PB 800, 3004 Drammen, Norway
Full list of author information is available at the end of the article

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/
publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Arora et al. Cardiovasc Diabetol (2019) 18:26 Page 2 of 9

Introduction of observation. The hypothesis was that reducing CV risk

Type 2 diabetes (T2D) is reported to affect 422 million factors is associated with a reduced CAD progression
people world-wide, with a projected increase to 642 mil- rate.
lion by 2040 [1]. Subjects with T2D have at least a two-
fold increased risk for cardiovascular (CV) disorders Methods
including coronary artery disease (CAD), stroke, periph- Patient population
eral arterial disease, cardiomyopathy and heart failure This is the primary IVUS report of the Asker and Bae-
[2, 3]. Furthermore, prospective trials have identified rum Cardiovascular Diabetes (ABCD) study, and a
that the absolute risk of coronary events in patients with detailed description of this study has been reported pre-
T2D is similar to patients with established coronary heart viously [13]. In brief, the ABCD study was a prospec-
disease without T2D [4, 5]. Although the risk of coro- tive, open, randomized, controlled study of 2 years of
nary events can be reduced by aggressive management intensive versus standard care in 120 patients with T2D
of co-existing risk factors and prophylactic treatment conducted at the Asker and Baerum Hospital, Gjet-
with aspirin, ACE inhibitor or statins, the universal use tum, Norway. Patients were included during the period
of such therapy is debated as the prevalence of asympto- January 2002 to February 2004. Inclusion criteria were
matic CAD in T2D remains unclear with estimates vary- T2D, age 18–75 years, and the presence of one or more
ing between 10 and 60% [6]. additional CV risk factor (defined as hypertension
Non-invasive screening for asymptomatic CAD in (treated or ambulatory systolic/diastolic blood pressure
patients with T2D is currently not recommended by the (BP) ≥ 140/90 mmHg), past or prior smoking, prema-
American Diabetes Association [7], predominantly based ture CAD in first degree family member (male < 55 years,
on the results of the Detection of Ischemia in Asympto- female < 65 years), microalbuminuria or dyslipidemia
matic Diabetics (DIAD) study [8]. However, according (treated or total cholesterol ≥ 5.0 mmol/L, high-density
to the European Society of Cardiology, this issue is still lipoprotein (HDL)-cholesterol (< 1.0 mmol/L in men,
under debate and the characteristics of the patients who or < 1.1 mmol/L in women or triglycerides ≥ 2.0 mmol/L).
should be screened for CAD need to be better defined Patients were randomized to 2 years of intensive,
[9]. hospital-based, structured multi-intervention (n = 60)
The accuracy and availability of non-invasive imaging or standard care (n = 60). Structured intensive multi-
techniques such as CT angiography, including CT angi- intervention comprised 6 months of lifestyle interven-
ography derived fractional flow reserve, has improved tion (i.e. advice on diet, exercise and smoking cessation
considerably [10], and these techniques may in many and reimbursement of cost associated with training) fol-
cases be the preferred option due to the associated lowed by targeted, pharmacological therapy to reach pre-
lower risk of complications than with invasive investiga- specified treatment goals (HbA1c ≤ 48 mmol/mol (6.5%),
tions. However, the utilization of more accurate, invasive total/LDL cholesterol < 5.0/3.0 mmol/L, systolic/diastolic
techniques, such as coronary angiography and the gold- blood pressure (BP) < 130/80 mmHg). The participants
standard modality of intravascular ultrasound (IVUS) were reviewed every 3 months over a period of 2 years by
[11] are more appropriate to determine the prevalence of a diabetologist in the hospital’s out-patient clinic.
asymptomatic CAD in patients with T2D. The standard care group remained under the care of
A detailed characteristic of the constitution of the their general practitioners who were encouraged to con-
coronary vascular bed could further help refine residual tinue with treatment according to current (2002) national
secondary CV risk assessment, e.g., by using maximal and American Diabetes Association [14] guidelines
intimal thickness (MIT), a predictor of all-cause mortal- (HbA1c < 7%, LDL-cholesterol < 2.6 mmol/L, systolic/
ity, myocardial infarction, and angiographic abnormali- diastolic BP < 130/80) and follow-up recommended at
ties [12]. 3-monthly intervals.
The purpose of the current study was to evaluate the All participants underwent a comprehensive diagnostic
prevalence and extent of asymptomatic CAD in patients work-up at baseline, including invasive coronary angiog-
with T2D, as compared to a reference population with- raphy regardless of symptoms or results of the non-inva-
out T2D and without symptomatic CAD, by utilizing sive cardiac tests. Patients could refrain from invasive
coronary angiography and IVUS. The hypothesis was testing and still participate in the study, and 91 of the 120
that patients with T2D have a higher silent coronary enrolled consented to invasive coronary angiography.
artery atheroma-burden than those without T2D. Sec- At 2 years follow-up, the diagnostic work-up at baseline
ondly, we explored the effect of a 2-year multi-inter- was repeated, excluding invasive coronary angiography,
ventional treatment strategy aimed to reduce CV risk in and all participants were transferred back to the care
T2D on progression of angiographic CAD over 7-years they had prior to study entry. It was prespecified that
Arora et al. Cardiovasc Diabetol (2019) 18:26 Page 3 of 9

the participants should enter a long-term follow-up, and Oslo, Norway) blinded to patient treatment. IVUS analy-
approximately 7 years after inclusion, an additional diag- sis was performed according to the guidelines for acqui-
nostic work-up was conducted, including coronary angi- sition and analysis of IVUS images by the American
ography supplemented with IVUS. Of the 120 patients College of Cardiology and European Society of Cardi-
included in the ABCD study, 85 participated in the long- ology [17]. Contour detection of both the lumen and
term follow-up [15], and 56 (46.7%) of these patients external elastic membrane (EEM) was performed at
had coronary angiography performed both at baseline approximately 1 mm intervals using validated software
and 7 years. These 56 patients (30 and 26 patients in the (QIVUS, v.3.0, Medis medical imaging systems, Leiden,
multi-intervention and control group, respectively) con- the Netherlands).
stitute the population of this sub-study. All 56 patients
were free from cardiopulmonary symptoms at baseline. IVUS endpoints
The reference material consisted of IVUS of donor MIT was utilized as the primary grayscale IVUS efficacy
hearts from 147 non-T2D donors that a priori were free variable. Previous studies have utilized MIT ≥ 0.5 mm
from symptomatic CAD, performed 7–11 weeks post as evidence of pathological intimal disease [12] and this
transplantation. cut-off was utilized in the current study. Other second-
ary IVUS variables were: (i) percent atheroma volume
Angiographic assessment (PAV) which expresses the summation of atheroma
Coronary angiography was performed with the percu- areas in proportion to the EEM area using the equa-
taneous radial or femoral approach using 6F diagnostic tion: PAV = ∑ ­(EEMarea − Lumenarea)/∑EEMarea) × 100
catheters (Cordis Corporation, Miami, Fla., USA) and and (ii) normalized total atheroma volume (TAV) using
the water-soluble, non-ionic, dimeric contrast medium the equation: TAV = ∑ ­(EEMarea − Lumenarea)/number
iodixanol (Visipaque 320 mg/mL; G.E.Healthcare, Oslo, of frames) × median number of frames in cohort. IVUS
Norway). Coronary artery angiogram data was evaluated endpoints in the ABCD sub-study population were com-
by experienced local staff blinded to treatment and was pared with the non-T2D reference population of heart
classified as 1-, 2- or 3-vessel disease according to the transplant donors.
presence of a stenosis greater than 50% of lumen diam-
eter. Stenosis of the left main coronary artery of > 50% of Statistical analysis
lumen diameter was considered to be 2-vessel disease. Analyses were performed with the SPSS v 24.0 statisti-
Inter-observer variability of angiographic classifications cal software (SPSS Inc. Chicago, IL). Data is expressed as
was 4.9%. mean ± SD or as median (interquartile range) as appro-
Further quantitative angiographic evaluation priate and a two-tailed p-value < 0.05 was considered sta-
was performed using an established scoring sys- tistically significant. Baseline characteristics and IVUS
tem [16]. Coronary segments were graded as grade endpoints were compared using Student’s t-test, Mann–
0, 1, 2, 3, 4 or occlusion based on the presence of Whitney test and Pearson’s Chi squared test as appro-
< 25%, < 50%, < 75%, ≥ 75% or occlusion defined as a > 95% priate. Change in angiographic severity and extent score
diameter stenosis with a severely reduced or no ante- was compared between treatment groups by performing
grade flow, respectively. CAD severity score was cal- analysis of covariance (ANCOVA) with the baseline value
culated as the average grade of the diseased coronary included as a covariate and treatment group as a fixed
segments (i.e. ≥ grade 1). CAD extent score was calcu- factor. To account for an age-effect on atheroma-bur-
lated for each patient based on the number of segments den, IVUS data was also analyzed with age-stratification
exhibiting lesions ≥ grade 1. (< 50 years, 50–60 years and > 60 years).

IVUS imaging Results

The trial protocol specified IVUS examination of the Baseline characteristics of the T2D cohort are given in
same major epicardial coronary artery (preferentially the Table 1. Mean age was 60.0 ± 8.0 years and mean dura-
left-anterior descending coronary artery) and this was tion of T2D was 5.9 ± 5.7 years. There was no significant
conducted while performing coronary angiography using difference in baseline characteristics between the treat-
a 20 MHz, 2.9F, monorail electronic Eagle Eye Gold IVUS ment groups, and also, the angiographic cohort had a
catheter (Volcano Corporation Inc, CA, USA). IVUS similar baseline characteristic profile as the overall cohort
images were acquired at a rate of 30 frames/s and pull- (n = 120) of the ABCD study (data not shown). The ref-
back speed of 0.5 mm/s. Images were stored digitally for erence population’s mean age was 46.0 ± 13.5 years
off-line analysis conducted after trial closure by a core (n = 24 ≥ 60 years).
laboratory (Oslo University Hospital, Rikshospitalet,
Arora et al. Cardiovasc Diabetol (2019) 18:26 Page 4 of 9

Table 1 Baseline characteristics and treatment allocation group, p = 0.03), whereas blood pressure and lipid levels
of IVUS sub-study population (n = 56) did not differ.
Demographics
Patient age (years) 60.0 ± 8.0 Angiographic trajectory
Female gender (%) 12 (21) The number of patients in the multi-interventional group
Duration of T2D (years) 5.9 ± 5.7 with 1, 2 and 3-vessel CAD changed from 3 (10.0%), 0
Hemodynamics (0%) and 1 (3.3%) at baseline to 4 (13.3%), 2 (6.7%) and
Systolic blood pressure (mmHg) 139.4 ± 18.6 0 (0%) patients at 7 years as compared to a change from
Diastolic blood pressure (mmHg) 81.6 ± 9.3 5 (19.2%), 4 (15.4%) and 1 (3.8%) at baseline to 7 (26.9%),
Angiographic findings 2 (7.7%) and 1 (3.8%) patients at 7 years in the standard
Normal 21 (38%) group (p = NS).
Wall changes 17 (30%) CAD severity score increased relatively by 42% (from
25–50% stenosis 4 (7%)
0.47 ± 0.84 to 0.67 ± 0.98%) in the multi-interventional
> 50% stenosis 14 (25%)
group and by 40% (from 0.84 ± 1.11 to 1.18 ± 1.06%)
Biochemistry
in the standard group from baseline to 7 year follow-
Hba1c (%) 7.5 ± 1.6
up, (p = 0.20 for between-group difference in change,
Total cholesterol (mmol/L) 5.0 ± 1.0
Fig. 1). CAD extent score increased by 33% in the multi-
Triglycerides (mmol/L) 1.7 ± 1.0
interventional group (from 0.60 ± 1.07 to 0.80 ± 1.30)
HDL-cholesterol (mmol/L) 1.3 ± 0.4
and by 30% in the standard group (from 1.15 ± 1.83
LDL-cholesterol (mmol/L) 2.9 ± 0.9
to 1.50 ± 1.68) from baseline to 7 years (p = 0.30 for
Microalbuminuria 26.2 ± 40.8
between-group difference in change, Fig. 1).
eGFR (mL/min/1.73 m2)(MDRD) 91.8 ± 19.2
hsCRP (mg/l)a 0.23 ± 0.34 Grayscale IVUS analysis
NT-proBNP (ng/L) b
8.6 ± 14.2
At the follow-up investigation, the overall mean
Medication
MIT, PAV and TAV in the T2D population were
Any oral antidiabetic medication (%) 42 (75%)
0.75 ± 0.27 mm, 33.8 ± 9.8% and 277.0 ± 137.3 mm3
Insulin 8 (14%)
as compared 0.41 ± 0.19 mm, 17.8 ± 7.3% and
Loop/thiazide diuretic (%) 8 (14%)
134.9 ± 100.6 mm3 in the reference population (all p-val-
ACE inhibitor (%) 9 (16%)
ues < 0.05—Table 2 and Fig. 2). Overall, 47 of 56 (83.9%)
ARB (%) 13 (23%)
of the T2D patients had a mean MIT ≥ 0.5 mm as com-
Statin therapy (%) 28 (50%)
pared to 39 (26.5%) patients in the reference population
Acetyl salicylic acid (%) 17 (30%)
(p < 0.001). Age-stratified prevalence of CAD (defined as
Treatment allocated
MIT ≥ 0.5 mm) in the T2D population was significantly
higher than the reference non-T2D population (p < 0.05,
Multi-intervention strategy 30 (53%)
Fig. 3). There was no significant difference between
Conventional therapy 26 (46%)
the T2D treatment groups in IVUS parameters with
T2D type 2 diabetes mellitus, eGFR estimated glomerular filtration rate, MDRD
modification of diet in renal disease, ACE angiotensin converting enzyme, ARB
mean MIT, PAV and normalized TAV 0.72 ± 0.26 mm,
angiotensin receptor blocker 32.2 ± 8.6% and 265.1 ± 131.9 mm3 in the multi-interven-
a
Data for hsCRP (n = 41) tion group as compared to 0.78 ± 0.29 mm, 35.7 ± 10.9%
b
Data for NT-proBNP (n = 34) and 290.7 ± 144.5 mm3 in the standard group (p-val-
ues > 0.05, Table 3 and Additional file 1: Figure S1).
Effects on cardiovascular risk factors
As previously reported [13], following 2 years of inter- IVUS analysis according to baseline coronary angiography
vention there was a significant between-group difference When considering IVUS findings at 7 years according to
in glycosylated hemoglobin (HbA1c), fasting plasma glu- baseline angiographic findings, there were no significant
cose, blood pressure and lipids favoring the multi-inter- differences between the treatment groups in MIT or PAV
vention group. Similarly, at the 7 year follow-up, there regardless of whether baseline angiography had been
was a non-significant trend to sustained difference in gly- normal (n = 21) or shown a stenosis of < 25% (n = 17)
caemia in favor of the multi-intervention group (HbA1c or > 25% (n = 18) (Additional file 2: Figure S2). Similarly,
7.0 ± 1.0% in multi-intervention vs 7.5 ± 1.2% in standard there was no significant difference in IVUS parameters
group, p = 0.067, fasting blood glucose 7.4 ± 1.9 mmol/L between the treatment groups when patients were strati-
in multi-intervention vs 9.5 ± 4.2 mmol/L in the standard fied according to baseline CAD extent score (Additional
file 3: Figure S3).
Arora et al. Cardiovasc Diabetol (2019) 18:26 Page 5 of 9

Fig. 1 Coronary artery disease (CAD) severity (a) and extent (b) score according to treatment group, p indicates p-value for between-group
difference in change in CAD severity and extent score from baseline to 7 years

Table 2 Comparison of quantitative IVUS results in the ABCD study population (n = 56) with a reference population
without T2D and without established CAD (n = 147)
IVUS parameter ABCD sub-study population Non-diabetic reference population (heart p-value
(n = 56) transplant donors) (n = 147)

Mean vessel area ­(mm2) 14.7 ± 4.2 16.1 ± 4.0 0.16

Mean lumen area ­(mm2) 9.6 ± 2.8 13.2 ± 3.5 < 0.001
Mean plaque area ­(mm2) 5.1 ± 2.5 2.9 ± 1.4 < 0.001
Percent atheroma volume (%) 33.8 ± 9.8 17.8 ± 7.3 < 0.001
Normalized total atheroma volume ­(mm3) 277.0 ± 137.3 134.90 ± 100.6 < 0.001
Mean maximal intimal thickness (mm) 0.75 ± 0.27 0.41 ± 0.19 < 0.001
Patients with MIT ≥ 0.5 mm 47 (84%) 39 (26.5%) < 0.001
Italic values indicate significance of p-value (p < 0.05)
IVUS intravascular ultrasound, T2D type 2 diabetes mellitus, CAD coronary artery disease, MIT maximal intimal thickness

Discussion a CAD equivalent by European and American guide-

The current ABCD trial is, to our knowledge, the first lines [18] implying a high (> 20%) 10-year CV risk for
IVUS investigation of asymptomatic CAD in T2D and all patients with T2D [18]. However, the validity of this
demonstrates that the burden of CAD is overwhelm- assumption has been questioned in recent years based
ingly high and that CAD progression is substantial. The on data indicating the potentially wide heterogeneity
trial also evaluated the efficacy of a multi-intervention in CV risk among T2D patients [19]. For example, a
strategy aimed to reduce CV risk, and despite a sus- meta-analysis by Bulugahapitiya et al. included 45,108
tained improvement in glycemic control, such inter- patients and revealed a 43% lower risk of developing
vention did not influence angiographic progression of CAD in patients with T2D without prior myocardial
CAD. infarction (MI) as compared to patients without T2D
with previous MI [20]. Given this heterogeneity, various
studies have been performed utilizing methods such as
Prevalence and detection of coronary artery disease nuclear imaging, echocardiography, carotid ultrasound
in type 2 diabetes and exercise stress-testing, to evaluate the impact
CAD is the leading cause of morbidity and mortality of non-invasive screening for CAD in asymptomatic
in patients with T2D. Previously, T2D was considered patients with T2D [21]. According to these studies, the
Arora et al. Cardiovasc Diabetol (2019) 18:26 Page 6 of 9

Fig. 2 Comparison of quantitative IVUS measurements in the T2D study population (n = 59) with a reference population (donor heart transplants)
without known coronary artery disease or type 2 diabetes (n = 147)

22% of patients had abnormal stress myocardial perfu-

sion imaging whereas Rajagopalan et al. [23] found that
58% of asymptomatic patients with T2D patients had
abnormal SPECT imaging.
Importantly, surrogate markers of CAD obtained
from non-invasive testing carry important prognostic
information in asymptomatic individuals with T2D,
including coronary artery calcium (CAC) by coronary
computed tomography angiography (CTA) [24, 25],
carotid atherosclerosis [26] and plaques [25], and aortic
stiffness [27]. Despite this and the diverging results of
occult CAD prevalence, current guidelines do not rec-
ommend universal screening for CAD among patients
with T2D, partly based on coronary computed tomog-
raphy angiography (CTA) studies [28, 29] showing that
a sizeable proportion of patients (25–30%) do not have
demonstrable plaque on CTA [19]. The ABCD trial is
the first trial to date to perform invasive IVUS imag-
ing, a gold-standard technique for evaluation of CAD,
in asymptomatic patients with T2D and reveals a CAD
prevalence of 84%, indicating a significantly higher
burden of disease than previously assumed. Given the
Fig. 3 Age-stratified prevalence of coronary heart disease (defined as increased vulnerability observed in coronary plaques in
MIT ≥ 0.5 mm) in the T2D study population (n = 59) with a reference
population (heart transplant donors) without coronary artery disease
subjects with diabetes and CAD [30] this prevalence is
or type 2 diabetes (n = 147). MIT maximal intima thickness, T2D type important to consider. Current guidelines although dif-
2 diabetes ferentiating their recommendations for choice of glu-
cose lowering medication according to the presence
or absence of cardiovascular disease, do however not
consider prevalent occult CAD in T2D patients and a
estimates of CAD prevalence in asymptomatic patients refined accurate estimate of risk and disease prevalence
with T2D vary widely with results ranging from 8 to is warranted in an effort to improve the applicability
50% [22]. For example, the DIAD study [8] showed that and validity of T2D management guidelines.
Arora et al. Cardiovasc Diabetol (2019) 18:26 Page 7 of 9

Table 3 Quantitative IVUS analysis of the T2D cohort according to allocated treatment
IVUS parameter Multi-interventional (n = 30) Standard therapy (n = 26) p-value

Mean vessel area (mm2) 14.9 ± 4.3 14.7 ± 4.1 0.86

Mean lumen area (mm2) 10.0 ± 2.9 9.3 ± 2.6 0.37
Mean plaque area (mm2) 4.9 ± 2.5 5.4 ± 2.6 0.49
Percent atheroma volume (%) 32.2 ± 8.6 35.7 ± 11.0 0.19
Normalized total atheroma volume ­(mm3) 265.1 ± 131.9 290.7 ± 144.6 0.49
Mean maximal intimal thickness (mm) 0.72 ± 0.26 0.78 ± 0.29 0.43
Patients with MIT ≥ 0.5 mm 26 (87%) 21 (81%) 0.55
IVUS intravascular ultrasound, T2D type 2 diabetes mellitus, MIT maximal intimal thickness

Progression of coronary artery disease assessed by IVUS is limited by the lack of baseline
A study from 1984 found no significant progression IVUS imaging that does not allow evaluation of disease
in extent score in a population with CAD of which the progression from baseline.
majority had their second angiogram performed due to The current neutral results of multi-interventional
persistent angina [31], but they found that high extent treatment on CV outcome and CAD extent/sever-
score was an independent, strong predictor of CAD pro- ity progression are in concordance with two previous
gression. Despite the relatively low extent score in our landmark trials. The ACCORD study [35] reported that
study, and the high use of statins, we found a substantial the use of intensive therapy targeting HbA1c levels did
progression in both the extent and severity of CAD. This not significantly reduce major cardiovascular events or
confirms a more aggressive atherosclerosis seen in T2D, mortality. The Factor 64 randomized trial [36] utilized
and is in line with a Korean study that demonstrated coronary CTA to identify CAD in patients with dia-
increased progression of coronary artery calcification in betes, and although more aggressive medical therapy
those with diabetes as compared to those without [32]. in those identified with CAD had a positive effect on
lipids, blood pressure, and glucose control, there was
Multi‑interventional therapy in type 2 diabetes no impact on death and coronary heart disease out-
A previous study in patients with T2D and microal- comes. Our results conflict however with the DIANA
buminuria from the pre-statin era, demonstrated that study [37], which showed decreased CAD progres-
an intensive multi-interventional therapy program sion rate with improved glycaemic control after 1 year
aimed at behavioral modification and pharmacologic treatment with voglibose or nateglinide in early T2D.
therapy targeting hyperglycemia, hypertension, dys- Nevertheless, an intervention period longer than the
lipidemia, and microalbuminuria reduced the risk of 2 years in the ABCD trial may ultimately be required
CV and microvascular events by about 50 percent to demonstrate a beneficial effect of a multi-interven-
[33]. The ABCD trial has previously reported that the tional strategy on CV outcome and CAD in this popu-
2 year structured, hospital based multi-intervention lation with more advanced T2D and further research is
significantly reduced estimated CV risk in T2D patients warranted. Furthermore, a more individualized multi-
[13], however, a subsequent long-term follow-up failed interventional treatment strategy with incorporation
to demonstrate an improvement in CV outcome and of newer therapeutic agents, such as, sodium glucose
mortality [15]. This is congruent with a recent study co-transporter-2 (SGLT-2) inhibitors [38], or glucagon
by Ueki et al. of the Japan Diabetes Outcome Interven- like peptide-1 (GLP-1) agonists [39] with evidence for
tion Trial 3 (J-DOIT3) [34], where also a lack of ben- benefit in patients with CV disease manifestations, may
efit on mortality and CV events was reported despite be required to reduce the residual CV risk.
8.5 years of effective multi-factorial, target-driven The present study has some limitations. The inter-
treatment in patients with T2D with additional CV risk vention period was relatively short and the number of
factors. The current report of the ABCD trial supports patients was relatively small, with also an unintended
these findings as evidenced by no significant differ- observation of small baseline imbalances in CAD extent
ence in progression of angiographic CAD between the and severity between the treatment groups, which may
multi-interventional and standard group. Furthermore, have influenced the chance to modulate the progression
there was no significant difference between the multi- by the intervention. IVUS imaging was not performed
interventional and standard group in IVUS parameters at baseline and this limits the possibility for an accurate
7 years after randomization. However, interpretation assessment of CAD disease progression over 7 years in
of the effect of multi-interventional therapy on CAD
Arora et al. Cardiovasc Diabetol (2019) 18:26 Page 8 of 9

the two treatment groups. Furthermore, the reference Acknowledgements

Not applicable.
population of heart transplant donors is a selected pop-
ulation free from CV risk factors and of notably lower Competing interests
age than the T2D cohort, and may not be representative APO and OEJ are employed by Boehringer Ingelheim.
of the general population. However, the authors believe Availability of data and materials
the data is unique as it provides a gold-standard assess- The dataset used during the current study are available from the correspond-
ment of CAD prevalence in asymptomatic patients with ing author on reasonable request.
T2D that challenges the assumptions of current guide- Consent for publication
lines that are based on non-invasive and less sensitive Not applicable.
methods to diagnose CAD.
Ethics approval and consent to participate
Written informed consent was obtained from all T2D patients. The study was
Conclusions approved by the regional ethical authority and was carried out in accord-
ance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice,
In conclusion, this sub-study of the ABCD trial demon- applicable local regulations and the Declaration of Helsinki.
strates that a multi-interventional treatment strategy
allows a sustained improvement in glycemic control but Funding
This study was funded by the South-Eastern Norwegian Regional Health
does not influence angiographic progression of CAD. Authority and by the Foundation of Internal Medicine at Baerum Hospital
IVUS evaluation confirms that an overwhelmingly large Vestre Viken HF.
proportion of asymptomatic T2D patients have CAD,
suggesting that the use of more aggressive and newer Publisher’s Note
prophylactic therapeutic agents addressing residual risk Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
may be warranted.
Received: 21 November 2018 Accepted: 19 February 2019

Additional files

References
Additional file 1: Figure S1. Maximal intimal thickness (MIT) and Percent
1. Diabetes Atlas 8th Edition. International Diabetes Federation. www.diabe​
Atheroma Volume (PAV) according to treatment group.
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Author details diology (ESC) and developed in collaboration with the European Associa-
1
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Trust, Gjettum, PB 800, 3004 Drammen, Norway. 3 Department of Radiology, nary computed tomography angiography derived fractional flow reserve
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tation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 5 Faculty 11. Nissen SE, Yock P. Intravascular ultrasound: novel pathophysiological
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versity Hospital, Oslo, Norway. vascular ultrasound evidence of angiographically silent progression in
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