Risk Stratification of Coronary Artery Disease in Asymptomatic Diabetic Subjects Using Multidetector Computed Tomography

Abstract

Background: Patients with type 2 diabetes mellitus (T2DM) show a greater risk for coronary artery disease (CAD), but the risk stratification in asymptomatic CAD patients has not been established. This study investigated the prevalence and severity for asymptomatic CAD and predictors in T2DM patients.

Methods and Results: In a multiclinic group, diabetic patients (320 men, 186 women) without known symptoms suggestive of CAD were recruited for multidetector computed tomography (MDCT). Patients were categorized according to severity of coronary atherosclerosis: Grade 1 (normal findings), Grade 2 (mild atherosclerosis without significant stenosis), Grade 3 (moderate stenosis/atherosclerosis, 50–74% stenosis), Grade 4 (moderate stenosis/atherosclerosis, 75–89% stenosis), Grade 5 (severe stenosis/atherosclerosis, ≥90% stenosis). The trend for severity grade of CAD was slightly higher in men than women (P=0.054). For critical lesions (combined Grades 3–5), the prevalence was almost equal (men 44% vs. women 37%; P=0.113). Multivariate models showed that in men, HbA_1c ≥7.4%, dyslipidemia, duration of diabetes, retinopathy, and other type of cardiovascular diseases were predictors of critical lesions and in women, duration of diabetes and retinopathy were predictors.

Conclusions: The prevalence and severity of asymptomatic CAD are comparably high in men and women with T2DM. Risk stratification by using MDCT might be useful to predict asymptomatic coronary lesions requiring coronary revascularization. (Circ J 2015; 79: 2422–2429)

Coronary artery disease (CAD) is a serious and potentially fatal complication of type 2 diabetes mellitus (T2DM).^1,2 CAD is often asymptomatic in these patients and has frequently progressed to an advanced state before it clinically manifests.³ However, a risk factor-based approach to identify the presence of CAD in asymptomatic diabetic patients has failed to improve clinical outcomes.⁴ Multidetector computed tomography (MDCT) has been proposed as an alternative imaging modality to evaluate patients with known or suspected CAD.^5,6 Using noninvasive MDCT screening, asymptomatic diabetic patients with a higher burden of CAD showed more future cardiac events.⁷ Choi et al reported that diabetic patients with asymptomatic CAD have a higher cardiac mortality risk than those with symptomatic CAD and that lack of revascularization therapy such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) can be responsible for the poor survival rate.⁸ Sorajja et al reported that CABG improved survival in asymptomatic diabetic patients without known CAD who had abnormal myocardial perfusion during stress single-photon emission computed tomography (SPECT).⁹ Therefore, if we could more effectively predict coronary lesions that require coronary revascularization therapy, clinical outcomes would probably improve in asymptomatic diabetic patients.

Previous studies identified DM as having a greater sex difference for associated risk of CAD.¹⁰ In the INTERHEART study (15,152 cases and 14,820 controls) exploring the risk factors for acute myocardial infarction, women with DM had an increased risk of developing cardiovascular disease (CVD) compared with men (odds ratio for nondiabetics, women 4.26 vs men 2.67).¹¹ Similarly, the Nurses’ Health Study found CVD mortality in women with DM to be 8.7-fold higher than in nondiabetic women.¹² The reason for this higher mortality rate in women is multifactorial and related to a higher risk factor burden, more microvascular complications such as neuropathy, retinopathy, and nephropathy, and an often less aggressive treatment of DM in women than in men.¹³ However, overall risk factor burden, including microvascular complications and glycemic control, along with risk factors, has not been considered in sex-associated risk stratification.

This study was performed to clarify the prevalence and severity of asymptomatic CAD, and the predictors in T2DM patients who had undergone standard risk management in diabetes clinics.

Methods

Subjects

From a multiclinic group of diabetologists in Fukuoka, Japan (Appendix S1), 534 diabetic patients without known CAD or suggestive symptoms were continuously recruited for MDCT between July 2005 and May 2008 at the Heart Center, Fukuoka Wajiro Hospital. The study protocol was in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical/Epidemiological Studies of the Japanese Ministry of Health, Labor, and Welfare, and received ethical approval from the institutional review boards of all participating institutes. All enrolled patients gave written informed consent. Exclusion criteria included known CAD, iodine-based contrast allergy, bronchial asthma, atrial fibrillation, severe heart failure, or renal failure (creatinine >1.5 mg/dl). Hypertension was defined as a systolic blood pressure ≥130/80 mmHg or the current use of antihypertensive treatment. Diabetes was defined as fasting plasma glucose (FPG) ≥6.99 mmol/L (126 mg/dl) or the current use of hypoglycemic treatment. Hyperlipidemia was defined as fasting serum low-density lipoprotein (LDL)-cholesterol ≥3.62 mmol/L (140 mg/dl), high-density lipoprotein (HDL)-cholesterol <1.03 mmol/L (40 mg/dl), triglycerides (TG) ≥1.58 mmol/L (140 mg/dl), and/or the current use of antihyperlipidemic treatment. Metabolic syndrome was defined according to the 2005 International Diabetes Federation guidelines,¹⁴ which include waist circumference ≥90 cm in men and ≥80 in women cm plus the presence of at least 2 of the following 4 factors: (1) TG ≥1.58 mmol/L (140 mg/dl), (2) HDL-cholesterol <1.03 mmol/L (40 mg/dl) in men and <1.29 mmol/L (50 mg/dl) in women, (3) elevated blood pressure (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or both), and (4) elevated FPG (≥5.6 mmol/L (100 mg/dl)).

As nondiabetic controls, we recruited consecutive 328 subjects (225 men, 103 women) who underwent MDCT coronary angiography (CAG) and 75-g oral glucose tolerance test between 2005 and May 2008 at the Fukuoka Wajiro Hospital. Subjects were excluded if they had DM or known CAD. The control subjects voluntarily undertook MDCT if they had atherosclerotic risk factors such as age ≥65 years, family history of CAD, hypertension, smoking, or dyslipidemia. According to the 2010 Appropriate Use Criteria for Cardiac Computed Tomography,¹⁵ cardiac CT is not necessarily recommended for asymptomatic individuals with low-to-moderate CAD risk. However, because the prevalence of CAD is not negligible even in asymptomatic subgroups,¹⁶ we used MDCT to evaluate such subjects after they had given written informed consent about the radiation-exposure related risk.

Multidetector CT Scan Protocol

Coronary CT angiography (CCTA) was performed using a 64-slice scanner (Sensation 64; Siemens Medical Solutions, Erlangen, Germany) following standard guidelines.¹⁵ After appropriate use of sublingual nitroglycerin and oral β-blockers, a low-osmolar nonionic contrast agent was injected, and a retrospective ECG-gated spiral scan was performed covering the region immediately beneath the aortic arch to the apex of the left ventricle during an inspiratory breath hold of 10–20 s. Scan parameters were: gantry rotation for 330–420 ms, spiral imaging with retrospective ECG gating and dose modulation, 750–850 mA, 120 kV, and 0.75–1-mm slice thickness. A multisegment algorithm was used to reconstruct overlapping images, typically at 75% of the cardiac cycle. If motion artifacts were present, additional reconstructions were made at different points of the RR interval, as needed. Patients with significant arrhythmia (atrial fibrillation or frequent premature beats) did not undergo imaging. All studies were interpreted at the time of acquisition by individuals with experience in MDCT imaging. The diagnostic accuracy of the CCTA for coronary luminal narrowing was validated by routine invasive CAG. Coronary calcification was defined as a plaque of at least 3 consecutive pixels (area=1.03 mm²) with density ≥130 Hounsfield units. Before CCTA, a noncontrast scan with prospective ECG trigger was performed to measure the coronary artery calcium (CAC) score. The CAC score was calculated according to the method described by Agatston et al.¹⁷ Coronary lesions were evaluated by interventional cardiologists unaware of the patients’ profiles, and patients were separated according to a newly defined 5-grade severity ranking for obstructive coronary artery lesions: Grade 1, almost normal findings; Grade 2, mild atherosclerosis without significant stenosis, Grade 3, moderate significant stenosis/atherosclerosis, indicating at least 1 lesion with 50–74% stenosis; Grade 4, moderate stenosis/atherosclerosis, indicating at least 1 lesion with 75–89% stenosis; Grade 5, severe stenosis/sclerosis, indicating at least 1 lesion with ≥90% stenosis.

Biochemical Measurements

Routine biochemical methods were used to determine plasma concentrations of glucose and serum concentrations of total and HDL-cholesterol, TG, creatinine, and glucose. Concentrations of LDL-cholesterol were estimated using Friedewald’s method.¹⁸ Glycated hemoglobin (HbA_1c) was measured by high-performance liquid chromatography and insulin by chemiluminescent enzyme immunoassay. The value for HbA_1c (Japan Diabetic Society [JDS]) (%) was converted to National Glycohemoglobin Standardization Program levels using the recommended formula.¹⁹ Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as follows: fasting glucose (mmol/L)×fasting insulin (µU/L)/22.5.²⁰ High-sensitivity C-reactive protein was measured by an immunonephelometric method (N Latex CRP II, Dade Behring Ltd, Tokyo, Japan).

Statistical Analysis

Values are expressed as the mean±SD unless otherwise indicated. Multigroup comparisons of variables were performed by 1- or 2-way ANOVA followed by Tukey-Kramer Honestly Significant Difference test or by Fisher’s exact probability test. Multiple logistic regression analysis was performed to adjust for confounding factors. Variables were treated as categorical otherwise indicated. Odds ratio is given as 2-tailed with 95% confidence interval. All analyses were performed using Jump version 10.0.2 software (SAS Institute Inc, Cary, NC, USA). P<0.05 was considered statistically significant.

Results

General Characteristics of Patients

Of the 534 diabetic patients who underwent cardiac MDCT, 27 with type 1 DM were excluded and 506 patients with T2DM were evaluated in the current study. Table 1 summarizes the baseline clinical variables for the 320 men and 186 women who had not experienced a CAD event or symptoms. Body weight and waist circumference were less in women than in men, but body mass index was comparable. Systolic blood pressure, prevalence of hypertension, and use of antihypertensive medications were comparable, but diastolic pressure was lower in women than in men. Prevalence of dyslipidemia, use of antihyperlipidemic drugs, waist obesity, and prevalence of metabolic syndrome were higher in women than in men. The rates of family history of diabetes and duration of diabetes were comparable between men and women. Although FPG levels were comparable between men and women, fasting insulin, HOMA-IR, and HbA_1c were higher in women. The use of oral antidiabetic drugs and insulin was comparable between men and women. Urinary albumin excretion was comparable, but macroalbuminuria was higher in men. The trend of diabetic retinopathy was comparable between men and women, as was the prevalence of neuropathy. Family history of cardiovascular diseases did not differ, and the prevalence of peripheral arterial, cerebrovascular, and aortic diseases was comparable between men and women.

Table 1. General Characteristics of the Study Patients With Asymptomatic Diabetes

	Men (n=320)	Women (n=186)	P value
Age (years)	63±9	66±8	0.000
≥65 years (%)	47%	54%	0.140
Body weight (kg)	65.9±12	55.7±10.6	<0.0001
BMI (kg/m2)	23.8±3.5	24±0.3	0.559
Waist circumference (cm)	86.9±9.6	82.9±10.8	<0.0001
Waist obesity (male ≥90 cm, female ≥80 cm)	31%	49%	<0.0001
Metabolic syndrome	28%	54%	<0.0001
BP (mmHg)	131/76±17/10	131/73±18/12	0.900
Hypertension	68%	67%	0.695
Antihypertensive drugs	50%	45%	0.354
Current or ex-smoker	35%/33%	7.5%/7.0%	<0.0001
Dyslipidemia	53%	71%	<0.0001
Antihyperlipidemic drugs	30%	56%	<0.0001
Family history for T2DM	46%	54%	0.118
Duration of diabetes (years)	12.4±9	10.9±7.8	0.049
Glucose (mg/dl)	151±49	144±43	0.153
Hemoglobin A1c (NGSP%)	7.48±1.24	7.72±1.35	0.043
Oral antidiabetic agents or insulin use (%)	77%	77%	1.000
Sulphonylureas (%)	42%	39%	0.511
Biguanides (%)	19%	23%	0.253
Thiazolidines (%)	13%	8%	0.108
Glinides (%)	6%	6%	1.000
α-glycosidase inhibitors (%)	20%	16%	0.343
Insulin use (%)	16%	18%	0.538
Urinary albumin excretion (mg/g creatine)	116±353	111±287	0.876
None	62%	65%	0.003
Microalbuminuria	25%	31%
Macroalbuminuria	14%	5%
Diabetic retinopathy
None	73%	67%	0.4039
Simple	17%	21%
Preproliferative+proliferative	10%	11%
Blind	0.0%	0.6%
Diabetic neuropathy	32%	27%	0.310
Family history of CVD	27%	7.6%	0.835
Other CVD
Peripheral arterial disease	7.5%	5.0%	0.128
Cerebrovascular disease	6.2%	2.8%	0.657
Aortic disease	1.3%	0.6%	0.657
Any of above	14%	8.4%	0.107

Mean±SD or %, P values represent difference between men and women. BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; T2DM, type 2 diabetes mellitus.

Severity Grade of Stenosis/Atherosclerosis Lesion by MDCT

Of the 320 diabetic men included in the analysis, only 56 (18%) presented with normal findings (Grade 1) and 264 (82%) presented with abnormal findings on MDCT (Table 2). Of the 264 men with abnormal findings, 76 showed moderate significant stenosis/atherosclerosis (Grade 3), 54 showed more than moderate stenosis/ atherosclerosis (Grade 4), and 10 showed severe stenosis/atherosclerosis (Grade 5). Combined, 64 (20%) had coronary lesions requiring possible PCI/CABG when assessed by interventional cardiologists. Of the 186 women, 53 (28%) presented with normal findings (Grade 1) and 133 (72%) patients had abnormal findings (vs. men, χ²=8.413, P=0.004). The trend for severity grade of coronary atherosclerosis was slightly higher in men than in women (P=0.054). When Grades 3, 4, and 5 were combined as critical lesions, the prevalence was almost equal between men and women (140/320 [44%] vs. 68/186 [37%], respectively, χ²=2.512, P=0.113). The prevalences of critical coronary artery lesions (Grade ≥3) was similar between men and women. The CAC scores (Agatston) was higher in men than in women, but the CAC score at each severity grade of stenosis/atherosclerosis lesion was comparable between men and women (Table 2). When the CAC score was categorized into 4 groups, the mean CAC score categories were statistically significant among Grade 1–5 in men and women (P<0.001), but the trend was not different between men and women (Table 2).

Table 2. Severity Grade of Stenosis/Atherosclerosis Lesion and CAC Score in Patients With Asymptomatic Diabetes

	Men (n=320)	Women (n=186)	P value
Severity grade of stenosis/atherosclerosis lesion
Grade 1	56 (18%)	53 (28%)	0.054
Grade 2	124 (39%)	65 (35%)
Grade 3	76 (24%)	40 (22%)
Grade 4	54 (17%)	22 (12%)
Grade 5	10 (3%)	6 (3.2%)
Critical coronary artery lesion (Grade ≥3)	140/320 (44%)	68/186 (37%)	0.113
CAC score (Agatston)
All	276±667	133±347	0.007
Grade 1	8±32	4±23	0.098
Grade 2	71±140	52±114
Grade 3	389±618*	192±407*
Grade 4	712±1,179**	324±469**
Grade 5	1,117±1,036**	1,027±799**

Number (%) or mean±SD.*P<0.01, **P<0.001 vs Grade 1. CAC, coronary artery calcium.

Prevalence and severity of stenosis/atherosclerosis lesion were compared between nondiabetic controls and T2DM patients (Table S1). Trend in severity grade of stenosis/atherosclerosis lesion, critical lesion (Grade ≥3) was significantly different between nondiabetic controls and T2DM men and women.

Logistic Regression Models Predicting Critical Coronary Lesions

In men, dyslipidemia, increased HbA_1c, duration of DM, macroproteinuria, and history of other type of cardiovascular disease (any of peripheral arterial, cerebrovascular, and aortic diseases) were the significant predictors for critical coronary lesions (Grade ≥3), whereas in women, duration of DM and presence of either retinopathy or neuropathy were the significant predictors for critical coronary lesions (Table 3).

Table 3. Univariate Logistic Regression Models Predicting Critical Coronary Lesions (Grade ≥3) in Patients With Asymptomatic Diabetes

Factors	All (n=506)				Men (n=320)				Women (n=186)
	OR	Lower†	Upper†	P value	OR	Lower†	Upper†	P value	OR	Lower†	Upper†	P value
Men (vs. women)	1.351	0.933	1.961	0.112	–				–
Elderly (≥ 65 years)	1.565	1.096	2.238	0.014	1.570	1.007	2.454	0.0464	1.671	0.914	3.093	0.096
Waist obesity (male ≥90 cm, female ≥80 cm)	0.972	0.674	1.398	0.878	0.991	0.609	1.607	0.970	1.199	0.648	2.243	0.564
Metabolic syndrome	1.007	0.694	1.458	0.970	1.095	0.662	1.804	0.722	1.111	0.606	2.049	0.734
BP ≥130/85 mmHg or medication	1.571	1.069	2.327	0.023	1.431	0.886	2.331	0.143	1.849	0.965	3.656	0.064
Current or ex-smoker	1.179	0.826	1.683	0.365	0.852	0.530	1.373	0.510	1.756	0.764	4.017	0.182
Dyslipidemia	1.440	1.001	2.08	0.050	1.727	1.106	2.712	0.016	1.195	0.618	2.363	0.599
Family history of CVD	0.930	0.620	1.386	0.721	0.759	0.455	1.255	0.284	1.339	0.686	2.590	0.389
HbA1c (NGSP%)
≤6.5 vs. >6.5	1.617	0.922	2.922	0.095	1.493	0.798	2.879	0.213	3.341	0.862	22.03	0.085
≤7.0 vs. >7.0	1.680	1.151	2.467	0.007	1.827	1.148	2.937	0.011	1.504	0.787	2.953	0.219
≤8.0 vs. >8.0	1.079	0.722	1.607	0.710	1.199	0.721	1.989	0.484	0.940	0.478	1.807	0.851
Duration of diabetes (years)
6–10 vs. ≤5	1.904	1.144	3.199	0.013	2.290	1.195	4.469	0.012	1.433	0.629	3.320	0.393
11–15 vs. ≤5	2.091	1.200	3.67	0.009	2.087	1.048	4.214	0.036	2.076	0.805	5.410	0.131
≥16 vs. ≤5	3.382	1.839	6.550	<0.0001	3.434	1.620	7.848	0.001	3.285	1.195	10.657	0.02
Simple retinopathy	2.103	1.316	3.371	0.002	1.864	1.016	3.443	0.044	2.812	1.325	6.015	0.007
Proliferative retinopathy	2.566	1.181	5.716	0.017	1.997	0.759	5.418	0.160	4.219	1.134	17.414	0.032
Any retinopathy	2.345	1.578	3.500	<0.0001	1.986	1.196	3.319	0.008	3.333	1.746	6.455	0.000
Microproteinuria	0.737	0.479	1.124	0.157	0.802	0.460	1.381	0.428	0.658	0.329	1.284	0.222
Macroproteinuria	1.943	1.076	3.558	0.028	2.567	1.304	5.227	0.006	0.432	0.063	1.878	0.278
Microproteinuria or microproteinuria	0.981	0.675	1.421	0.918	1.222	0.770	1.939	0.394	0.624	0.321	1.183	0.150
Neuropathy	1.262	0.855	1.860	0.241	0.971	0.600	1.566	0.904	2.034	1.041	3.990	0.038
Other types of CVD	1.939	1.113	3.412	0.019	2.513	1.294	5.052	0.006	0.867	0.260	2.561	0.801
Peripheral arterial disease	1.876	0.914	3.930	0.087	2.020	0.858	4.992	0.108	1.429	0.343	5.595	0.607
Cerebrovascular disease	2.438	1.062	5.913	0.035	3.726	1.385	11.78	0.008	0.430	0.022	2.982	0.421
Aortic disease	2.115	0.348	16.16	0.408	3.756	0.475	76.36	0.217	ND

^†95% CI. CI, confidence interval; ND, not determined; OR, odds ratio. Other abbreviations as in Table 1.

Multivariate logistic regression models showed that in men, HbA_1c ≥7.4%, dyslipidemia, duration of DM, any retinopathy, and other type of cardiovascular disease were the significant predictors, and in women, duration of DM and any retinopathy were the significant predictors (Table 4). Multivariate logistic regression analysis including men and women in 1 model showed that men, age (≥65), dyslipidemia, duration of DM and any retinopathy were significant predictors (Table S2).

Table 4. Multivariate Logistic Regression Models Predicting Critical Coronary Lesions (Grade ≥3) in Patients With Asymptomatic Diabetes

Factors	All (n=506)				Men (n=320)				Women (n=186)
	OR†	Lower†,‡	Upper†,‡	P value	OR††	Lower††,‡	Upper††,‡	P value	OR††	Lower††,‡	Upper††,‡	P value
Elderly (≥65 years)	1.616	1.119	2.341	0.011	1.575	0.997	2.499	0.052	1.739	0.932	3.302	0.085
Metabolic syndrome	1.051	0.657	1.679	0.835	0.754	0.461	1.231	0.259	1.942	0.822	4.595	0.128
HbA1c ≥7.0 NGSP%	1.668	1.129	2.482	0.010	2.071	1.283	3.380	0.003	1.647	0.843	3.314	0.146
BP ≥130/85 mmHg or medication	1.489	0.991	2.252	0.057	1.407	0.854	2.338	0.183	1.546	0.758	3.222	0.236
Dyslipidemia	1.668	1.132	2.476	0.01	2.045	1.265	3.341	0.004	1.252	0.631	2.546	0.526
Duration of diabetes >5 years	2.121	1.361	3.365	0.001	2.317	1.314	4.202	0.004	2.24	1.059	5.025	0.041
Any retinopathy	2.626	1.740	3.991	<0.0001	2.146	1.275	3.646	0.004	3.844	1.947	7.763	0.000
Macroproteinuria or microproteinuria	0.938	0.631	1.391	0.751	1.217	0.748	1.983	0.429	0.555	0.269	1.112	0.103
Neuropathy	1.179	0.790	1.756	0.419	0.923	0.564	1.504	0.750	1.786	0.883	3.609	0.105
Other types of CVD	1.578	0.888	2.825	0.121	2.254	1.144	4.583	0.021	0.614	0.157	2.004	0.442

^†Adjusted by age, sex, BMI, and smoking status; ^††adjusted by BMI and smoking status; ^‡95% CI. Abbreviations as in Tables 1,3.

After the patients were categorized by age (<65 vs. ≥65 years) and duration of DM (≤5 vs. >5 years, median years of DM duration) (Figure S1), all or part of dyslipidemia, nephropathy and other types of cardiovascular disease were the significant predictors for critical coronary lesions in men (except for age ≥65 years, DM duration >5 years), whereas retinopathy was the only predictor in women (except for age ≥65 years, DM duration ≤5 years).

Discussion

The major findings of this study were: (1) the prevalence and severity of asymptomatic CAD were comparable between in diabetic men and women patients who had undergone standard risk management; (2) predictors for asymptomatic CAD in diabetic patients were sex linked (in men, HbA_1c ≥7.4%, dyslipidemia, duration of DM, any retinopathy, and other cardiovascular disease, and in women, duration of DM and any retinopathy).

Asymptomatic CAD in Men and Women With DM

Of the 320 diabetic men, 82% presented with abnormal findings on MDCT (Table 2). Of these men with abnormal findings, 24% showed moderately significant stenosis/atherosclerosis (Grade 3), 17% showed more than moderate stenosis/atherosclerosis (Grade 4), and 3% showed severe stenosis/atherosclerosis (Grade 5). Combined, 20% had coronary lesions requiring possible PCI/CABG. Of the 186 diabetic women, 72% presented with abnormal findings (vs. men, χ²=8.413, P=0.004). Although the trend for severity grade of coronary stenosis/atherosclerosis was slightly higher in men, the prevalence of critical lesions (Grade≥3) was comparable between men and women. Halon et al evaluated 427 consecutive asymptomatic diabetic patients with no history of coronary disease (age 55–74 years, 58% women) by CCTA and reported that men had a higher prevalence than women for any coronary atheroma (82% vs. 73%, P=0.028), multivessel coronary atheroma (67% vs. 46%, P<0.001) and any coronary stenosis (31% vs. 17%, P=0.001). The trend in severity grade of stenosis/atherosclerosis lesion and critical lesion (Grade ≥3) was all different between nondiabetic controls and T2DM patients, both men and women (Table S1). In agreement with previous studies, our study showed a higher prevalence of asymptomatic CAD in both sexes of diabetic patients than in nondiabetic patients.²¹

Although the sex differences in CCTA-identified CAD in diabetic patients have not yet been fully clarified, asymptomatic diabetic patients of both sexes show poor prognosis.²² Choi et al reported that although the severity of coronary atherosclerosis was similar in asymptomatic and symptomatic patients, revascularization therapy was performed less frequently in asymptomatic than symptomatic patients (26.8% vs. 62.0%, P<0.001).⁸ Asymptomatic patients experienced a similar number of major adverse cardiac events (MACEs: death, non-fatal myocardial infarction, and revascularization) as symptomatic patients (32% vs. 28%), but had higher cardiac mortality (26% vs. 9%; P<0.001). However, patients who underwent revascularization therapy at the time of CAD diagnosis in these 2 groups showed similar MACE and cardiac mortality (asymptomatic vs. symptomatic; 20.0% vs. 22.5% and 6.7% vs. 5.3%, respectively; P>0.05). Collectively, diabetic patients with asymptomatic CAD have a higher cardiac mortality risk than those with symptomatic CAD, and lack of revascularization therapy may be responsible for the poor survival rates.^9,10

Sex-Linked Risk for Asymptomatic CAD in Diabetes

Our results showed that predictors for asymptomatic CAD were sex-linked; in men, predictors were HbA_1c ≥7.4%, dyslipidemia, duration of DM, any retinopathy, and other types of cardiovascular disease, and in women, predictors were duration of DM and any retinopathy. To our knowledge, this is the first report to study precisely the sex-linked risk factors for prevalence and severity of asymptomatic CAD in patients with T2DM.

There is increasing evidence that individuals with microvascular complications of DM are at increased risk for macrovascular complications such as CAD. Although the relationship of microalbuminuria with vascular disease has been well described,^23,24 recent studies also suggest that retinopathy may be associated with CVD. In fact, retinopathy, especially proliferative diabetic retinopathy, is associated with CAD and CVD events, and cardiovascular mortality.^25–27 Those studies indicate that retinopathy may be independently associated with CAD and CVD events or mortality even after adjusting for standard cardiovascular risk factors, DM duration, and/or glycemic control.

Reaven et al reported a strong association of proliferative retinopathy with a direct measure of coronary atherosclerosis burden by measuring CAC in a subset of T2DM individuals in the Veteran Affairs Diabetes Trial (VADT) of tight glycemic control.²⁸ In the VADT, the majority of subjects were men (95% of 204 participants) and 39% had a prior history of CVD. In the present study, we confirmed their observation of the link between retinopathy and coronary atherosclerosis by assessing obstructive stenosis, which goes beyond CAC scoring for prediction of future CAD.²⁹ Interestingly, either simple or proliferative retinopathy was a significant predictor for critical coronary lesions (Grade ≥3) in both men and women after adjusting for other classical coronary risk factors. When the overall risk factor burden, including microvascular complication, glycemic control, and classical coronary risk factors, were considered, sex-linked predictors of CAD were selected. In men, the predictors for asymptomatic CAD were HbA_1c ≥7.4%, dyslipidemia, duration of DM, any retinopathy, and other types of cardiovascular disease, all in agreement with previous reports.^7,30 However, in women, duration of DM and any retinopathy were the sole predictors. Our results suggest that there may be shared mechanisms underlying both retinopathy and clinical CAD in men and women, but standard cardiovascular risk factors and glycemic control do not appear to contribute equally to the relationship. On the other hand, our multivariate model including men and women found that duration of DM and retinopathy were still the significant predictors (Table S1). Duration of DM and presence of diabetic retinopathy regardless of sex difference should be more emphasized as predictors of asymptomatic CAD.

Study Limitations

First, screening for CAD in diabetic patients is not validated. MDCT allows noninvasive imaging of the coronary arteries, including detection of coronary atherosclerosis by calculating the calcium score and by performing noninvasive angiography. Although with the 64-MDCT, high sensitivity (≤93%) and specificity (≤96%) for the detection of significant (≥50% luminal narrowing) stenosis have been reported, there is no solid evidence that this technique-based approach to screening for asymptomatic cardiac ischemia can improve clinical outcome in diabetic patients.^31,32 Second, CAC is an important technical limitation of CT angiographic quantitation. Artifacts caused by “blooming” encountered in the evaluation of the significantly calcified vessel are problematic for accurate CTA assessment of vessel stenosis.¹⁵ When we could not assess coronary stenosis because of severe calcification, we tried to assess the lesions by invasive CAG, which was otherwise excluded from the analysis. In 50 subjects unclassified by MDCT because of severe calcification, 18 were classified as Grade 3, 16 as grade 4 and 6 as grade 5 by subsequent invasive CAG, and 10 who did not consnet to invasive CAG were excluded from the study. Third, we assessed nephropathy by the prevalence of microalbuminuria or macroalbuminuria. Although albuminuria is a good marker for CAD prediction, its combination with estimated glomerular filtration rate may serve as a better predictor of clinical outcomes by emphasizing an earlier phase of nephropathy.³³ Fourth, we assessed medications for hyperglycemia, dyslipidemia, and hypertension, but did not take into account the class of drugs, which can influence the coronary atherosclerosis burden.³³ Fifth, the lack of followup of outcomes of the patients is an important limitation. Recently, the FACTOR64 trial demonstrated that screening for CAD in asymptomatic DM patients with good metabolic control does not confer better outcomes.³⁴ Therefore, the present study, despite being observational, may provide additional information by proposing a novel risk model based on sex. Current ESC guidelines propose several engines to predict the risk of CAD in DM patients.^35,36 Therefore, it may be required to see how our model performs compared with the engines proposed by these guidelines.

Conclusions

The prevalence and severity of asymptomatic CAD are extremely high in this group of patients with T2DM who underwent standard risk management. Risk stratification, including microangiopathy, duration of DM and other risk factors, can be useful in predicting asymptomatic coronary lesions. This approach may provide better prediction for coronary lesions requiring coronary revascularization therapy.

Acknowledgments

M. Shimabukuro analyzed the data and wrote the manuscript. T.S. designed and conducted the study, and researched the data. T.H. and K.N. researched the data, and discussed and reviewed the manuscript. H.M. and M. Sata reviewed the manuscript; Members of the Fukuoka diabetologists group undertook data collection and patient management (see Appendix S1).

This study was supported in parts by grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (20590651, 23591314, 20590542); the Ministry of Health, Labour, and Welfare (MHLW), Japan.

Disclosures

All authors declare no conflicts of interest.

Supplementary Files

Supplementary File 1

Appendix S1. List of Participating Investigators

Table S1. Comparison of severity grade of stenosis/atherosclerosis lesion between nondiabetic controls and T2DM

Table S2. Mutivariate logistic regression models predicting critical coronary lesions (Grade ≥3) in men or women with T2DM

Figure S1. Univariate logistic regression models predicting critical coronary lesions (Grade ≥3) in type 2 diabetic patient groups stratified by sex, age and diabetes duration.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-15-0325

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