Impact of diabetes duration and degree of carotid artery stenosis on major adverse cardiovascular events: a single-center, retrospective, observational cohort study

The incidence of diabetes-related morbidity and mortality declined between 1990 and 2010 owing to improvements in medical treatment [1]. Despite the presence of certain controversial findings, diabetes duration is considered an important contributor to the progression of atherosclerotic cardiovascular disease (CVD); moreover, carotid atherosclerosis is linked to a higher risk of major adverse cardiovascular events (MACE) [2‐8]. Although previous studies have assessed the association between diabetes duration and the risk of MACE [9‐11], it is unclear whether there is a comparable increased risk in patients with type 2 diabetes mellitus (T2DM) without clinical CVD. Many population-based studies on the relationship of the carotid intima-media thickness and the presence of focal plaque with CVD have shown that Doppler ultrasound (DUS) screening of carotid artery stenosis (CAS) can identify potentially high-risk patients in whom subsequent MACE may occur [12, 13]. Nevertheless, it is unknown whether both a longer duration of diabetes and a higher degree of CAS could result in an increased risk for the subsequent occurrence of MACE, in patients with T2DM, without clinical CVD. Further, it is also uncertain whether carotid DUS screening could be a valuable tool that can assist in CVD risk stratification for the application of preventive strategies in these patients.

In the present study, we aimed to investigate the impact of diabetes duration and CAS on the subsequent occurrence of MACE in patients with T2DM, without clinical CVD, and to determine the risk factors associated with clinical outcomes in these patients.

Of the 3136 consecutive patients with T2DM who first visited the outpatient clinic of our diabetes center and were aged >50 years, we excluded 934 patients (29.8%) with prior CVD, 65 (2.1%) with a history of carotid or coronary revascularization, and 52 (1.7%) with severe CAS on baseline DUS requiring carotid revascularization. A further 79 patients (2.5%) who were lost to follow-up were also excluded from the analysis. The remaining 2006 patients (64.0%) without clinical CVD at baseline, and with a reported CAS of <70% on baseline DUS and regular follow-ups, were included in the analysis (Fig. 1). Eligible patients were stratified into four groups according to the diabetes duration and CAS degree as follows: group 1 (n = 1281, 63.9%), group 2 (n = 532, 26.5%), group 3 (n = 109, 5.4%), and group 4 (n = 84, 4.2%).

The baseline characteristics of the patients are presented in Table 1. During the mean follow-up period of 55.7 ± 21.2 months, the MACE incidence was found to be 5.9, 8.6, 11.9, and 20.2% in groups 1–4, respectively (Table 2). The difference was significantly greater in patients with a longer diabetes duration and significant CAS (p < 0.001). Analysis of the individual MACE components indicated a trend toward an increased incidence of stroke (p < 0.001), but not of all-cause mortality (p = 0.694), in parallel with a longer diabetes duration and the presence of significant CAS, whereas the risk of MI was significantly higher in patients with diabetes duration <10 years and significant CAS (group 3) (p = 0.039). Kaplan–Meier survival analysis showed that patients with a longer diabetes duration and significant CAS had a decreased MACE-free survival rate (p < 0.001), as compared with those with a shorter diabetes duration and nonsignificant CAS (Fig. 2; Additional file 1: Figure S1).

When the combined effects of diabetes duration and CAS were analyzed on multivariate Cox proportional hazard regression analysis, after adjusting for confounding variables, patients with both a longer diabetes duration and significant CAS demonstrated additive and very high risks for MACE occurrence (HR, 2.07; 95% CI 1.17–3.66; p = 0.012; Table 3) and stroke (HR, 3.38; 95% CI 1.54–7.44; p = 0.002; Additional file 2: Table S1). Male sex (HR, 1.98; 95% CI 1.10–3.57; p = 0.024), hypertension (HR, 1.66; 95% CI 1.03–2.70; p = 0.039), and poor glycemic control, as reflected by the glycated hemoglobin level (HR, 1.27; 95% CI 1.09–1.48; p = 0.002), were all significantly associated with MI (Additional file 2: Table S2), whereas age (HR, 1.05; 95% CI 1.00–1.11; p = 0.039), chronic kidney disease (HR, 4.29; 95% CI 1.41–13.04; p = 0.010), and insulin use (HR, 2.54; 95% CI 1.01–6.38; p = 0.047) were associated with all-cause mortality (Additional file 2: Table S3). Both a longer diabetes duration and significant CAS were not associated with increased risks of MI (HR, 1.60; 95% CI 0.57–4.50; p = 0.374) and all-cause mortality (not applicable). Multivariate analyses that evaluated the respective effects of diabetes duration and CAS on MI indicated that CAS was significantly associated with the risk of MI (p = 0.007), whereas diabetes duration was not associated with any such risk (p = 0.908) (data not shown).

The major finding of the present study on patients with T2DM without clinical CVD was that the cumulative risk of MACE is significantly higher in those with a longer diabetes duration and significant CAS. Although previous studies have described the risk of MACE conferred by the presence and severity of CAS [4, 18], the association between the diabetes duration and MACE occurrence remains controversial; in fact, certain studies have indicated an association, whereas others have not [19, 20]. Furthermore, no reports definitely document the cumulative effects of both a longer diabetes duration and significant CAS on long-term clinical outcomes in patients with T2DM, without clinical CVD. The present study evaluated the impact of both diabetes duration and CAS degree, and found that a longer diabetes duration and significant CAS had additive and much higher risks for MACE and stroke, although the diabetes duration did not affect the risk of MI.

The risk of MI was significantly higher in patients with diabetes duration <10 years and significant CAS (group 3), which primarily included those with male sex and a higher prevalence of hypertension. Considering that male sex and hypertension were significantly associated with an increased risk of MI in our analysis (Additional file 2: Table S2), and that the number of patients in groups 3 and 4 was small, we speculated that these baseline differences may have affected the MI incidence between the study populations. Additional large cohort studies are required to evaluate the association between diabetes duration and MI in patients with T2DM without clinical CVD. Our current results also showed that the rate of all-cause mortality was markedly low, as compared with that in other population-based studies, because our study included only the first event of each outcome and most of the deaths from cardiovascular causes were excluded from all-cause mortality.

CVD is the leading cause of morbidity and mortality worldwide, and its prevention is less costly than the treatment of its complications. Hence, the identification of subclinical disease during the asymptomatic phase has emerged as a public health and economic objective [21]. Cardiovascular risk assessment is generally recommended based on conventional risk factors. However, the predictive ability is only moderate, and a significant percentage of patients, irrespective of the conventional risk factors, present with subclinical atherosclerosis on DUS imaging along with coronary artery calcification [22, 23]. Although DUS screening of the carotid artery can identify potentially high-risk patients in whom subsequent MACE may occur, and some studies have assessed the association between CAS and MACE risk [24‐28], the impact of both diabetes duration and CAS on the MACE risk of patients with T2DM without clinical CVD remains unclear. Furthermore, although previous studies had described the risk of MACE conferred by the presence and severity of CAS in blacks and whites, there are very few reports available for Asians [4]. According to the data from the Department of Measurement and Health Information of the World Health Organization, there is a significant difference in the risk of MACE between different racial–ethnic groups; stroke is more prominent than MI in Asian general populations compared with Western general populations [29, 30]. Therefore, our findings may serve as novel data that could aid in the optimal surveillance and management of MACE risk in Asian patients with T2DM without clinical CVD.

Glucose intolerance and diabetes are risk factors for stroke and MI in Asia, as in Western countries [31]. Although Asian populations are presently less obese than Western populations, the recent Westernization of dietary habits has resulted in increasing body mass index in most Asian countries. Moreover, the prevalence of glucose intolerance and diabetes may increase further. A large-scale meta-analysis project, the Asia Pacific Cohort Studies Collaboration, showed that the HRs of diabetes for ischemic stroke and MI are similar for both Asian and Western countries [32]. The prevalence of diabetes has been increasing throughout Asia, and the speed of increase is much faster than in Western countries [29]. Trends in increased prevalence of diabetes and higher risks of diabetes-related MACE reported by several population-based studies showed the importance of the development of primary prevention programs for this vulnerable and fastest-growing higher-risk population in Asia. In our study, the degree of CAS, as detected by using carotid DUS screening, is a simple and noninvasive marker of subclinical atherosclerosis associated with an increased risk of MACE in patients with T2DM, without clinical CVD. Furthermore, DUS screening could be a valuable tool that can assist in cardiovascular risk stratification for the application of preventive strategies.

This study has some notable limitations. First, our findings may have been subject to selection and information bias owing to the retrospective study design; hence, the incidence of MACE may have been underestimated, and the number of excluded patients was considerable. Moreover, despite efforts to optimize blood pressure, glucose, and lipid control during the management of patients at our diabetes center, we sometimes failed to achieve management goals defined by the annually updated Standards of Medical Care in Diabetes by the American Diabetes Association [33, 34]. We could not analyze microvascular complications. Furthermore, we could not evaluate carotid plaque characteristics such as ulceration, surface irregularities, and morphologic composition, because our study cohort received DUS as a routine screening for cardiovascular risk factors at our diabetes center. For routine screening of subclinical atherosclerosis of the carotid artery, the availability, ease of measurement, and cost will be of major importance in choosing the imaging methodology [4]. Imaging of carotid plaque and measurement of CAS degree is a simple noninvasive and cost-effective method. Although some methods, such as measurements of plaque area and volume, may be better in risk prediction than our method [35‐37], these imaging methodologies are more complex, time consuming, expensive, and not readily available [4]. There could be intra- and inter-observer variability affecting our analyses because the reliability of DUS examination highly depends on the expertise of the examiner and the knowledge and experience of the interpreting physician. Carotid DUS was performed by accredited radiologists in our diabetes center, and all images were reviewed by two experienced vascular surgeons. Second, our study cohort was preselected for being otherwise healthy patients with T2DM without clinical CVD. Therefore, our results may not be applicable to the general population with diabetes, and we could not compare our findings with those of other population-based studies [38, 39]. Furthermore, the cohort consists of only Korean Asians and may not be representative of other Asians or other racial–ethnic minority groups; our findings should be interpreted with caution with respect to different racial–ethnic groups because the environmental and genetic factors may differ among various racial–ethnic groups, and there may be racial–ethnic differences in the prevalence of MACE in patients with T2DM. Third, we calculated the diabetes duration at baseline by using the participant self-reported age at diabetes onset, which may have been inaccurate owing to the lag between the time of disease onset and diagnosis. There may have been several years of dysglycemia, which also increases cardiovascular risk. Furthermore, our analysis between diabetes duration and MACE was complicated by the fact that a longer diabetes duration is associated with older age, and the residual confounding effects of this association cannot be excluded. Furthermore, our current findings were obtained at a single center, resulting in a small sample size, which may limit the overall relevance of our results. Lastly, the mean follow-up duration may not have been sufficient for the occurrence of MACE.

The findings of the present study on patients with T2DM without clinical CVD indicated that there is a significantly higher risk of MACE in patients with a longer diabetes duration and significant CAS. In fact, both diabetes duration and CAS have additive and very high risks for MACE and stroke.