In this study, the prevalence of ASCVD was 15.29% in T2DM patients. Age, female sex, the family history of ASCVD and hyperglycemia were risk factors of ASCVD, similar to previous research results. Coexisting diseases with T2DM, such as hypertension and hyperlipidemia are defined ASCVD risk factors, while DM itself is considered to have a CAD risk equivalent. ASCVD is the main cause of morbidity and mortality in diabetic patients, accounting for the biggest burden of DM directly or indirectly. The 2007-2008 China National Diabetes and Metabolic Disorders Study reported that the defined total of ASCVD prevalence was 1.44%, including 0.83% of stroke and 0.63% of CHD in Chinese adults over 20 years of age (19). The Da Qing impaired glucose tolerance (IGT) and Diabetes Study found the leading cause of death for patients with diabetes is ASCVD after 23-year follow-up (20).
It is very important for ASCVD to be detected and intervened timely. Due to the fact that the sensory nerve becomes insensitive and even lost in patients with diabetes, symptoms of ASCVD become asymptomatic or atypical. A variety of cardiovascular risk assessment tools having been proposed to assess the risk of developing ASCVD are available, such as Framingham risk score (FRS), Adult Treatment Panel III (ATP-III), EURO- the Systematic Coronary Risk Evaluation (SCORE), Reynolds risk score (RRS), QRISK2 and the Chinese ten-year appraisal method for ischemic cardiovascular disease (ICVD), etc. But the suitability of these screening assessment tools are limited because the ethnic, region, environment, and the way of life of patients are different. Moreover, computed tomography (CT) and angiography can detect the evidence of stenosis or occlusion of vasculars directly, but these clinical application can result in radiation exposure and sometimes unnecessary invasive diagnosis and treatment. Therefore, it’s necessary to look for a kind of both simple and non-invasive methods to identify ASCVD early in clinical.
In spite of growing controversy，more evidence shows that microvascular diseases in T2DM has a predictive value on developing ASCVD. Micro- and macrovascular complications of T2DM have a “common soil”. Since the Framingham Heart Study and the Framingham Eye Study had reported the association between DR and the occurrence of cardiovascular events, people gradually realized the importance of DR beyond visual damage. The Atherosclerosis Risk in Communities (ARIC) study also found that DR was associated with an increased risk of ischemic stroke [hazard ratio (HR), 2.34; 95% confidence interval (CI), 1.13 to 4.86] over an average follow-up of 7.8 years in the middle-aged persons with diabetes, independent of other risk factors (8). Another ARIC study (21) showed that after controlling for traditional cardiovascular risk factors, participants with retinopathy had more than 2.5-fold higher risk of developing heart failure (HF) than those without retinopathy (HR 2.71; 95% CI 1.46 to 5.05). This association remained significant after further adjustments for glycemic control, carotid atherosclerosis, and serum markers of endothelial dysfunction (HR 2.20, 95% CI 1.08 to 4.47). Recently, A meta-analysis showed that DR was significantly associated with increased risk of stroke [risk ratio (RR), 1.74; 95%CI 1.35 to 2.24], compared with patients without DR. Furthermore, DR was associated with a marginal increased risk of HF in patients with DM (RR 2.24; 95% CI 0.98 to 5.14) (9). Retinopathy proved to be an independent risk marker for CVD in patients with T2DM (22).
However, there is limited knowledge regarding whether this association is observed consistently in Asian populations, especially in Chineses. There exist differences in the epidemiologic and risk associations of ASCVD between white and Asian populations. There is a potential need for an ethnicity-specific risk model of ASCVD. Furthermore, what remains disputed is whether each stage of DR is associated with increased risk of ASCVD. A report from Finland showed that during the 7-year follow-up, only in patients with PDR at baseline, the risk of CHD events was statistically significantly higher compared with patients without DR (OR 2.31, 95% CI 1.21 to 4.40) (23). However, the Japan Diabetes Complications Study (JDCS) (24), comprised 2,033 patients with T2DM, comfirmed that the presence of DR was found consistently to be associated with an increased risk of stroke and CHD after 8 years of follow-up, and further elucidated that even mild to moderate NPDR had a higher risk of CHD (HR 1.69; 95% CI 1.17-2.97) and stroke (HR 2.69; 95% CI 1.03-4.86) after adjusting for traditional cardiovascular risk factors. In our research, those T2DM patients with an eGFR <60 ml/min/1.73m2 were excluded specifically to avoid the confounding factor of renal insufficiency, which was associated with an increased risk of atherosclerosis. We found that the presence of DR was significantly associated with an increased risk of ASCVD in Chinese with T2DM. Furthermore, the incidence of ASCVD increased along with the severity of DR. After adjustment for age, sex and other traditional risk factors, PDR rather than NPDR was significantly associated with and an independent risk factor for ASCVD. In the presence of PDR, risk of ASCVD was 7-fold in T2DM patients and PDR offered risk information beyond that provided by those established risk factors.
DR is closely related with ASCVD in epidemiology, similar pathophysiological processes may be also contributed in DR and diabetes-accelerated atherosclerosis. First, traditional risk factors for ASCVD, such as hypertension, hyperlipidemia, duration of hyperglycemia, magnitude of glycemic control and metabolic syndrome (MetS) are well known risk factors for progression and development of DR (7, 25). Secondly, neovascularization (retinal angiogenesis) is a key hallmark of PDR, and angiogenesis is also a common feature observed in advanced atherosclerotic lesions (26, 27). Early pathological changes of macro- and microvascular have similarities, perhaps microcirculation change can accelerate the progress of macrovascular lesions. In addition, more and more evidence support a major role for the unifying mechanism in the pathogenesis of diabetic macrovascular, as well as microvascular, complications (28). These mechanisms what are hexosamine pathway, activation of protein kinase C, oxidative stress, pathological effects of the renin-angiotensin-aldosterone system (RAAS), advanced glycation end product (AGE) formation, inflammation and modification of circulating macromolecules, etc, not only influence the development of DR, also affect the progress of atherosclerosis (29).
Our study has several limitations that must be taken into account. First of all, it may have unpredictable selection bias. Secondly, ASCVD patients in this article are confirmed cases by hospital, so that some potential ASCVD patients may be missed. This might lead to an underestimation of the prevalence of ASCVD in T2DM patients. Thirdly, as these associations are cross-sectional, the study design is incapable of estimating causal relation directly; therefore, our findings may suggest that PDR is an indicator, but not predictor of ASCVD. The adverse effects of DR on ASCVD in Chinese population should be confirmed further in a larger cohort study with a broader spectrum of potential confounding factors. However, we have no reasons to believe these would substantially bias the associations reported herein.
In conclusion, all our data confirm that DR associates strongly with ASCVD in the Chinese population with T2DM. With the severity of DR increasing, the risk of ASCVD also increases. After adjustment for traditional risk factors, PDR is an independent risk marker for ASCVD. Retinal blood vessel is the only microvascular which can be directly observed, it would certainly be exciting to assess whether the retinal microvasculature can be used as a ‘window’ into the state of the cardiovascular complications in patients with diabetes. DR is not only one of the most common microvascular complications of diabetes, but also a “warning sign” for ASCVD. Based on this research findings, we hope that clinicians should pay more attention to systemic vascular risk of the patients with DR, especially PDR, and suggest to incorporate PDR to clinical cardiovascular risk stratification in patients with diabetes.