The relationship between carotid disease and retinopathy in diabetes: a systematic review

Background Since studies of the relationship between carotid disease and diabetic retinopathy (DR) have shown apparent inconsistencies, the aim of this study was to conduct a systematic review of available published data. Methods Electronic databases were searched independently by two reviewers, according to an iterative protocol, for relevant articles. The search term used was “diabetes AND (carotid disease OR intima-media OR carotid plaque OR carotid stenosis OR carotid arterial disease OR carotid artery disease OR carotid atherosclerosis) AND (retinopathy OR diabetic retinopathy)”. Results From 477 publications, 14 studies were included. There were differences in the variables used as markers of carotid disease and DR across the included studies. Ten studies used carotid disease as the dependent variable, and the remainder used DR. All but one study involved cross-sectional data. Most studies reported a statistically significant association between at least one parameter of carotid disease as assessed by ultrasound and DR presence or severity. Only four studies reported no significant association. A common limitation was the use of convenience participant sampling. Conclusions There appears to be an increased likelihood of DR when there is ultrasonographic evidence of carotid disease, and vice versa. The available studies suggest that there may be a direct relationship between DR and carotid macrovascular disease and/or that these complications co-exist due to shared risk factors. If carotid disease is detected, retinal assessment should be performed. If DR is identified, intensive cardiovascular disease risk management should be considered. Additional longitudinal studies are needed to assess the directionality of the association.


Background
Diabetic retinopathy (DR) is a common microvascular complication affecting over one-third of people with diabetes mellitus [1]. It is one of the leading causes of moderate or severe visual impairment globally [2]. Known modifiable risk factors comprise hyperglycemia, hypertension and dyslipidemia [1,3], but the pathophysiology of DR is not fully understood. Several biochemical mechanisms have been suggested including increased oxidative stress, inflammation, neurodegeneration and upregulation of vascular endothelial growth factor (VEGF) [4]. Despite screening programs aimed at early detection, there are few treatments for DR and most can only be used to prevent worsening of established disease [5]. There is, therefore, a need for improved understanding of the epidemiology of DR including risk factors so that it can be identified earlier, new preventive strategies and treatments developed, and vision loss prevented or delayed.
Diabetic retinopathy is characterised by vascular lesions including microaneurysms, hemorrhages and exudates [4]. Less severe DR typically refers to mild to moderate non-proliferative diabetic retinopathy (NPDR), while more severe DR generally comprises severe NPDR or proliferative diabetic retinopathy (PDR) which have a greater effect on vision [4,6]. The Early Treatment Diabetic Retinopathy Study protocol is commonly used to assess the severity of DR [6][7][8][9][10]. According to this scheme, mild NPDR consists of at least one microaneurysm without evidence of other pathological lesions [6]. When NPDR progresses to PDR there is evidence of neovascularisation [6].
Appropriately intensive management of hyperglycemia and hypertension reduces the risk of DR [3,4]. Of the few available specific treatments, intravitreal anti-VEGF agents, such as aflibercept, ranibizumab and bevacizumab, are now considered as a first-line treatment for vision-threatening DR but not all patients respond and these therapies are costly [5,11]. Laser photocoagulation, which used to be the first-line treatment, and intravitreal corticosteroids are also used to treat severe DR [3][4][5]11]. In type 2 diabetes (T2D), fenofibrate is a treatment that can prevent DR progression. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which recruited 9795 participants, showed fenofibrate reduced the need for laser treatment and, in those with pre-existing DR, the risk of progression [12]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study, which involved 10,251 participants, showed that those in the fenofibrate and statin arm had lower odds of DR progression after 4 years than those in the placebo and statin only arm [13]. Nevertheless, there is still a residual risk of DR progression despite these interventions.
Carotid arterial disease is a major macrovascular complication of diabetes. It is generally assessed by ultrasound which can detect atherosclerotic plaque and quantify intima-media thickness (IMT; see Additional file 1: Figure S1) [14,15]. The Mannheim consensus considers plaque to be a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value, or demonstrates a thickness of ≥ 1.5 mm as measured from the media-adventitia interface to the intima-lumen interface [16]. The degree of stenosis associated with a plaque is expressed as a percentage of the lumen diameter. The IMT can be measured in the common carotid artery (CCA), at the bifurcation and in the internal carotid artery (ICA) [16]. Carotid disease is associated with stroke and cardiovascular disease [14,15]. A review of six studies found an increased risk of cardiovascular events in people with a higher CCA IMT [17]. The presence and number of plaques have also been associated with greater risk of cardiovascular disease, but the combination of both increased CIMT and plaque may be a better measure [18]. People with an IMT ≥ 1 mm and those with high grade stenosis are considered to be at very high risk of cardiovascular events [14].
Microvascular disease in diabetes has been associated with macrovascular disease, a relationship that may reflect shared risk factors [19]. However, the specific association between carotid arterial disease as a manifestation of proximal macrovascular disease and DR as a form of microangiopathy is not well established. As the carotid artery supplies blood to the retina, it is possible carotid disease has a direct effect on the development of DR. The aim of the present systematic review was, therefore, to assess the evidence linking carotid disease and DR in people with diabetes.

Search strategy and selection criteria
An iterative protocol developed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement was followed [20]. The electronic databases Embase, PubMed and MEDLINE were searched. The Boolean search term used was "diabetes AND (carotid disease OR intima-media OR carotid plaque OR carotid stenosis OR carotid arterial disease OR carotid artery disease OR carotid atherosclerosis) AND (retinopathy OR diabetic retinopathy)". Studies were eligible for inclusion if they specifically assessed the relationship between carotid disease and DR using statistical analyses appropriate to the study design with relevant results clearly displayed and an effect size given. In cases where studies assessed the relationship but did not give effect sizes or clear results, the authors were contacted and studies were included if this information was provided. A minimum sample size of 50 participants (to reduce likelihood of type II error) and a statistical analysis that, as a minimum, assessed the effect of age and sex on the association between carotid disease and DR were required. Studies were restricted to those reported in English and conducted in adults. Those not specifying diabetes type and the criteria for determining carotid disease and DR were excluded. In vitro and animal studies, case studies, case series and conference abstracts were also excluded. The search included articles published to end-2019. The summary measures used were those reported in individual studies.
Two reviewers (JD and WD) independently conducted the literature search and reviewed all the articles assessing eligibility and extracting required information. The data from included studies were entered into pre-defined fields including the country where the research was conducted, year(s) the data were collected, study design, aims, definitions, type of diabetes, sample size, methods, results, covariates and limitations. The reference lists of the included articles were reviewed to ensure articles that met the inclusion criteria were not inadvertently excluded due to search terms. The risk of bias of each study was assessed according to guidelines in the Cochrane handbook [21]. The quality of the individual studies was assessed using the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational and Cross-Sectional Studies [22]. Although a metaanalysis was considered, this was not appropriate.

Results
The process of article selection is summarised in Fig. 1. The search identified 477 publications. After excluding duplicates, those not available in English and those of inappropriate format (notes, editorials etc.), 228 abstracts were assessed for relevance and 43 full-text articles were suitable for further evaluation. We emailed authors of four publications for further information, but only received a response from one [23] and excluded the three studies for which no response was received [24][25][26]. No further papers were identified from checking reference lists of relevant papers. The final number of journal articles included in the review was 14 (see Fig. 1).
These 14 publications were from 10 different countries including three from South Korea [10,27] and two each from Spain [7,28] and Brazil [23,29]. The Spanish papers were from the same study but one included participants with type 1 diabetes (T1D) [28] while the other included people with T2D [28]. The Brazilian publications were also from the same study sample, the Rio de Janiero Type 2 Diabetes Cohort Study (RDJ), but assessed different outcomes and so both publications were included [23,29]. Most of the studies were cross-sectional and only one (the RDJ) included longitudinal data [23]. The characteristics of the included studies are shown in Table 1. The sample size ranged from 87 to 1607 participants. Most study samples comprised people with (T2D) but three included participants with T1D [7,30,31].
There was heterogeneity between the studies included in our review. There were noticeable differences in the variables used as markers of carotid disease and DR, as described in Table 2. Measures used to assess carotid disease included measurement of intima media thickness (IMT), plaque, stenosis, or a combination of these. In addition to using different variables as markers of carotid disease, there were also differences in analyses as studies either used continuous variables, a clinically relevant level to split the data into two groups, or percentiles. Two studies assessed DR severity [7,28] [23]. While most other studies determined the severity of DR in their participants, a dichotomous variable (DR absent or present) was used to assess the association with carotid disease. The methods by which DR was graded also varied between the studies. Four specifically stated that the ETDRS grading system was used and one used the International Clinical Diabetic Retinopathy Disease Severity Scale, but many did not give sufficient detail often simply stating that an ophthalmologist graded DR (see Table 2). Due to the significant methodological differences between these studies, a meta-analysis was not appropriate. The methods, results and limitations of these studies are summarised in Table 3. Ten studies used carotid disease as the dependent variable in analysis [7,10,23,[27][28][29][31][32][33][34] and the remaining four used DR as the dependent variable [8][9][10]30]. However, as only one study had a longitudinal component (with carotid disease as dependent variable), the directionality of any association was not able to be determined. The results from the cross-sectional studies suggest that there is some association between the two complications (see Table 4). In general, there was a statistically significant relationship between one or more measure of carotid disease and DR. Four of the 14 studies reported no statistically significant association between any carotid disease variable and any DR variable [10,23,30,32].
The four main carotid variables identified were CCA IMT, other measures of IMT including combinations with CCA IMT, plaque or stenosis, and other carotid disease that mostly comprised a combination of carotid variables. Half of the studies assessed only one carotid disease variable [7-10, 30, 32, 33] while the other half assessed more than one carotid disease variable [10, 23, 27-29, 31, 34]. Of the seven studies which assessed multiple such variables, three found a significant relationship between DR and carotid plaque only [28,29,31], one reported an association with CCA IMT only [27], two reported no significant association [10,23] and one reported a significant association with all carotid variables assessed [34]. Of all included studies, two reported that DR was significantly associated with a combined measure of plaque and IMT [10,34]. Nine of the 14 papers specifically assessed the relationship with plaque/ stenosis and DR and six reported a significant association [7,28,31,33,34]. Plaque was often significantly associated with carotid disease, but this finding was not consistent across all studies.
Ten studies assessed the relationship with CCA IMT and DR. Three of these found a significant association, two reported CCA IMT was associated with any DR [27,34] and one reported an association with mild NPDR [8].
Interestingly, the two studies that reported an association between any DR and CCA IMT used a cut-off point for CCA IMT of ≥ 1 mm [27,34] while those that reported no association assessed CCA IMT as a continuous variable or split the IMT by tertiles [10,[28][29][30][31]. Some of these studies may have had insufficient statistical power, especially as one comprised just 87 participants [30], and only one provided a sample size calculation [28]. Four studies assessed other measures of IMT, of which one determined an association between DR and internal carotid artery (ICA) IMT [28] and one reported that the mean IMT of the ICA, CCA and bifurcation was associated with DR [9]. There did not appear to be a single marker of carotid disease that consistently identified an increased likelihood of DR presence or severity. However, most studies have shown that there is a relationship between at least one measure of carotid disease and DR.
While most studies showed a significant association between carotid disease and DR, four studies reported no significant relationship. Three of these were of good quality [10,23,30], while one was of poor quality [32]. The study by Araszkiewicz et al. had a small sample size compared to the other studies and excluded those with carotid stenosis > 50%; this probably also excluded those with a high common carotid artery (CCA) IMT which may explain the lack of association [30]. Hjelmgren et al. assessed the relationship with stenosis and defined stenosis as a narrowing of > 50%, excluding less severe cases [32]. In the study by Yun et al., CCA IMT was analysed by tertiles, the highest of which ranged from 0.79 to 1.30 mm, including those without clinically significant intima-media thickening of ≥ 1 mm [10]. However, this study also assessed the relationship with carotid stenosis and found no significant association [10]. The longitudinal RDJ study found no statistically significant association between any measure of carotid disease and new or worsening DR, but this sample was outpatient clinicbased [23]. The lack of association seen in some studies may be due to methodological differences.
A common limitation was that most studies used convenience sampling and recruited participants from hospitals and clinics. This increases the likelihood of selection bias, as these participants are more likely to be complex and therefore not representative of the general population of people with diabetes. There was, however, one population-based study [9] and one study that recruited participants from a community-based health program [34]. Measurement bias for DR and carotid disease was another limitation in many studies, with few studies reporting on inter-or intra-rater agreement or quality control measures. Other limitations and potential sources of bias included assessment of only one eye or one carotid artery, and exclusion of participants with a      Table S1. Overall, five studies were of poor quality [8,[30][31][32][33], one fair quality [27] and the remaining eight were of good quality [7,9,10,23,28,29,34]. There were no conflicts of interest identified in any of the studies.

Discussion
This is the first systematic review to assess the relationship between carotid arterial disease and DR. In most included studies there was a statistically significant association between at least one carotid disease parameter and DR presence or severity as assessed from either an increased risk of DR in the presence of carotid disease or an increased risk of carotid disease in people with known DR. No specific carotid disease variable was consistently associated with DR. Although this may reflect significant methodological differences between the studies, most that assessed the relationship between carotid stenosis/plaque and DR reported a significant association. In addition, as only one study utilised longitudinal data and found no association, the directionality of this relationship remains unknown. There is evidence that macrovascular disease is associated with the microvascular complications of diabetes.
A recent meta-analysis has shown that DR is associated with an increased risk of stroke [35]. Diabetic retinopathy has also been shown to increase cardiovascular disease risk [36], and the severity and progression of DR was associated with cardiovascular disease in the ACCORD study [37]. A significant association between carotid disease and changes in the retinal microvasculature has also been found in adolescents with T1D [38]. Diabetic retinopathy has also been associated with other markers of peripheral arterial disease [39], peripheral vascular disease in T1D [40], and arterial stiffness [41].
The mechanisms underlying the relationship between carotid disease and DR are not well established, although there are several theories. First, the "common soil" hypothesis suggests that microvascular and macrovascular complications share risk factors including hyperglycemia, dyslipidemia and hypertension [19,29,42]. The Hoorn Diabetes Care System cohort study also showed that glycaemic variability was associated with both microvascular and macrovascular disease [43]. Second, it has been suggested that signs of microvascular damage in the eye could reflect concurrent microcirculatory disease in the heart and major arteries [36]. One study found that the presence of DR was associated increased neovascularisation in the vasa vasorum of the carotid artery, although there were no differences in IMT or carotid plaque by DR status [44]. Nevertheless, increased Table 4 Summary showing which studies reported significant and non-significant associations between carotid disease and retinopathy neovascularisation of the vasa vasorum has been associated with atherosclerosis and plaque in another study [45]. Although microvascular damage may be a potent underlying cause of macrovascular disease [46], we cannot evaluate this from the studies included in this review as the only longitudinal study assessed whether carotid disease was associated with new or worsening DR, and thus whether macrovascular disease affected microvascular complications.
Lastly, proximal macrovascular disease may directly affect the microvasculature. Interestingly, almost half of the studies in this review excluded participants with known cardiovascular disease, which is a common complication of diabetes. Of these, most reported a significant association between DR and carotid disease [7,10,27,28,34], although one found no association [30]. As there were still statistically significant associations in the absence of known cardiovascular disease, that there may be more to the relationship between carotid disease and DR than simply long term exposure to shared risk factors, supporting a direct relationship between carotid disease and DR.
The presence of stenosis or plaque was more often significantly associated with DR than other measures of carotid disease. As the carotid artery supplies the ophthalmic artery, it is possible that microemboli or plaque fragments from the carotid could dislodge and travel to the retina [47] thus contributing to the microvascular occlusion and ischaemia that occur in DR. Alternatively, carotid stenosis has a greater effect on the blood flow through the carotid artery than thickening measured by IMT. It is plausible that significant stenosis causing disruption of carotid blood flow could impact the blood supply to the retina. Improved retinal blood flow assessed by optical coherence tomography angiography has been reported in participants with carotid stenosis > 70% after carotid endarterectomy [48], and there is evidence that vision improves after carotid endarterectomy [49]. However, as some studies found that IMT was independently associated with DR, more than one mechanism is likely with a combination of common soil and direct relationships.

Conclusions
We found that there is insufficient published evidence to determine the nature, including the directionality, of the relationship between DR and carotid disease. Well conducted longitudinal studies are required to determine the direction of this association. A significant association was reported in most evaluable studies, but whether these two complications are independent but co-exist or if one contributes to the other can only be determined by well-conducted longitudinal studies. Nevertheless, our findings have clinical implications. Should carotid atherosclerosis or stenosis be detected in an individual with diabetes, we recommend that retinal examination is performed and, conversely, intensified cardiovascular risk management should be considered if DR is detected.
Additional file 1: Figure S1. Diagram of a carotid artery with plaque at the bifurcation. Table S1. The quality of the included studies.