{'fraction_non_alphanumeric': 0.026086127140063906, 'fraction_numerical': 0.02026801468834947, 'mean_word_length': 5.301081730769231, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Association between diabetic eye disease and other complications of diabetes: Implications for care. A systematic review

The aim of this systematic review was to examine the associations between diabetic retinopathy (DR) and the common micro‐ and macrovascular complications of diabetes mellitus, and how these could potentially affect clinical practice. A structured search of the PubMed database identified studies of patients with diabetes that assessed the presence or development of DR in conjunction with other vascular complications of diabetes. From 70 included studies, we found that DR is consistently associated with other complications of diabetes, with the severity of DR linked to a higher risk of the presence of, or of developing, other micro‐ and macrovascular complications. In particular, DR increases the likelihood of having or developing nephropathy and is also a strong predictor of stroke and cardiovascular disease, and progression of DR significantly increases this risk. Proliferative DR is a strong risk factor for peripheral arterial disease, which carries a risk of lower extremity ulceration and amputation. Additionally, our findings suggest that a patient with DR has an overall worse prognosis than a patient without DR. In conclusion, this analysis highlights the need for a coordinated and collaborative approach to patient management. Given the widespread use of DR screening programmes that can be performed outside of an ophthalmology office, and the overall cost‐effectiveness of DR screening, the presence and severity of DR can be a means of identifying patients at increased risk for micro‐ and macrovascular complications, enabling earlier detection, referral and intervention with the aim of reducing morbidity and mortality among patients with diabetes. Healthcare professionals involved in the management of diabetes should encourage regular DR screening.


| INTRODUCTION
Diabetic retinopathy (DR) is the most common complication of diabetes and remains the leading cause of blindness among working-age individuals in most developed countries. 1,2 DR has long been considered a microvascular complication of diabetes; however, growing evidence suggests that abnormalities in retinal function can be detected in patients without any evidence of microvascular abnormalities, and the American Diabetes Association defined DR as a highly specific neurovascular complication. 3,4 DR is characterized by degeneration of endothelial cells and pericytes in retinal capillaries, which leads to ischaemia and the formation of microaneurysms. 5 In the advanced stage of the disease, pathologic proliferation of retinal vessels occurs via upregulation of proangiogenic mediators, particularly vascular endothelial growth factor (VEGF). 5 The resulting alterations of the retinal microvasculature and increased leakage from the retinal vessels may lead to sight-threatening vision loss. 5 As the number of adults with diabetes worldwide is projected to increase from 415 million to 642 million by 2040, 6 DR represents a significant global health threat. According to recent estimates, DR accounts for 2.6 million cases of moderate to severe vision impairment worldwide, and this figure is expected to rise to 3.2 million by 2020. 7 A pooled analysis of data from 35 studies conducted in the United States, Europe, Asia and Australia estimated that in 2010, worldwide, the number of patients with diabetes who had DR or vision-threatening DR (VTDR) was 92.6 and 28.4 million, corresponding to prevalence rates of 34.6% and 10.2%, respectively. 1 The global number of patients with diabetes who have retinopathy in the general population is projected to reach 191 million by 2030. 8 Longer duration of diabetes is a major risk factor for DR. 9 One study estimated that individuals who have type 1  96% CI, 7.10-10.63), compared with individuals who have type 2 diabetes mellitus (T2DM) for less than 10 years. 1 However, more recently, DR has also been reported with various prevalence rates in patients with newly diagnosed diabetes mellitus. 2 Treatment of DR significantly improved after the introduction of pharmacological agents with anti-VEGF activity. In phase III clinical trials of patients with diabetic macular oedema (DMO), a complication of DR, anti-VEGF therapy improved visual acuity from baseline and lowered the risk of progression to proliferative DR (PDR), indicating that VEGF inhibitors can interfere with the underlying pathogenesis of retinopathy. 10,11 However, delayed DR screening and detection can hamper treatment. In one UK study, there was a significant trend (P = 0.0004) relating time from diagnosis of T2DM to detection of worsening retinopathy at screening. 12 The consequences of delayed detection of DR extend beyond suboptimal visual acuity outcomes; increasing evidence links retinopathy to other microvascular complications of diabetes, most notably nephropathy and cardiac autonomic neuropathy (CAN). [13][14][15][16] Retinopathy has also been linked to macrovascular comorbidities, including stroke, myocardial infarction and, potentially, heart failure. [17][18][19] Additionally, a recent meta-analysis of epidemiological observational studies found that patients with diabetes who have DR are at increased risk of all-cause mortality, compared with patients with diabetes who do not have retinopathy (risk ratio [RR], 2.33; 95% CI, 1.92-2.81). 19 With regard to the link between DR and cardiovascular events, Alonso et al. conducted a cross-sectional study of patients with T2DM who did not have renal deficits or prior history of cardiovascular disease (CVD). They found that the percentage of patients with carotid plaques, a risk factor for ischaemic stroke, 20 was higher among those with DR than among those without DR (68.0% vs 52.2%; P = 0.0045). 17 Other research has demonstrated that, not only is DR associated with future cardiovascular events, but also that the risk of these events increases with increasing severity of DR (hazard ratio [HR], 1.49; 95% CI, 1.12-1.97 for mild retinopathy and HR, 2.35; 95% CI, 1.47-3.76 for severe retinopathy). 18 Similar associations have been observed between DR and cerebrovascular events. [21][22][23] Our analysis aimed to further elucidate the relationships between DR and micro-and macrovascular complications, and to identify any examples where the presence of DR increases the risk of having or developing other complications of diabetes. Irrespective of the directionality of any such relationships, that is, whether DR is antecedent to or develops after other complications, an increased awareness and understanding of these relationships can help promote timely referral and discussion between ophthalmologists and the other healthcare professionals involved in the management of these co-morbities, including diabetologists, cardiologists, vascular surgeons and nephrologists. There is currently a lack of communication between the diverse healthcare disciplines involved in the treatment of patients with diabetes, which can lead to a breakdown in the care pathway and contributes to suboptimal patient outcomes. DR screening can be performed effectively outside the ophthalmologist's office by trained personnel (eg, primary care physician's office, optometrist, mobile unit). Indeed, this approach is generally deemed more practical and efficient than screening at ophthalmology offices. 24 The identification of patients with DR and a greater understanding of the wider relevance of DR may provide an opportunity to identify patients who are at increased risk of the presence or development of other diabetic complications, thus forming the basis for enhanced inter-disciplinary communication with the aim of improving patient outcomes.

| Research questions
The aim of this study was to answer the following research questions: • Is there a link between DR and the micro-and macrovascular complications of diabetes?
• Does DR increase the risk of other complications of diabetes?
• What is the clinical significance of the associations between DR and other complications of diabetes?
Diabetes search terms were restricted to title content, and the remaining search terms were limited to title and abstract. Only peerreviewed original research studies and reviews were included, and no geographical, date or language restrictions were applied.

| Data extraction
For the first stage of the selection process, identified titles were screened for relevance. If the publication passed this stage, the abstract was read to verify relevance, and if this was confirmed, the full text of the paper was assessed against the inclusion and exclusion criteria. Extracted information included study design, population characteristics, conclusions and limitations. Precedence was given to studies specifically designed to investigate the relationship between DR and other complications of diabetes, and to studies in which statistical analyses were adjusted for confounding factors.

| Study selection
Of 3028 potentially relevant papers initially identified through the PubMed search, 2418 were excluded because they were not relevant to the research questions. The abstracts of the remaining 610 papers were read, which led to the exclusion of an additional 330 papers. This resulted in a total of 280 papers of which the full text was assessed for relevance. Of these papers, 71 met the criteria for inclusion in the structured review.

| DR and other microvascular complications of diabetes
A correlation was found between DR and other microvascular complications of diabetes, specifically, nephropathy and neuropathy. A summary of the findings of the reviewed studies that examined the relationship between DR and these microvascular complications is presented in Tables 1 and 2.

| Nephropathy
Diabetic nephropathy affects approximately 40% of patients with diabetes and is characterized by increased urinary albumin excretion (UAE). It is categorized into stages, microalbuminuria (UAE >20 μg/ min and ≤199 μg/min) and macroalbuminuria (UAE ≥200 μg/min), and it is associated with increased mortality. 35 Glomerular filtration rate (GFR), a measure of renal function, is also used to assess the presence of diabetic nephropathy. 35 Overall, risk estimates from the reviewed studies suggest a correlation between DR and nephropathy, and between DR and declining renal function (Table 1).

DR and albuminuria
In a cross-sectional study of patients with T1DM or T2DM, the presence and severity of DR were significantly predictive of nephropathy. 14 Multivariate logistic regression showed that nephropathy was the only complication of diabetes independently associated with DR, and that retinopathy increased the likelihood of developing nephropathy by 4.37 times. However, the predictive value of DR was strongest for T1DM. 14 These findings have been confirmed in other studies that identified DR as a significant independent predictor of progression to micro-or macroalbuminuria in patients with T1DM 15 or T2DM 25 . Risk of nephropathy has been shown to increase with DR severity, 14 and PDR was identified as a significant independent marker of incident nephropathy in a 25-year follow-up study in T1DM. 26 Interestingly, data from the Diabetes Control and Complications Trial (DCCT) in T1DM demonstrated that progression of DR independently increases the risk of development of nephropathy, and also showed that the development of nephropathy increases the risk of DR progression. 27 Although a previous study demonstrated that these two complications influence the incidence of each other, 36 a retrospective study in T2DM demonstrated that the association between DR and diabetic nephropathy is unidirectional and that renal injury precedes retinal damage. 37 Accordingly, several studies have shown that nephropathy is a risk factor for DR, including severe forms of retinopathy. 28,[30][31][32] Concerning T1DM, a 20-year prospective study by Romero-Aroca et al. found that both micro-and macroalbuminuria correlated with the development of VTDR but not with the development of any DR. 28 In the same study, DR was a significant risk factor for nephropathy. 28 Notably, in a 10-year prospective analysis of patients with T1DM, macroalbuminuria was identified as a significant independent risk factor for the development of DMO, but not of DR. 29 Concerning T2DM, Hammes et al. analysed data from 6478 patients. The presence of microalbuminuria was found to independently increase the risk of DR, severe DR and DMO, and the risk further increased in the presence of macroalbuminuria. 30 However, research has also shown that nephropathy did not affect development or progression of DMO, although it was an independent risk factor for DR, PDR and the progression from non-proliferative DR (NPDR) to PDR. 31 Previously, macroalbuminuria, but not microalbuminuria, had been found to be significantly associated with increasing severity of DR and with progression from NPDR to PDR in T2DM. 32 Diabetic symmetric polyneuropathy is also a major risk factor for foot ulcers and amputations. 49 Concerning CAN, reported prevalence rates among individuals with diabetes vary from 17% to 66% in T1DM, and from 31% to 73% in T2DM. 50 Nerve injury occurs in both the autonomic and peripheral nervous systems, increasing the likelihood of experiencing heart rate abnormalities that progress to resting tachycardia, as well as orthostatic hypotension, ischaemia, CVD, chronic kidney disease and anaemia. 50

| Cerebrovascular complications
An early case-control study identified DR as a risk factor for nonembolic ischaemic stroke in individuals with diabetes, independent of smoking, blood pressure and other complications of diabetes. 52 The findings were later supported by a population-based, prospective study of patients with diabetes that found DR to be significantly correlated with incident stroke, although no association was identified between DR grade and increasing risk of ischaemic stroke. 53 This differs from the results of the Wisconsin Epidemiologic Study of Diabetic Retinopathy in T1DM, which demonstrated an association between DR severity and increased odds of stroke. 54 Similarly, in the Finnish Diabetic Nephropathy (FinnDiane) Study, severe DR independently increased the risk of stroke, cerebral infarction and cerebral haemorrhage in patients with T1DM who were followed for 9 years, and the risk increased if patients had concomitant diabetic nephropathy. 22 Further analysis of this data set revealed severe DR to be independently associated with haemorrhagic stroke but not with ischaemic stroke, 21 whereas a large prospective study in patients with T2DM who were followed for 5 years found DR to be correlated with smallartery ischaemic stroke, but not with large-artery ischaemic stroke or haemorrhagic stroke. 23 An analysis of data from the Japan Diabetes Complications Study revealed that even patients with mild to moderate NPDR had an increased risk of stroke after adjusting for traditional cardiovascular risk factors. 55 Furthermore, in the Atherosclerosis Risk in Communities (ARIC) Brain MRI Study, DR was associated with the emergence of subclinical brain infarcts. 56

| Cardiovascular complications
Increased carotid intima-media thickness (cIMT) is a broadly accepted marker for early or subclinical atherosclerosis, 59 69 It is worth noting, however, that, in a prospective study of individuals with T2DM who were followed for up to 8 years, even mild to moderate DR increased the risk of CHD and stroke. 55 In addition, in a case-controlled study, the odds ratio of myocardial perfusion defects in an asymptomatic patient who
had diabetes with DR in comparison to patients who had diabetes without DR was 11.7 (95% CI, 3.7-37). 95 Overall, the above findings are consistent with those from other prospective studies, indicating that DR, particularly advanced DR, is an independent risk factor for CVD in patients with diabetes. 65 73 Notably, the association did not remain after adjusting for the presence of macroalbuminuria. 73 However, this contrasts with results from the Atherosclerosis Risk in Communities (ARIC) Study in T2DM, in which adjusting for nephropathy had minimal impact on the association between DR and CHD. 96 In this study, the risk of incident CHD increased with DR severity, and severe DR was also a significant independent risk factor for fatal CHD. 96 In the ACCORD Eye Study, DR severity and progression were associated with the composite outcome of first occurrence of nonfatal myocardial infarction, non-fatal stroke or cardiovascular death in patients with T2DM. 18 Analyses revealed that the risk of this primary outcome increased by 38% for every category of change in DR severity. 18 Elsewhere, retinopathy and PDR have been shown to increase the risk of cardiovascular or all-cause mortality in patients with T1DM and patients with T2DM. 74-76  PDR. 82 A number of papers have also identified DR as a key risk factor for lower extremity amputation in both patients with T1DM and patients with T2DM. 79,[83][84][85][86][87] Notably, patients who have T2DM and undergo lower extremity amputation (LEAs) have been found to be at higher risk of developing DR than those without LEAs. 88 This was also observed in the ADVANCE-ON post-trial observational study in T2DM, which demonstrated that lower extremity ulceration or amputation, as a major presentation of PAD, increased the risk of retinal photocoagulation or blindness. 89 PAD is diagnosed using the ABI, with values less than 0.9

| Peripheral complications
indicative of the disease. 97 22 and was associated with small-artery ischaemic stroke in patients with T2DM. 23 Evidence presented here also demonstrates that DR is associated with subclinical atherosclerosis, [61][62][63] and that the presence of this complication is independently correlated with cIMT and carotid plaques in T2DM populations. 17,61,65 Two studies showed that DR is associated with increased risk of CHD-related events and mortality 53,55 and, overall, DR was found to be an independent risk factor for CVD. 65,[70][71][72] Similarly, outcomes from the reviewed studies demonstrate that DR, and particularly PDR, is a strong risk factor for PAD, which carries a risk of lower extremity ulceration and amputation. [90][91][92] Therefore, worsening DR could prove useful as a marker for individuals at increased risk of these serious macrovascular complications. Specifically, the evidence indicates that patients with diabetes who have PDR are more likely than those with NPDR to have an abnormal ABI. 91 Furthermore, DR was identified as an independent risk factor for foot ulceration and a key risk factor for lower extremity amputation. [77][78][79] Interestingly, two studies found that patients with diabetes who have non-healing foot ulcers or who have undergone lower extremity amputation are at risk of DR development and progression. 82,89 We performed a comprehensive search of the literature that resulted in the inclusion of 71 studies, with a total of over 400 000 patients, and the approach taken to review was objective and systematic, complying with several of the key items included in the PRISMA checklist for systematic reviews and meta-analyses. One limitation of our study was that only the PubMed literature database was searched.
Despite this, our findings are an important contribution to the understanding of the relationship between DR and the micro-and macrovascular complications of diabetes and, as such, provide valuable information to support the wider multidisciplinary team that is involved in the care of individuals with diabetes. In particular, the findings underscore the need for prompt screening and referral for DR, which can both reduce vision loss and, potentially, identify patients at increased risk of other complications of diabetes. This highlights the need for a coordinated and collaborative approach to patient management on the part of all the healthcare professionals involved in diabetes care in order to optimize clinical outcomes. A risk assessment model that incorporates DR presence as an input factor, rather than an outcome, may provide a powerful tool for identifying individuals at high risk of potentially life-threatening complications of diabetes.
Indeed, a study has demonstrated that incorporation of microvascular complications into cardiovascular risk algorithms improves CVD risk prediction in T2DM. 100 The ability to identify the individuals most at risk of developing complications could improve the targeting of preventive treatments, potentially reducing morbidity and mortality among patients with diabetes. Further exploration in this area is warranted.

Author contributions
All authors contributed to the concept development, determining the search strategy and evaluating the results for inclusion, and provided critical review of the manuscript.