Received: 12 July 2018 Revised: 12 September 2018 Accepted: 25 September 2018

DOI: 10.1111/dom.13550

REVIEW ARTICLE

Association between diabetic eye disease and other

complications of diabetes: Implications for care.
A systematic review
Ian Pearce MBChB1 | Rafael Simó MD2 | Monica Lövestam-Adrian MD3 |
David T. Wong MD4 | Marc Evans MD5

1
St Paul's Eye Unit, Royal Liverpool University
Hospital, Liverpool, UK The aim of this systematic review was to examine the associations between diabetic retinopathy
2
Vall d'Hebron Research Institute (VHIR) and (DR) and the common micro- and macrovascular complications of diabetes mellitus, and how these
Centro de Investigación Biomédica en Red de could potentially affect clinical practice. A structured search of the PubMed database identified studies
Diabetes y Enfermedades Metabólicas
of patients with diabetes that assessed the presence or development of DR in conjunction with other
Asociadas (CIBERDEM), Barcelona, Spain
3
vascular complications of diabetes. From 70 included studies, we found that DR is consistently associ-
Lund University Hospital, Lund, Sweden
4
ated with other complications of diabetes, with the severity of DR linked to a higher risk of the pres-
St. Michael's Hospital, University of Toronto,
Toronto, Canada ence of, or of developing, other micro- and macrovascular complications. In particular, DR increases
5
University Hospital Llandough, Llandough, the likelihood of having or developing nephropathy and is also a strong predictor of stroke and cardio-
Wales, UK vascular disease, and progression of DR significantly increases this risk. Proliferative DR is a strong risk
Correspondence factor for peripheral arterial disease, which carries a risk of lower extremity ulceration and amputation.
Marc Evans, University Hospital Llandough, Additionally, our findings suggest that a patient with DR has an overall worse prognosis than a patient
Penlan Road, Llandough CF64 2XX, Wales,
without DR. In conclusion, this analysis highlights the need for a coordinated and collaborative
UK.
Email: [email protected] approach to patient management. Given the widespread use of DR screening programmes that can
Funding information be performed outside of an ophthalmology office, and the overall cost-effectiveness of DR screening,
Support for this project was provided by the the presence and severity of DR can be a means of identifying patients at increased risk for micro-
Vision Academy, a Bayer-sponsored initiative
and macrovascular complications, enabling earlier detection, referral and intervention with the aim of
comprising over 70 leading retinal specialists.
reducing morbidity and mortality among patients with diabetes. Healthcare professionals involved in
the management of diabetes should encourage regular DR screening.

KEYWORDS

diabetes complications, diabetic retinopathy

1 | I N T RO D UC T I O N DR is characterized by degeneration of endothelial cells and peri-

cytes in retinal capillaries, which leads to ischaemia and the formation
Diabetic retinopathy (DR) is the most common complication of diabe- of microaneurysms.5 In the advanced stage of the disease, pathologic
tes and remains the leading cause of blindness among working-age proliferation of retinal vessels occurs via upregulation of proangiogenic
individuals in most developed countries.1,2 DR has long been consid- mediators, particularly vascular endothelial growth factor (VEGF).5 The
ered a microvascular complication of diabetes; however, growing evi- resulting alterations of the retinal microvasculature and increased leak-
dence suggests that abnormalities in retinal function can be detected age from the retinal vessels may lead to sight-threatening vision loss.5
in patients without any evidence of microvascular abnormalities, and As the number of adults with diabetes worldwide is projected to
the American Diabetes Association defined DR as a highly specific increase from 415 million to 642 million by 2040,6 DR represents a sig-
3,4
neurovascular complication. nificant global health threat. According to recent estimates, DR

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Diabetes Obes Metab. 2019;21:467–478. wileyonlinelibrary.com/journal/dom 467
468 PEARCE ET AL.

accounts for 2.6 million cases of moderate to severe vision impairment to or develops after other complications, an increased awareness and
7
worldwide, and this figure is expected to rise to 3.2 million by 2020. understanding of these relationships can help promote timely referral
A pooled analysis of data from 35 studies conducted in the and discussion between ophthalmologists and the other healthcare
United States, Europe, Asia and Australia estimated that in 2010, professionals involved in the management of these co-morbities,
worldwide, the number of patients with diabetes who had DR or including diabetologists, cardiologists, vascular surgeons and nephrol-
vision-threatening DR (VTDR) was 92.6 and 28.4 million, correspond- ogists. There is currently a lack of communication between the diverse
ing to prevalence rates of 34.6% and 10.2%, respectively.1 The global healthcare disciplines involved in the treatment of patients with dia-
number of patients with diabetes who have retinopathy in the general betes, which can lead to a breakdown in the care pathway and con-
population is projected to reach 191 million by 2030.8 tributes to suboptimal patient outcomes. DR screening can be
Longer duration of diabetes is a major risk factor for DR.9 One
performed effectively outside the ophthalmologist's office by trained
study estimated that individuals who have type 1 diabetes mellitus
personnel (eg, primary care physician's office, optometrist, mobile
(T1DM) for 20 years or more are 2.7 times more likely to develop
unit). Indeed, this approach is generally deemed more practical and
retinopathy (relative risk [RR], 2.69; 96% confidence interval [CI],
efficient than screening at ophthalmology offices.24 The identification
2.47-2.93), and are 8.7 times more likely to have VTDR (RR, 8.69;
of patients with DR and a greater understanding of the wider rele-
96% CI, 7.10-10.63), compared with individuals who have type 2 dia-
vance of DR may provide an opportunity to identify patients who are
betes mellitus (T2DM) for less than 10 years.1 However, more
at increased risk of the presence or development of other diabetic
recently, DR has also been reported with various prevalence rates in
complications, thus forming the basis for enhanced inter-disciplinary
patients with newly diagnosed diabetes mellitus.2
communication with the aim of improving patient outcomes.
Treatment of DR significantly improved after the introduction of
pharmacological agents with anti-VEGF activity. In phase III clinical tri-
als of patients with diabetic macular oedema (DMO), a complication
2 | M A T E R I A L S A N D M ET H O D S
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 2.1 | Research questions
of retinopathy.10,11 However, delayed DR screening and detection The aim of this study was to answer the following research questions:
can hamper treatment. In one UK study, there was a significant trend
(P = 0.0004) relating time from diagnosis of T2DM to detection of
• Is there a link between DR and the micro- and macrovascular
worsening retinopathy at screening.12
complications of diabetes?
The consequences of delayed detection of DR extend beyond
• Does DR increase the risk of other complications of diabetes?
suboptimal visual acuity outcomes; increasing evidence links retino-
• What is the clinical significance of the associations between DR
pathy to other microvascular complications of diabetes, most notably
and other complications of diabetes?
nephropathy and cardiac autonomic neuropathy (CAN).13–16 Retino-
pathy has also been linked to macrovascular comorbidities, including
stroke, myocardial infarction and, potentially, heart failure.17–19 Addi- 2.2 | Literature search strategy
tionally, a recent meta-analysis of epidemiological observational stud-
A literature search of the PubMed database was performed using a
ies found that patients with diabetes who have DR are at increased
structured approach to identify relevant studies. The search term
risk of all-cause mortality, compared with patients with diabetes who
combination used was: ((((((diabetes) OR diabetic) OR diabetes melli-
do not have retinopathy (risk ratio [RR], 2.33; 95% CI, 1.92-2.81).19
tus)) AND (((retinopathy) OR eye disease) OR macular disease))) AND
With regard to the link between DR and cardiovascular events,
(((((((((neuropathy) OR neurological complication*)) OR ((((nephropathy)
Alonso et al. conducted a cross-sectional study of patients with T2DM
OR renal disease) OR microalbuminuria) OR kidney disease)) OR
who did not have renal deficits or prior history of cardiovascular
((((((coronary heart disease) OR myocardial ischemia) OR cardiovascu-
disease (CVD). They found that the percentage of patients with carotid
lar disease) OR cardiovascular event*) OR myocardial infarction) OR
plaques, a risk factor for ischaemic stroke,20 was higher among those
atherosclerosis)) OR (((((((cerebrovascular accident) OR cerebral infarc-
with DR than among those without DR (68.0% vs 52.2%;
tion) OR cerebral ischemia) OR cerebrovascular disease) OR stroke)
P = 0.0045).17 Other research has demonstrated that, not only is DR
associated with future cardiovascular events, but also that the risk of OR cerebrovascular event*) OR transient ischemic attack)) OR

these events increases with increasing severity of DR (hazard ratio ((((((((intermittent claudication) OR vasculopathy) OR peripheral artery

[HR], 1.49; 95% CI, 1.12-1.97 for mild retinopathy and HR, 2.35; 95% disease) OR ulcer) OR gangrene) OR peripheral vascular disease) OR
CI, 1.47-3.76 for severe retinopathy).18 Similar associations have been necrosis) OR amputation))) AND ((((((((((risk) OR risk factor) OR associa-
observed between DR and cerebrovascular events. 21–23 tion) OR correlation) OR logistic regression) OR predictive) OR predic-
Our analysis aimed to further elucidate the relationships between tor) OR predictive factor) OR link) OR relationship)).
DR and micro- and macrovascular complications, and to identify any Diabetes search terms were restricted to title content, and the
examples where the presence of DR increases the risk of having or remaining search terms were limited to title and abstract. Only peer-
developing other complications of diabetes. Irrespective of the direc- reviewed original research studies and reviews were included, and no
tionality of any such relationships, that is, whether DR is antecedent geographical, date or language restrictions were applied.
PEARCE ET AL. 469

2.3 | Study selection 3 | RE SU LT S

Inclusion criteria were: (a) studies involving a population of patients
with diabetes, with no restriction on clinical characteristics, glycated 3.1 | Study selection
haemoglobin [HbA1c] and comorbidity or treatment history, and
Of 3028 potentially relevant papers initially identified through the
(b) studies that evaluated the presence or development of DR in con-
PubMed search, 2418 were excluded because they were not relevant
junction with other vascular complications of diabetes.
to the research questions. The abstracts of the remaining 610 papers
were read, which led to the exclusion of an additional 330 papers. This
2.4 | Data extraction resulted in a total of 280 papers of which the full text was assessed

For the first stage of the selection process, identified titles were for relevance. Of these papers, 71 met the criteria for inclusion in the
screened for relevance. If the publication passed this stage, the structured review.
abstract was read to verify relevance, and if this was confirmed, the
full text of the paper was assessed against the inclusion and exclusion
3.2 | DR and other microvascular complications of
criteria. Extracted information included study design, population
diabetes
characteristics, conclusions and limitations. Precedence was given to
studies specifically designed to investigate the relationship between A correlation was found between DR and other microvascular compli-
DR and other complications of diabetes, and to studies in which statistical cations of diabetes, specifically, nephropathy and neuropathy. A sum-
analyses were adjusted for confounding factors. mary of the findings of the reviewed studies that examined the

TABLE 1 Studies describing the association between DR and nephropathy and renal decline

Reference
Study design (n) Independent variable Dependent variable OR/HR/RR (95% CI) P value
Study population
14
El-Asrar Cross-sectional (648) DR Nephropathy All: OR = 4.37 (2.19-8.71) <0.05
T1DM & T2DM T1DM: OR = 8.02 (1.95-33) <0.05
T2DM: OR = 2.48 (1.02-6.03) <0.05
Mild to moderate NPDR OR = 3.78 (1.86-7.67) <0.05
Severe NPDR OR = 7.17 (2.43-20.61) <0.05
PDR OR = 23.56 (8.49-66.11) <0.05
P. Rossing15 Prospective (537) DR Progression to RR = 1.90 (1.26-2.88) <0.01
T1DM microalbuminuria/
macroalbuminuria
Parving25 Cross-sectional (32208) DR Microalbuminuria/ OR = 1.49 (1.38-1.62) <0.0001
T2DM macroalbuminuria
Karlberg26 Prospective (184) PDR Nephropathy OR = 2.98 (1.18-7.51) 0.02
T1DM
Kramer 201327 Retrospective DR progression Nephropathy HR = 1.72 (1.30-2.27) <0.001
T1DM (1365) development
Nephropathy development DR progression HR = 1.62 (1.23-2.13) 0.001
Romero-Aroca 201228 Prospective DR Overt nephropathy OR = 3.92 (2.97-7.69) 0.030
T1DM (110) Microalbuminuria STDR OR = 5.98 (1.83-19.53) 0.003
Overt nephropathy STDR OR = 6.202 (1.35-28.34) 0.019
Romero-Aroca 201129 Prospective Overt nephropathy DMO HR = 0.68 (0.51-0.90) 0.008
T1DM (334)
Hammes 201530 Longitudinal Microalbuminuria DR OR = 1.16 (1.11-1.20) <0.0001
T2DM (64784) Severe DR OR = 1.20 (1.14-1.27) <0.0001
DMO OR = 1.31 (1.09-1.58) <0.0001
Macroalbuminuria DR OR = 1.28 (1.12-1.39) <0.0001
Severe DR OR = 1.51 (1.36-1.67) <0.0001
DMO OR = 2.77 (2.11-3.66) <0.0001
Jeng31 Longitudinal Nephropathy NPDR HR = 5.01 (4.68-5.37) <0.001
T1DM & T2DM (53453) PDR HR = 9.70 (8.15-11.50) <0.001
Progression from HR = 2.25 (1.68-3.02) <0.001
NPDR to PDR
Savage32 Cross-sectional (947) Macroalbuminuria Increasing severity OR = 2.89 (1.73-4.61) 0.0001
T2DM of DR
Progression to PDR OR = 3.92 (2.02-7.63) 0.0001
33
Takagi Prospective DR Microalbuminuria HR = 1.57 (1.17-2.12) <0.003
T2DM (1802) Decrease in eGFR HR = 1.36 (1.08-1.71) 0.008
Moriya34 Retrospective DR + microalbuminuria Macroalbuminuria HR = 11.55 (5.24-25.45) <0.01
T2DM (1475)

Abbreviations: CI, confidence interval; DMO, diabetic macular oedema; DR, diabetic retinopathy; eGFR, estimated glomerular filtration rate; HR, hazard
ratio; NPDR, non-proliferative diabetic retinopathy; OR, odds ratio; PDR, proliferative diabetic retinopathy; RR, relative risk; STDR, sight-threatening dia-
betic retinopathy; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
470 PEARCE ET AL.

relationship between DR and these microvascular complications is Interestingly, data from the Diabetes Control and Complications
presented in Tables 1 and 2. Trial (DCCT) in T1DM demonstrated that progression of DR indepen-
dently increases the risk of development of nephropathy, and also
3.2.1 | Nephropathy showed that the development of nephropathy increases the risk of
Diabetic nephropathy affects approximately 40% of patients with dia- DR progression.27 Although a previous study demonstrated that these
betes and is characterized by increased urinary albumin excretion two complications influence the incidence of each other,36 a retro-
(UAE). It is categorized into stages, microalbuminuria (UAE >20 μg/ spective study in T2DM demonstrated that the association between
min and ≤199 μg/min) and macroalbuminuria (UAE ≥200 μg/min), DR and diabetic nephropathy is unidirectional and that renal injury
and it is associated with increased mortality.35 Glomerular filtration precedes retinal damage.37 Accordingly, several studies have shown
rate (GFR), a measure of renal function, is also used to assess the pres- that nephropathy is a risk factor for DR, including severe forms of
ence of diabetic nephropathy.35 Overall, risk estimates from the retinopathy.28,30–32 Concerning T1DM, a 20-year prospective study
reviewed studies suggest a correlation between DR and nephropathy, by Romero-Aroca et al. found that both micro- and macroalbuminuria
and between DR and declining renal function (Table 1). correlated with the development of VTDR but not with the develop-
ment of any DR.28 In the same study, DR was a significant risk factor
DR and albuminuria for nephropathy.28 Notably, in a 10-year prospective analysis of
In a cross-sectional study of patients with T1DM or T2DM, the pres- patients with T1DM, macroalbuminuria was identified as a significant
ence and severity of DR were significantly predictive of nephro- independent risk factor for the development of DMO, but not of
pathy.14 Multivariate logistic regression showed that nephropathy DR.29 Concerning T2DM, Hammes et al. analysed data from
was the only complication of diabetes independently associated with 6478 patients. The presence of microalbuminuria was found to inde-
DR, and that retinopathy increased the likelihood of developing pendently increase the risk of DR, severe DR and DMO, and the risk
nephropathy by 4.37 times. However, the predictive value of DR was further increased in the presence of macroalbuminuria.30 However,
14
strongest for T1DM. These findings have been confirmed in other research has also shown that nephropathy did not affect development
studies that identified DR as a significant independent predictor of or progression of DMO, although it was an independent risk factor for
progression to micro- or macroalbuminuria in patients with T1DM15 DR, PDR and the progression from non-proliferative DR (NPDR) to
or T2DM25. Risk of nephropathy has been shown to increase with DR PDR.31 Previously, macroalbuminuria, but not microalbuminuria, had
severity,14 and PDR was identified as a significant independent been found to be significantly associated with increasing severity of
marker of incident nephropathy in a 25-year follow-up study in DR and with progression from NPDR to PDR in T2DM.32
26
T1DM.

TABLE 2 Studies describing the association between DR and diabetic neuropathy

Reference
Study design (n) Independent variable Dependent variable OR/HR (95% CI) P value
Study population
Kostev38 Retrospective DR Neuropathy OR = 2.96 (2.08-4.22) <0.05
T2DM (45633
[German cohort only])
Jurado39 Cross-sectional DR DPN OR = 5.18 (2.70-10.00) 0.000
T2DM (307)
Abougalambou40 Prospective Neuropathy DR OR = 2.91 (2.21-3.82) <0.001
T2DM (1077)
Lin41 Retrospective DPN Any DR HR = 5.41 (4.92-5.94) <0.001
DPN (5031 NPDR HR = 5.63 (5.11-6.21) <0.001
[+20 124 controls]) PDR HR = 3.67 (2.57-5.23) <0.001
Zander42 Cross-sectional Neuropathy Maculopathy T1DM: OR = 3.5 (NR) <0.01
T1DM & T2DM (33659) T2DM: OR = 3.1 (NR) <0.01
Witte43 Prospective DR CAN OR = 1.70 (1.11-2.60) 0.01
T1DM (956)
Ko44 Prospective DR CAN OR = 1.51 (1.03-2.23) 0.036
T2DM (1021)
Voulgari45 Cross-sectional DR CAN T1DM: OR = 1.13 (1.04-1.41) 0.01
T1DM & T2DM (600) T2DM: OR = 1.24 (1.16-1.35) 0.008
Huang16 Cross-sectional NPDR CAN OR = 2.73 (1.14-6.54) 0.024
T2DM (174) PDR OR = 11.19 (4.15-30.16) <0.001
H. T. Chen46 Cross-sectional PDR CAN OR = 6.85 (2.32-20.20) <0.001
T2DM (674)
Gaspar47 Retrospective DR Orthostatic hypertension T1DM: OR = 8.09 (1.65-39.62) <0.01
T1DM & T2DM (187) T2DM: OR = 4.08 (1.83-9.10) <0.001

Abbreviations: CAN, cardiac autonomic neuropathy; CI, confidence interval; DPN, diabetic peripheral neuropathy; DR, diabetic retinopathy; HR, hazard
ratio; NPDR, non-proliferative diabetic retinopathy; NR, not reported; OR, odds ratio; PDR, proliferative diabetic retinopathy; T1DM, type 1 diabetes
mellitus; T2DM, type 2 diabetes mellitus.
PEARCE ET AL. 471

DR and declining renal function population-based study in Taiwan, patients with DPN exhibited an
In a single-centre observational cohort study by Takagi et al., the pres- increased risk of DR and advanced DR compared with a matched
ence of DR was a common predictor of both albuminuria onset and cohort of patients with diabetes who did not have DPN.41 Notably,
decreased estimated GFR (eGFR) in patients with T2DM.33 In earlier when stratified according to DR severity, the risk of DPN was greater
research, also involving patients with T2DM, Rossing et al. found a in patients with PDR than in those with NPDR.41 A significant associa-
significant correlation between degree and presence of DR at baseline tion has also been found between diabetic maculopathy and neuro-
48
and increased rate of eGFR decline. Interestingly, in the Japan Dia- pathy in both patients with T1DM and patients with T2DM, taking
betes Complications Study, patients with T2DM who had both micro- into account both peripheral neuropathy and CAN.42
albuminuria and DR at baseline had the highest risk of developing
macroalbuminuria and displayed significantly faster eGFR decline
DR and CAN
(−1.92 mL min−1 1.73 m−2 y−1; P < 0.01) compared with those with
−1 −2 −1 In the EURODIAB Prospective Complications Study, Witte
one of the two complications (−0.69 mL min 1.73 m year ;
−1 −2 −1 et al. investigated potential risk factors for CAN in patients with
P < 0.01) or with neither complication (−0.54 mL min 1.73 m y ;
P < 0.01).34 T1DM.43 They found that the presence of DR or PDR at baseline was
significantly associated with CAN incidence (P < 0.05) after control-
3.2.2 | Neuropathy ling for sex, diabetes duration and HbA1c; 17% of 956 patients devel-
DR was found to be associated with two neuropathies: diabetic oped the complication over the 7.3 years of follow-up, corresponding
peripheral neuropathy (DPN) and CAN (Table 2). DPN is estimated to to an incidence rate of 23.4 per 1000 person-years. The association
affect 30% to 50% of individuals with diabetes; it is characterized by remained significant after multivariate regression analyses.43 A similar
peripheral nerve injury and manifests most commonly as distal sym- conclusion was drawn from a seven-year follow-up study of patients
metric polyneuropathy (DSP). Symptoms of DSP include pain, numb- with T2DM who had normal cardiac autonomic function at baseline.
ness and weakness in the lower limbs, which may lead to falls.49 Logistic regression revealed that the presence of DR was predictive of
Diabetic symmetric polyneuropathy is also a major risk factor for foot CAN progression after adjusting for age, hypertension, smoking and
ulcers and amputations.49 Concerning CAN, reported prevalence rates diabetes duration.44
among individuals with diabetes vary from 17% to 66% in T1DM, and Overall, the above findings are consistent with those of a cross-
50
from 31% to 73% in T2DM. Nerve injury occurs in both the auto- sectional study by Voulgari et al. indicating that the odds of CAN are
nomic and peripheral nervous systems, increasing the likelihood of independently increased by the presence of DR in both T1DM and
experiencing heart rate abnormalities that progress to resting tachy- T2DM patient populations,45 and with the results of a study of
cardia, as well as orthostatic hypotension, ischaemia, CVD, chronic patients with T2DM showing that increasing DR severity is associated
kidney disease and anaemia.50 Additionally, individuals with diabetes with a higher risk of developing CAN.16 A significant positive correla-
who have CAN are at increased risk of mortality compared with those tion between DR severity and risk of CAN in patients with T2DM was
without.50 also reported by Chen et al. after adjusting for age, sex, diabetes dura-
tion and HbA1c.46 Additionally, after logistic regression analysis, the
DR and DPN/DSP
authors identified PDR as the most significant single risk factor for
In a retrospective study of longitudinal data from patients with newly CAN.46
diagnosed T2DM, collected from nationwide general practitioners in Of note are the results of a 10-year follow-up study that found
Germany and the UK, the presence of microvascular complications, DR to be significantly more prevalent in individuals with diabetes who
defined as DR plus nephropathy, was found to be independently asso- have orthostatic hypertension, a major clinical feature of CAN, com-
ciated with neuropathy; in particular, DR was identified as a significant
pared with individuals without.47
risk factor for neuropathy in the German cohort.38 Furthermore, the
longitudinal Rochester Diabetic Neuropathy Study demonstrated that
DR severity was an independent risk factor for DPN severity in
3.3 | DR and macrovascular complications of
patients with T1DM.51 A positive correlation between DPN and DR
diabetes
was also found in the cross-sectional North Catalonia Diabetes Study,
in which the presence of retinopathy, together with age, HbA1c and In addition to the microvascular complications described above,

plasma levels of high-density lipoprotein cholesterol, was used in a the presence of DR has also been associated with development of the
model to evaluate the risk of DPN. Based on these four parameters macrovascular complications of diabetes, specifically, cerebrovascular
selected by logistic regression analysis, the sensitivity and specificity complications (stroke, cerebral infarction/haemorrhage), cardiovascular
of the model for diagnosis of DPN was 74.2% and 74.9%, complications (atherosclerosis, cardiovascular events, coronary heart
39 disease [CHD]) and peripheral complications (foot ulcers, lower extrem-
respectively.
Other studies, including a prospective analysis of patients with ity amputations, peripheral arterial disease [PAD]). The key findings
T2DM in Malaysia, showing that neuropathy is an independent risk of the reviewed studies examining the relationship between DR and
40
factor for progression of retinopathy, found neuropathy to be a pre- various types of macrovascular complications of diabetes are presented
dictor of DR onset and progression. Similarly, in a retrospective in Tables 3–5.
472 PEARCE ET AL.

TABLE 3 Studies describing the association between DR and cerebrovascular complications

Reference
Study design (n) Independent variable Dependent variable OR/HR/RR (95% CI) P value
Study population
52
Petitti Case-control (2124) DR Ischaemic stroke RR = 4.0 (1.0-14.5) <0.05
T1DM & T2DM
Cheung 200753 Prospective (1617) DR Ischaemic stroke HR = 2.34 (1.13-4.86) <0.05
T1DM & T2DM
B. E. Klein54 Prospective (996) DR/step Stroke OR = 1.6 (1.1-2.3) 0.01
T1DM
Hägg 201322 Observational follow-up (4803) Severe DR Stroke HR = 3.0 (1.9-4.5) <0.05
T1DM Cerebral infarction HR = 2.7 (1.6-4.4) <0.05
Cerebral haemorrhage HR = 3.9 (1.7-8.9) <0.05
Hägg 201421 Observational follow-up (4803) Severe DR Haemorrhagic stroke HR = 2.99 (1.18-7.55) 0.021
T1DM
Kawasaki 201355 Prospective (2033) Mild to moderate DR Stroke HR = 1.69 (1.03-2.80) 0.04
T2DM
Hankey23 Prospective, observational (9795) History of DR Small-artery ischaemic stroke HR = 1.82 (1.08-3.07) 0.03
T2DM
Cheung 201056 Prospective (810) DR Incident cerebral infarct OR = 7.35 (1.72-31.34) NR
T1DM & T2DM Incident lacunar infarct OR = 5.32 (1.23-23.03)
Lip57 Registry (8962) DR Stroke/thromboembolism RR = 1.21 (0.80-1.84) 0.37
T1DM & T2DM
Chou58 Registry (50180) DR Ischaemic stroke HR = 1.11 (0.95-1.30) 0.204
T1DM & T2DM

Abbreviations: CI, confidence interval; DR, diabetic retinopathy; HR, hazard ratio; NR, not reported; OR, odds ratio; RR, relative risk; T1DM, type 1 diabetes
mellitus; T2DM, type 2 diabetes mellitus.

3.3.1 | Cerebrovascular complications marker.17,60–65 In a cross-sectional analysis of patients with T2DM,

An early case-control study identified DR as a risk factor for non- DR severity was associated with elevated cIMT after controlling for
embolic ischaemic stroke in individuals with diabetes, independent of other risk variables.60 These findings are consistent with those from
smoking, blood pressure and other complications of diabetes.52 The the Chennai Urban Rural Epidemiology Study (CURES-2)61 and several
findings were later supported by a population-based, prospective other cross-sectional investigations.62–64 Furthermore, Li et al. found
study of patients with diabetes that found DR to be significantly cor- the presence of retinal microvascular abnormalities, defined as DR or
related with incident stroke, although no association was identified retinal arteriosclerosis, to be independently associated with increased
between DR grade and increasing risk of ischaemic stroke. 53
This dif- cIMT in both men and women with T2DM, and with increased carotid
fers from the results of the Wisconsin Epidemiologic Study of Diabetic plaque presence in men with T2DM.66 In research by de Kreutzenberg
Retinopathy in T1DM, which demonstrated an association between et al. DR alone, or co-existing with nephropathy, was significantly and
DR severity and increased odds of stroke. 54
Similarly, in the Finnish independently associated with carotid plaque presence in patients
Diabetic Nephropathy (FinnDiane) Study, severe DR independently with T2DM,67 and Alonso et al. showed DR to be independently cor-
increased the risk of stroke, cerebral infarction and cerebral haemor- related with cIMT, carotid artery plaque presence and carotid burden
rhage in patients with T1DM who were followed for 9 years, and the in patients with T2DM.17
22 Contrary to the evidence described above, DR presence was not
risk increased if patients had concomitant diabetic nephropathy.
Further analysis of this data set revealed severe DR to be indepen- associated with increased cIMT in a cross-sectional study that exam-
dently associated with haemorrhagic stroke but not with ischaemic ined the relationship between DR severity and risk factors for sub-
21 clinical CVD in a cohort of individuals with diabetes who had no
stroke, whereas a large prospective study in patients with T2DM
who were followed for 5 years found DR to be correlated with small- history of clinical CVD.68 However, the study found that severe reti-
artery ischaemic stroke, but not with large-artery ischaemic stroke or nopathy doubled the odds of a high coronary artery calcium (CAC)
23 score and a low ankle-brachial index (ABI) after adjusting for cardio-
haemorrhagic stroke. An analysis of data from the Japan Diabetes
Complications Study revealed that even patients with mild to moder- vascular risk factors, HbA1c, nephropathy and diabetes duration.68 A
ate NPDR had an increased risk of stroke after adjusting for traditional correlation between PDR and high CAC scores was also identified in
55
cardiovascular risk factors. Furthermore, in the Atherosclerosis Risk the Veterans Affairs Diabetes Trial (VADT). Through logistic regres-
in Communities (ARIC) Brain MRI Study, DR was associated with the sion analysis, PDR presence in patients with T2DM was estimated to
56
emergence of subclinical brain infarcts. increase the likelihood of a CAC score greater than 400 by six times,
compared with no PDR presence.69 It is worth noting, however, that,
3.3.2 | Cardiovascular complications in a prospective study of individuals with T2DM who were followed
Increased carotid intima-media thickness (cIMT) is a broadly accepted for up to 8 years, even mild to moderate DR increased the risk of
marker for early or subclinical atherosclerosis, 59
and several studies CHD and stroke.55 In addition, in a case-controlled study, the odds
have demonstrated an association between DR and this ratio of myocardial perfusion defects in an asymptomatic patient who
PEARCE ET AL. 473

TABLE 4 Studies describing the association between DR and cardiovascular complications

Reference
Study design (n) Independent variable Dependent variable OR/HR/RR/β (95% CI) P value
Study population
R. Klein60 Cross-sectional cIMT DR OR = 1.09 (1.01-1.17) 0.02
T2DM (1600)
Rema61 Cross-sectional cIMT DR OR = 3.60 (1.51-8.46) 0.004
T2DM (600)
Liu62 Cross-sectional cIMT DR OR = 1.84 (1.02-3.31) 0.043
T2DM (1607)
Saif63 Cross-sectional cIMT DR NR <0.0001
T2DM (140)
Son64 Cross-sectional cIMT DR OR = 6.57 (1.68-25.71) 0.007
T2DM (142)
L. X. Li66 Cross-sectional DR cIMT All: β = 0.078 (0.080-0.262) <0.001
T2DM (2870) Men: β = 0.067 (0.026-0.269) 0.018
Women: β = 0.087 (0.058-0.334) 0.005
Carotid plaques All: OR = 1.72 (1.32-2.24) <0.001
Men: OR = 2.17 (1.54-3.05) <0.001
de Kreutzenberg67 Cross-sectional DR Carotid plaques OR = 3.44 (1.71-7.57) 0.0011
T2DM (662)
Alonso17 Cross-sectional DR ICA-IMT NR 0.017
T2DM (312) Carotid plaques OR = 1.71 (1.03-2.85) 0.0366
Plaque burden OR = 3.17 (1.75-5.75) <0.0001
Kawasaki 201168 Cross-sectional VTDR CAC OR = 2.33 (1.15-4.73) <0.05
T1DM & T2DM (972) Low ABI OR = 2.54 (1.08-55.99) <0.05
Reaven69 Cross-sectional PDR CAC OR = 9.0 (1.7-49.2) 0.011
T2DM (204)
Kawasaki 201355 Prospective Mild NPDR CHD HR = 1.62 (1.02-2.58) 0.04
T2DM (2033) Mild to moderate NPDR CHD HR = 1.69 (1.09-2.63) 0.02
Any CVD HR = 1.92 (1.33-2.75) <0.01
Gimeno-Orna70 Prospective NPDR Incident CVD HR = 1.61 (1.20-2.60) 0.017
T2DM (458) PDR HR = 2.95 (1.10-3.56) 0.019
Roy 200771 Prospective Moderate DR CVD OR = 3.19 (1.19-8.57) 0.01
T1DM (483) Severe DR OR = 3.88 (1.39-10.80) 0.01
Targher72 Prospective DR Incident CVD Men: HR = 1.61 (1.20-2.60) All <0.001
T2DM (406) Women: HR = 1.67 (1.30-2.80)
PDR Men: HR = 3.75 (2.00-7.40)
Women: HR = 3.81 (2.20-7.30)
Park65 Prospective DR CHD OR = 2.39 (1.63-3.51) <0.001
T2DM (557)
Torffvit73 Prospective STDR CVD RR = 4.40 (NR) <0.05
T1DM (462)
Cheung 200753 Prospective Any DR Incident CHD HR = 1.99 (1.33-3.00) NR
T2DM (1524) Any DRa HR = 1.91 (1.18-3.08)
Mild/moderate DR HR = 1.89 (1.22-2.92)
Severe DR Fatal CHD HR = 2.57 (1.25-5.27)
Severe DR HR = 5.38 (1.54-18.82)
Gerstein18 Prospective Change in retinal severity ACCORD composite HR per category change: 1.38 (1.10-1.74) <0.05
T2DM (3433)
Rajala74 Prospective DR CVD mortality OR = 5.6 (2.6-19.0) <0.05
T1DM & T2DM (107)
Juutilainen75 Prospective Background DR CVD mortality HR = 1.52 (1.15-1.99) 0.003
T2DM (824) CHD mortality HR = 1.47 (1.06-2.02) 0.020
PDR CVD mortality HR = 3.43 (2.01-5.85) <0.001
CHD mortality HR = 3.45 (1.87-6.36) <0.001
Kramer 201176 Meta-analysis DR All-cause mortality T1DM: OR = 3.65 (1.05-12.66) NR
T1DM & T2DM (19234) T2DM: OR = 2.41 (1.87-3.10)

Abbreviations: ABI, ankle-brachial index; β, β coefficient; CI, confidence interval; cIMT, carotid intima-media thickness; CAC, coronary artery calcium;
CHD, coronary heart disease; CVD, cardiovascular disease; DR, diabetic retinopathy; HR, hazard ratio; ICA-IMT, internal carotid artery intima-media thick-
ness; NPDR, non-proliferative diabetic retinopathy; NR, not reported; OR, odds ratio; PDR, proliferative diabetic retinopathy; RR, relative risk;
STDR, sight-threatening diabetic retinopathy (defined as clinically significant macular oedema and/or severe non-proliferative DR, or clinically significant
macular oedema and/or PDR); T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; VTDR, vision-threatening diabetic retinopathy (defined as
clinically significant macular oedema or PDR).
a
Adjusted for nephropathy.
474 PEARCE ET AL.

TABLE 5 Studies describing the association between DR and peripheral complications

Reference
Study design (n) Independent variable Dependent variable OR/HR/RR (95% CI) P value
Study population
77
Baba Longitudinal DR Hospitalization with ulcer HR = 3.86 (2.26-6.59) <0.001
T2DM (1296)
Leymarie78 Cross-sectional DR Ulcer OR = 4.2 (2.4-7.4) <0.05
T1DM and T2DM (555)
Bruun79 Registry DR Ulcer at diabetes diagnosis OR = 6.21 (2.13-18.10) <0.001
T2DM (1381) Amputation OR = 6.43 (2.59-15.90) <0.001
Parisi80 Cross-sectional DR Ulcer OR = 1.68 (1.08-2.62) 0.022
T1DM & T2DM (1455)
Tomita81 Retrospective DR + microalbuminuria Ulcer HR = 6.84 (3.48-13.41) <0.001
T2DM (1305)
Harris Nwanyanwu82 Retrospective Non-healing ulcers PDR HR = 1.54 (1.15-2.07) <0.05
T1DM & T2DM (4617)
Chaturvedi83 Prospective DR Amputation T1DM: RR = 2.4 (1.0-5.9) NR
T1DM & T2DM (3443) T2DM: RR = 3.6 (1.8-7.2)
Hämäläinen84 Prospective DR Amputation OR = 6.1 (1.9-19.6) 0.0024
T1DM & T2DM (733)
Lai85 Retrospective DR Amputation HR = 2.07 (1.12-3.82) <0.05
T2DM (1588)
Rodrigues86 Retrospective DR Amputation OR = 5.20 (2.15-12.75) 0.00
T1DM & T2DM (129)
Saltoglu87 Retrospective DR Amputation OR = 2.25 (1.19-4.25) 0.012
T1DM & T2DM (455)
Tsai88 Registry Amputation DR HR = 2.24 (1.79-2.80) <0.0001
T2DM (2011)
Mohammedi89 Prospective Chronic ulceration or amputation DR HR = 1.53 (1.01-2.30) 0.04
T2DM (11140)
X. Li90 Cross-sectional DR Low ABI OR = 1.83 (1.14-2.93) 0.004
T2DM (3924)
S. C. Chen91 Cross-sectional PDR Abnormal ABI OR = 1.72 (1.15-2.56) 0.008
T2DM (2001)
Y. W. Chen92 Cross-sectional PDR Abnormal ABI OR = 3.61 (1.15-11.26) 0.027
T2DM (1544) Abnormal TBI OR = 2.84 (1.19-6.74) 0.018
Abnormal duplex OR = 3.28 (1.00-10.71) 0.049
Critical limb ischaemia OR = 5.52 (2.14-14.26) <0.001
Roy 200893 Prospective Severe DR LEAD OR = 4.93 (1.13-21.55) 0.0002
T1DM (483)
Yan94 Cross-sectional Borderline ABI DR OR = 1.19 (1.04-1.37) <0.05
T2DM (12772)

Abbreviations: ABI, ankle-brachial index; CI, confidence interval; DR, diabetic retinopathy; HR, hazard ratio; LEAD, lower extremity arterial disease;
NR, not reported; OR, odds ratio; PDR, proliferative diabetic retinopathy; RR, relative risk; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus;
TBI, toe-brachial index.

had diabetes with DR in comparison to patients who had diabetes in patients with T2DM.18 Analyses revealed that the risk of this
without DR was 11.7 (95% CI, 3.7-37).95 primary outcome increased by 38% for every category of change in
Overall, the above findings are consistent with those from other DR severity.18 Elsewhere, retinopathy and PDR have been shown to
prospective studies, indicating that DR, particularly advanced DR, is increase the risk of cardiovascular or all-cause mortality in patients
an independent risk factor for CVD in patients with diabetes.65,70–72 with T1DM and patients with T2DM.74–76
Furthermore, Torffvit et al. demonstrated that the presence of VTDR
in patients with T1DM increases the risk of incident CHD by 4.4 times, 3.3.3 | Peripheral complications
compared with no DR presence.73 Notably, the association did not Neuropathic and vascular complications caused by diabetes can lead
73
remain after adjusting for the presence of macroalbuminuria. How- to the development of diabetic foot ulcers and infections, and cause
ever, this contrasts with results from the Atherosclerosis Risk in Com- amputations. Several studies have shown that DR is an independent
munities (ARIC) Study in T2DM, in which adjusting for nephropathy risk factor for foot ulceration in individuals with diabetes.77–80 How-
had minimal impact on the association between DR and CHD.96 In this ever, a retrospective analysis of patients with T2DM by Tomita
study, the risk of incident CHD increased with DR severity, and severe et al. found retinopathy to significantly increase the risk of developing
DR was also a significant independent risk factor for fatal CHD.96 ulcers only in the presence of microalbuminuria after adjusting for
In the ACCORD Eye Study, DR severity and progression were neuropathy and macroangiopathy.81 Furthermore, it has been shown
associated with the composite outcome of first occurrence of non- that, among individuals with newly diagnosed NPDR, those with
fatal myocardial infarction, non-fatal stroke or cardiovascular death non-healing foot ulcers have an increased risk of progressing to
PEARCE ET AL. 475

PDR.82 A number of papers have also identified DR as a key risk factor between DR and CAN, with prospective studies indicating that the
for lower extremity amputation in both patients with T1DM and risk of developing the latter increases in the presence of retinopathy
patients with T2DM.79,83–87 and that, in individuals with T2DM, DR stage is independently corre-
Notably, patients who have T2DM and undergo lower extremity lated with CAN.16,45 As both CAN and DR have been identified as
amputation (LEAs) have been found to be at higher risk of developing predictors of cardiovascular morbidity and mortality in several pro-
DR than those without LEAs. 88
This was also observed in the spective studies of individuals with diabetes,65,70–72,99 it may be inter-
ADVANCE-ON post-trial observational study in T2DM, which demon- esting to investigate whether both conditions in conjunction is
strated that lower extremity ulceration or amputation, as a major pre- associated with a greater risk of cardiovascular complications, com-
sentation of PAD, increased the risk of retinal photocoagulation or pared with the presence of either complication alone. If this were the
89
blindness. PAD is diagnosed using the ABI, with values less than 0.9 case, screening for CAN in patients who have diabetes with DR could
indicative of the disease.97 Li et al. demonstrated that DR was inde- help identify high-risk groups, for monitoring and early detection of
pendently associated with a low ABI in patients with T2DM, irrespec- clinical progression to CVD. Outcomes from the reviewed studies also
tive of age. 90
However, Chen et al. found PDR, but not NPDR, to be demonstrate that DR is a significant risk factor for DPN,38,40,41,51 and
correlated with an abnormal ABI in patients with T2DM after adjust- that the risk of developing this complication is greater in the presence
ment for HbA1c.91 This result was replicated in another study, in of PDR than with early-stage retinopathy.41
which PDR was found to be independently associated with other As for the relationship between DR and the macrovascular com-
measures of PAD, such as the toe-brachial index, Doppler ultrasound plications of diabetes, risk estimates from several large prospective
and critical limb ischaemia.92 In addition, a prospective study in studies indicate that DR is a strong predictor of stroke, and that pro-
African-Americans with T1DM found that DR severity at baseline was gression of DR significantly increases the risk of this complica-
a significant independent risk factor for the incidence of lower tion.22,52,53 Severe DR was found to independently increase the risk
extremity arterial disease, defined as present if a patient has had an of cerebral infarction and cerebral haemorrhage in patients with
amputation or angioplasty for poor circulation, or if there is an T1DM,22 and was associated with small-artery ischaemic stroke in
absence of major arterial pulse in the legs.93 However, in patients with patients with T2DM.23 Evidence presented here also demonstrates
T2DM, a borderline ABI (0.90-0.99) has been identified as an indepen- that DR is associated with subclinical atherosclerosis,61–63 and that
dent predictor of DR and other microvascular and macrovascular the presence of this complication is independently correlated with
complications. 94 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 mortality53,55 and, overall, DR was found to be an inde-
4 | DISCUSSION pendent risk factor for CVD.65,70–72 Similarly, outcomes from the
reviewed studies demonstrate that DR, and particularly PDR, is a
The present structured analysis has provided clear evidence support- strong risk factor for PAD, which carries a risk of lower extremity
ing relationships between DR and complications of diabetes, including ulceration and amputation.90–92 Therefore, worsening DR could prove
micro- and macrovascular conditions and events. Although many of useful as a marker for individuals at increased risk of these serious
these associations have been identified in cross-sectional and retro- macrovascular complications. Specifically, the evidence indicates that
spective studies, several have been confirmed in prospective investi- patients with diabetes who have PDR are more likely than those with
gations, based on multivariate analyses that controlled for the NPDR to have an abnormal ABI.91 Furthermore, DR was identified as
influence of traditional or other known risk factors. an independent risk factor for foot ulceration and a key risk factor for
With regard to microvascular outcomes, DR was found to lower extremity amputation.77–79 Interestingly, two studies found that
15,25,26
increase the likelihood of nephropathy and to be a significant patients with diabetes who have non-healing foot ulcers or who have
and independent predictor of progression to micro- or undergone lower extremity amputation are at risk of DR development
macroalbuminuria,15 but it remains unclear whether albuminuria and progression.82,89
increases the risk of retinopathy.29,30,37 In this regard, Kotlarsky We performed a comprehensive search of the literature that
et al. concluded that renal injury precedes retinal damage, but they resulted in the inclusion of 71 studies, with a total of over 400 000
stated that prospective studies are required to confirm this conclu- patients, and the approach taken to review was objective and system-
sion.37 Additionally, the reviewed evidence indicates that DR corre- atic, complying with several of the key items included in the PRISMA
34,48
lates with declining GFR and, specifically, that retinopathy checklist for systematic reviews and meta-analyses. One limitation of
severity at baseline is a predictor of the rate of decline of eGFR.48 An our study was that only the PubMed literature database was searched.
important implication of the above findings is that close monitoring of Despite this, our findings are an important contribution to the under-
individuals with DR for the presence of other microvascular complica- standing of the relationship between DR and the micro- and macro-
tions, particularly albuminuria and impaired glomerular function, may vascular complications of diabetes and, as such, provide valuable
help prevent progression to more serious kidney disease.34,98 Further- information to support the wider multidisciplinary team that is
more, as evidence suggests that DR severity parallels the severity of involved in the care of individuals with diabetes. In particular, the find-
nephropathy, a key area of further research is whether systemic inter- ings underscore the need for prompt screening and referral for DR,
ventions to prevent the progression of one might influence the pro- which can both reduce vision loss and, potentially, identify patients at
gression of the other. A strong association was also observed increased risk of other complications of diabetes. This highlights the
476 PEARCE ET AL.

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