Pathophysiology/Complications

O R I G I N A L A R T I C L E

Proliferative Diabetic Retinopathy in Type

2 Diabetes Is Related to Coronary Artery
Calcium in the Veterans Affairs Diabetes
Trial (VADT)
PETER D. REAVEN, MD1 KATHY GLANDER, BBA4 ship appears to be present in both type 1
NICHOLAS EMANUELE, MD2 WILLIAM DUCKWORTH, MD1 and type 2 diabetes (4 –11). Importantly,
THOMAS MORITZ, PHD3 CARLOS ABRAIRA, MD5 most (4,5,7–11), but not all (9), of these
RONALD KLEIN, MD4 FOR THE VETERANS AFFAIRS DIABETES studies have indicated that retinopathy
MATHEW DAVIS, MD4 TRIAL (VADT)* may be independently associated with
CVD events or mortality even after taking
into account standard cardiovascular risk
OBJECTIVE — Increasing evidence suggests that macrovascular disease and retinopathy may factors, diabetes duration, and/or glyce-
be more closely linked than previously believed. We determined the relationship between mic control. Results from these studies
retinopathy and coronary atherosclerosis as measured by computed tomography– detectable suggest that there may be shared risk fac-
coronary artery calcium (CAC).
tors or mechanisms underlying both reti-
RESEARCH DESIGN AND METHODS — The cross-sectional association between nopathy and clinical CVD and that the
CAC and retinopathy was assessed on a Veteran Affairs Diabetes Trial subsample of 204 subjects relationship does not appear to be ex-
with a mean duration of type 2 diabetes of 12.3 ⫾ 8.3 years. plained by standard cardiovascular risk
factors or glycemic control. This raises the
RESULTS — Retinopathy was correlated with CAC (r ⫽ 0.19, P ⫽ 0.006). Median CAC possibility that other novel risk factors or
increased across retinopathy categories: 197 in those with no retinopathy, 229 in those with disease pathways may contribute to both
microaneurysms only, 364 in those with mild nonproliferative diabetic retinopathy (NPDR), 300 retinopathy and CVD.
in those with moderate to severe NPDR, and 981 in those with proliferative diabetic retinopathy Because studies to date have been
(PDR). Stepwise multivariable linear regression analysis was performed to find a parsimonious generally limited to understanding the re-
subset of relevant risk factors to include along with PDR in predicting CAC. After adjustment for
lationship of retinopathy to CVD clinical
either this subset of standard factors (P ⫽ 0.047) or a more extensive panel of risk factors (P ⫽
0.035), PDR was significantly associated with CAC. Moreover, using logistic regression, indi- events, it is unclear whether these shared
viduals with PDR were approximately sixfold more likely to have CAC ⬎400 than those with no risk factors or disease mechanisms con-
PDR, even after adjustment for other CVD risk factors. tribute to these events through thrombo-
sis, plaque instability, or atherosclerosis.
CONCLUSIONS — These data indicate an important relationship between retinopathy and Better understanding of these events will
extent of CAC and suggest the potential to identify and treat shared risk factors for these common not only provide direction toward identi-
micro- and macrovascular complications. fying the novel factors underlying the
relationship between micro- and macro-
Diabetes Care 31:952–957, 2008 vascular disease but may also provide
insight into how to best use the rela-

T
here is increasing evidence that in- has been well described (1–3), studies tively easily assessed microvascular dis-
dividuals with microvascular com- now suggest that retinopathy may also be ease to predict risk of macrovascular
plications of diabetes are also at associated with cardiovascular disease disease.
increased risk for clinical complications (CVD). In fact, retinopathy, especially Thus, in this study we sought to in-
of macrovascular diseases such as myo- proliferative diabetic retinopathy (PDR), vestigate the association of retinopathy
cardial infarctions and cardiovascular is associated with incident coronary heart with a direct measure of coronary athero-
mortality. Although the relationship of disease events, CVD events, and cardio- sclerosis burden (by measuring coronary
microalbuminuria with vascular disease vascular mortality (4 –11). This relation- artery calcium [CAC]) in a subset of well-
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● characterized individuals with type 2 di-
abetes that are participating in the Veteran
From the 1Carl T. Hayden VA Medical Center, Phoenix, Arizona; the 2Edward Hines, Jr., VA Hospital, Hines,
Illinois; the 3Cooperative Studies Program Coordinating Center, Edward Hines, Jr., VA Hospital, Hines, Affairs Diabetes Trial (VADT) of tight gly-
Illinois; the 4University of Wisconsin, Madison, Wisconsin; and the 5Miami VA Medical Center, Miami, cemic control.
Florida.
Corresponding author: Peter Reaven, MD, Phoenix VAMC, 650 E. Indian School Road (111E), Phoenix, RESEARCH DESIGN AND
AZ 85012-1892. E-mail: peter.reaven@va.gov.
Received for publication 9 October 2007 and accepted in revised form 10 February 2008. METHODS — Data for this study de-
Published ahead of print at http://care.diabetesjournals.org on 3 March 2008. DOI: 10.2337/dc07-1926. rive from baseline examinations of partic-
*A complete list of participating investigators is available in the APPENDIX. ipants in the Risk Factors, Atherosclerosis
Abbreviations: CAC, coronary artery calcium; CVD, cardiovascular disease; NPDR, nonproliferative and Clinical Events in Diabetes (RACED)
diabetic retinopathy; PDR, proliferative diabetic retinopathy; VADT, Veterans Affairs Diabetes Trial.
© 2008 by the American Diabetes Association.
study (12), a seven-site substudy of the
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby VADT. A detailed description of the
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. VADT with exclusion and inclusion crite-

952 DIABETES CARE, VOLUME 31, NUMBER 5, MAY 2008


ria has been previously described (13).
Approximately 95% of all subjects who
were recruited into the VADT study, at
sites participating in the RACED study,
also agreed to receive coronary calcium
scans.
The VADT baseline examination in-
cluded a medical history, physical exam-
ination, and collection of blood for
measurement of traditional cardiovascu-
lar risk factors. Height and weight were
measured to the nearest 0.1 cm and 0.5
kg, respectively, and BMI (weight in kilo-
grams divided by the square of height in
meters) was calculated. Information re-
garding current medical health status in-
cluding history of diabetes, hypertension,
prior CVD, and medication use was col-
lected by a questionnaire administered by
research staff as previously described
(13). A non-Hispanic white variable was
generated because this race-ethnicity
grouping effectively identifies those with
greater CAC in this and other cohorts
(12,14,15). All laboratory assays, includ-
ing plasma total cholesterol, triglycerides,
HDL cholesterol concentrations, and
A1C, were measured in the central labo-
ratory at Tufts University. Lipid values
were assayed using standard enzymatic
methods, and LDL cholesterol was calcu-
lated using the Friedewald equation. A1C
was measured using an immunoaffinity
method that was referenced against the
national standard methodology as de-
rived from the Diabetes Control and
Complications Trial (13). Urinary protein
and creatinine were measured on random
morning urine samples, and an albumin-
to-creatinine ratio was calculated.
Assessment of retinopathy
Patients consented to a set of seven-field
standard 30° stereoscopic color photo-
graphs of both eyes at the baseline exam
according to the Diabetes Retinopathy
Study protocol (13). The Fundus Photo-
graph Reading Center of the University of
Wisconsin assessed the photographs us-
ing the Early Treatment Diabetic Retinop-
athy Study modification of the Airlie
House classification and severity scale;
the score from the eye with the most se-
vere retinopathy was used (16).
Assessment of CAC scores
CAC was determined by electron-beam
computed tomography cardiac scanning
using Imatron C150XL scanners (GE
Imatron, South San Francisco, CA) as pre-
viously described (12,17). Readers at the
centralized reading center, which were
DIABETES CARE, VOLUME 31, NUMBER 5, MAY 2008
blinded to the demographic and clinical
information, performed calcium scoring.
A threshold of 4 pixels and 130
Hounsfield units was used for identifica-
tion of calcified lesions. Each focus ex-
ceeding the minimum volume criteria was
scored using the algorithm developed by
Agatston et al. (18). Total coronary cal-
cium scores were determined by sum-
ming individual lesion scores from each
of four anatomic sites (left main, left an-
terior descending, circumflex, and right
coronary arteries). A calibration phantom
was scanned under the chests of each par-
ticipant at each scanning center to allow
calibration of the images to identical stan-
dards, as previously described (12,17).
Statistical analyses
Statistical analyses were performed with
the SAS statistical package (release 8.2;
SAS Institute, Cary, NC). For the descrip-
tion of the data parameters with a normal
distribution, means ⫾ SD are reported.
Parameters with a skewed distribution are
reported as medians (interquartile range),
and proportions are given for categorical
variables. Significant differences between
the levels of retinopathy were assessed us-
ing one-way ANOVA or the Kruskal-
Wallis where appropriate. Linear and
logistic regression models were used to
investigate the association of CAC with
risk factors, including retinopathy. The
log of CAC ⫹ 1 was used to include pa-
tients with a score of zero in the linear
regression models. Univariate linear re-
gression analysis was applied to examine
the association of CAC with each covari-
ate. Stepwise regression models were
created to find appropriate and parsimo-
nious subsets of traditional risk factors to
include in the initial multivariate linear
(and logistic) regression analyses in order
to investigate the independent association
of retinopathy with CAC. Subsequent re-
gression analyses contained additional
risk factors to provide more complete
models for presentation.
RESULTS — Our study population in-
cluded 204 subjects with type 2 diabetes
with a mean diabetes duration of 12.3 ⫾
8.3 years and had characteristics very
similar to those of the overall VADT co-
hort (38). The majority of subjects were
male (95%) and non-Hispanic white
(70%), with a mean age of 62.0 ⫾ 9.2
years. Prevalence of hypertension (80%)
and a prior history of smoking (70%) was
high in this population, and 39% had
some prior history of CVD. Shown in Ta-
Reaven and Associates
ble 1 are characteristics of the population
across categories of retinopathy. Age,
BMI, history of smoking, hypertension,
and CVD history, as well as values of A1C
and LDL and HDL cholesterol, were not
significantly different between groups.
While total cholesterol and triglyceride
levels did vary between groups, only du-
ration of diabetes and insulin use showed
a clear increasing trend across categories
(from no retinopathy to PDR).
To investigate the potential relation-
ship between retinopathy and CAC, we
first determined that retinopathy (Early
Treatment of Diabetic Retinopathy Study
scores) was significantly correlated with
CAC (r ⫽ 0.19, P ⫽ 0.006). We then ex-
amined the median CAC score across ret-
inopathy categories (Fig. 1). For those
with no retinopathy, the median CAC
score was 197; for microaneurysm only,
229; for mild NPDR, 364; and for moder-
ate to severe NPDR, 300. Most striking
was the significantly higher CAC values in
individuals with PDR: 981 (P ⬍ 0.01).
To determine whether the association
between PDR and CAC was independent
of other standard risk factors for these
conditions, we first performed multivari-
able linear regression analyses. To avoid
over-fitting of the models, we chose to
initially limit the number of variables in-
cluded to those with evidence of relevant
model effects. Therefore, stepwise vari-
able selection was initially performed to
find a parsimonious subset of risk factors
to include along with PDR in predicting
CAC. After adjustment for these factors
(age, non-Hispanic white status, HDL
cholesterol, insulin use, and prior CVD
events), PDR was significantly (P ⫽
0.047) associated with CAC (Table 2).
This translated into an ⬃3.2-fold increase
in individuals’ CAC scores if PDR was
present. Interestingly, the ␤ coefficients
and P values for the other variables
changed very little (data not shown) when
PDR was included in the model, suggest-
ing that the association between PDR and
CAC does not appear to be mediated
through these other risk factors. The ad-
dition of variables such as BMI, smoking,
hypertension history, A1C, diabetes du-
ration, lipid levels, and albumin-to-
creatinine ratio in the models was found
to not contribute to the extent of CAC and
increased the strength of the PDR-CAC
relationship (Table 2).
We also explored the relationship of
PDR with common clinical categories of
CAC (0 –10, 11–100, 101– 400, and
⬎400), recognizing that prior studies
953
Diabetic retinopathy and atherosclerosis

Table 1—Subject characteristics by retinopathy category

Mild Moderate to
Total No retinopathy Microaneurysms NPDR severe NPDR PDR P
n 204 68 37 49 35 15
Age (years) 62.0 60.0 60.6 64.7 63.3 62.4 0.07
BMI (kg/m2) 31.4 31.5 31.5 30.7 32.1 31.2 0.67
Diabetes duration (years) 12.3 8.9 11.2 13.3 15.0 21.3 0.01
Smoker (%) 16 19 21 8 17 8 0.33
Non-Hispanic white (%) 70 71 60 63 83 80 0.19
Hypertension (%) 80 78 74 80 89 93 0.34
A1C (%) 9.2 9.2 8.9 9.2 9.3 9.6 0.63
Total cholesterol (mg/dl) 176 187 176 171 162 173 0.01
Median triglycerides (mg/dl) 157 184 151 141 138 179 0.01
LDL cholesterol (mg/dl) 102 110 99 102 93 97 0.06
HDL cholesterol (mg/dl) 36 36 36 38 36 37 0.80
Insulin use (%) 60 53 42 71 69 87 0.005
Median urinary albumin-to-creatinine ratio 16.5 15.5 8.0 13.0 40.5 39.0 0.01
(␮g/mg)
CVD (%) 30 24 32 27 37 60 0.07
Data are means except where indicated.

have demonstrated that individuals with
CAC ⬎400 are at very high risk for prev-
alent and incident CVD. Impressively, in
80% of the subjects with PDR, CAC was
⬎400 (P ⫽ 0.001), and 100% of the sub-
jects with PDR had CAC scores ⬎250.
To determine whether this strong as-
sociation between PDR and the highest
risk category of CAC scores was explained
by factors other than retinopathy, we per-
formed multivariable logistic regression
analyses. Of the many standard risk fac-
Figure 1—CAC scores by retinopathy category. Median (25th-75th percentile range) values are
presented. Differences between the levels of retinopathy were assessed using Kruskal-Wallis. NL,
no retinopathy; MA, microaneurysms; M/S, moderate to severe. P ⬍ 0.01.
tors assessed in these models, age, non-
Hispanic white status, prior CVD events,
and PDR were all significantly associated
with CAC ⬎400 (Table 3). In fact, indi-
viduals with PDR were over sixfold more
likely to have CAC ⬎400 than those with
no PDR, even after adjustment for other
CVD risk factors. Similar or higher odds
ratios for PDR were also present in models
that excluded women or all subjects with
known CVD disease or when a less selec-
tive model was used that included many
additional risk factors (Table 3).
CONCLUSIONS — Our data show a
rather striking relationship between dia-
betic retinopathy, especially PDR, and
coronary calcium deposition, a reliable
estimate of coronary atherosclerosis. This
relationship was present whether CAC
was assessed as a continuous outcome or
in clinical categories. In fact, in this cohort
of 204 patients, 80% of the individuals
who had PDR had CAC scores ⬎400.
Thus, the presence of PDR was associated
with a greater than sixfold increased risk
of having CAC ⬎400, a value that is in-
creasingly recognized as placing individ-
uals at a particularly high risk for future
clinical cardiovascular events (19,20).
Because of the moderate sample size
of this substudy, variable selection proce-
dures were initially used in order to dis-
card less statistically important factors
and thus identify relevant factors that
could be included, along with PDR, in
models to predict CAC. In these analyses
and in subsequent more complete mod-
els, it did not appear that BMI, hyperten-
sion, lipid levels (other than HDL
cholesterol), A1C, smoking history, or
even the more novel risk factors plasmin-
ogen activator inhibitor-1 or fibrinogen
(data not shown) were useful in predict-
ing CAC. Although plasma cholesterol
levels and blood pressure abnormalities
have been associated with CAC in some
but not all studies (21–27), these associ-
ations may be more difficult to identify in

954 DIABETES CARE, VOLUME 31, NUMBER 5, MAY 2008


Table 2—Multivariate linear regression model with the dependent variable log (CAC ⴙ 1)
Age (per 10 years)
Non-Hispanic white vs. other
HDL cholesterol (per 5 mg/dl)
Insulin use (yes/no)
CVD at baseline (yes/no)
PDR (yes/no)
PDR (yes/no)*
*Adjusted for the above-shown variables as well as BMI, duration of diabetes, smoking, A1C, total choles-
terol, triglycerides, history of hypertension, and urinary albumin-to-creatinine ratio. For this more complete
model, n ⫽ 195 (PDR ⫽ 15) instead of the original 204, as not all measures were available.
an older cohort of subjects with diabetes
that receives numerous medications for
these conditions. Consistent with other
reports (12,17,27–29), age, HDL choles-
terol, race-ethnicity status, and prior CVD
were each significantly related to CAC. In-
terestingly, baseline use of insulin, possi-
bly because it indicates long-standing and
complicated diabetes, was also a signifi-
cant predictor of coronary atherosclerosis
burden. However, PDR remained associ-
ated with CAC, even after adjusting for
these factors. Thus, the relationship be-
tween PDR and CAC score could not fully
be accounted for by traditional historical
or laboratory-measured cardiovascular
risk factors. These data, therefore, pro-
vide additional support for the hypothesis
that PDR and CAC share a common un-
derlying pathophysiology that may be
mediated, at least in part, by nontradi-
tional risk factors.
One potential implication of a strong
and independent relationship between
retinopathy, especially PDR, and severe
coronary atherosclerosis is that the non-
invasive measurement of PDR, in combi-
nation with standard risk factors, may
provide a relatively useful assessment of
clinically relevant atherosclerosis. This
possibility deserves evaluation in addi-
tional studies.
These results are consistent with sev-
eral prior studies demonstrating that mi-
crovascular disease is related to both
macrovascular disease events and overall
mortality (2,3). In fact, substantial evi-
dence now exists that both microalbu-
minuria and retinopathy are independent
risk factors for CVD events and mortality
(2–5,7–11,30). Although the studies in
type 1 diabetes are limited in number
(9,31), this relationship between retinop-
athy and CVD is present in both type 1
and type 2 diabetic populations and ap-
pears strongest for proliferative retinopa-
thy (4,5,7–11).
DIABETES CARE, VOLUME 31, NUMBER 5, MAY 2008
␤ SE of ␤ P oxidative damage, formation of advanced
0.440 0.07 ⬍0.001
0.312 0.141 0.028
⫺0.090 0.035 0.007
0.395 0.135 0.004
0.761 0.145 ⬍0.001
0.497 0.249 0.047
0.608 0.287 0.035
Our study has several unique advan-
tages compared with previous studies.
Whereas many of the prior studies only
used opthalmoscopic exams or one- or
two-field retinal photographs of one or
occasionally both eyes, the current study
used the gold standard seven-field stereo-
scopic color photographs of both eyes to
provide a more sensitive and comprehen-
sive assessment of retinopathy. In addi-
tion, the fundus photographs were
centrally analyzed at the Retinopathy
Reading Center at the University of Wis-
consin, a facility with extensive experi-
ence in retinopathy assessment for many
landmark clinical studies of retinopathy.
Moreover, this study clearly demonstrates
that there is a direct relationship of reti-
nopathy, and PDR in particular, not just
with CVD events as previously shown,
but also with the burden of coronary ath-
erosclerosis. Of note, this association re-
mained robust and significant using
several different approaches to analyze
CAC. Only one other study, comprised of
a small group of patients preselected for
suspected CVD, has explored the rela-
tionship between retinopathy and coro-
nary atherosclerosis and demonstrated a
relationship between retinopathy, as-
sessed during opthalmoscopic fundus ex-
ams, and coronary angiogram severity
(32).
Several biochemical pathways have
Table 3—Multivariate logistic regression model with the dependent variable CAC >400
Age (per 10 years)
Non-Hispanic white vs. other
CVD at baseline (yes/no)
PDR (yes/no)
PDR (yes/no)*
*Adjusted for the above-shown variables as well as BMI, duration of diabetes, smoking, A1C, total choles-
terol, triglycerides, history of hypertension, and urinary albumin-to-creatinine ratio. For this more complete
model, n ⫽ 195 (PDR ⫽ 15) instead of the original 204, as not all measures were available.
Reaven and Associates
been proposed to account for diabetic ret-
inopathy, including polyol accumulation,
glycation end products, stimulation of ac-
tivation pathways such as PKC, and in-
creased levels of various growth factors
(33–35). Each of these pathways has also
been implicated in the initiation and/or
progression of atherosclerosis. In addi-
tion, ischemia of small retinal vessels is
believed to be particularly relevant for the
development of new vessel proliferation
in the retina (36). Similarly, recent studies
have also implicated the contribution of
plaque ischemia and small vessel angio-
genesis in progression of atherogenesis
(37). Thus, there are clearly several novel
pathways that may contribute to both ret-
inopathy and atherosclerosis and may
help explain our demonstration of a close
relationship between PDR and atheroscle-
rosis. Measurement of novel risk factors
that will reflect activity of these pathways
and processes are needed in future studies
to provide further insight into the specific
mechanisms that underlay the association
of retinopathy with atherosclerosis.
Several limitations of this study de-
serve mention. Because this is a cross-
sectional study, and the subcohort of the
VADT has a relatively modest number of
subjects with PDR that are predominantly
male, we recognize that these novel find-
ings need confirmation in larger cohorts
with greater female representation and in
prospective studies. Importantly, this
subset of subjects with coronary calcium
scans appears to have demographic and
risk factor characteristics similar to those
of the entire diabetic cohort of the VADT
(38). Similarly, the percentages of indi-
viduals in this cohort with mild or moder-
ate/severe NPDR and PDR are essentially
the same as those recently reported in the
overall VADT population (39). For these
reasons, and because the substudy is being
conducted at seven sites around the coun-
try, we believe that the results from these
OR CI P
2.2 1.4–3.4 0.0003
2.8 1.2–6.5 0.02
14.8 6.4–33.8 ⬍0.001
6.2 1.3–29.2 0.022
9.0 1.7–49.2 0.011
955
Diabetic retinopathy and atherosclerosis
individuals are representative of the larger
VA population.
In summary, these data indicate a sur-
prising relationship between retinopathy
and the extent of CAC and, if confirmed
in other studies, suggest that identifying
type 2 diabetic patients with PDR may
help ascertain who is at uniquely high risk
for clinical CVD, indicating that it may be
possible to identify and treat shared risk
factors for these common micro- and ma-
crovascular complications.
APPENDIX
Additional Participating
Investigators
Christian Meyer, MD, John Matchette,
PA, Dawn Schwenke, PhD, Phoenix
VAMC; Jayendrah H. Shah, MD, South-
ern Arizona VA Health Care System;
Sundar Muduliar, MD, Robert Henry,
MD, VA San Diego Healthcare System;
Moti Kayshap, MD, Long Beach VAMC;
Jennifer B. Marks, MD, Hermes Florez,
Miami VAMC; R. Harsha Rao, MD, VA
Pittsburgh Healthcare System; Nasrin
Azad, MD, Lily Agrawal, MD, Hines VA
Hospital; Steven Goldman, MD, Southern
Arizona VA Health Care System; Michael
Criqui, MPH, MD, University of Califor-
nia, San Diego; Robert Detrano, MD, Uni-
versity of California, Irvine; Mathew
Budoff, MD, Harbor UCLA Medical Cen-
ter; Michael Wright, MD, University of
California, San Diego; George Kondos,
MD, University of Illinois, Chicago Med-
ical Center; Steven Reis, MD, University
of Pittsburgh Medical Center; and Joseph
Horgan, MD, Health Test Scan Center.
Acknowledgments — Financial support was
provided by the Department of Veterans Af-
fairs Cooperative Studies Program of the VA
Office of Research and Development, National
Institutes of Health Grant RO1067690, the
Kronos Research Institute, and a clinical re-
search award from the American Diabetes As-
sociation.
We acknowledge the contributions of the
Hines VA Cooperative Studies Program Coor-
dinating Center, the Tufts Lipid Metabolism
Laboratory, and the Harbor UCLA EBCT
Reading Center.
Results from this study were presented in
abstract form at the 67th annual meeting of the
American Diabetes Association, Chicago, Illi-
nois, 22–26 June 2007.
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