Diabetic Retinopathy

Original Investigation | Diabetes and Endocrinology
Association of Diabetic Retinopathy and Diabetic Kidney Disease

With All-Cause and Cardiovascular Mortality in a Multiethnic
Asian Population
Charumathi Sabanayagam, MD, PhD; Miao Li Chee, BSc; Riswana Banu, DipSci; Ching-Yu Cheng, MD, PhD; Su Chi Lim, PhD; E. Shyong Tai, MB, ChB;
Thomas Coffman, MD; Tien Y. Wong, MD, PhD
Abstract Key Points

Question Among persons with
IMPORTANCE The association of diabetic microvascular complications such as diabetic retinopathy
diabetes, are diabetic retinopathy (DR)
(DR) and diabetic kidney disease (DKD) with mortality in populations is not clear.
and diabetic kidney disease (DKD)
associated with higher risk of mortality?
OBJECTIVE To examine the association of DR and DKD separately and jointly with all-cause and
cardiovascular disease (CVD) mortality in a multiethnic Asian population. Findings In this cohort study that
included 2964 Asian (Chinese, Malay,
DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study was conducted including and Indian) persons with diabetes
2964 adults between the ages of 40 and 80 years with diabetes who participated in the Singapore followed up for a median of 8.8 years,
Epidemiology of Eye Diseases study (baseline, 2004-2011). Data analysis was performed from the presence of DR was associated with
January to May 2018. higher all-cause mortality independent
of presence of DKD. Persons with both
EXPOSURES Diabetic retinopathy ascertained from retinal photographs and DKD from estimated DKD and DR had the highest rate of
glomerular filtration rate. mortality, with the excess risk largely
associated with DKD.
MAIN OUTCOMES AND MEASURES All-cause and CVD mortality obtained by linkage with the
Meaning In this study, for patients with
National Registry of Births and Deaths until May 2017.
diabetes, the presence of DR and DKD
were risk factors for mortality, and
RESULTS Of the 2964 adults (mean [SD] age, 61.8 [10.0] years; 1464 [49.4%] female; 592 Chinese,
identification and appropriate
1052 Malay, and 1320 Indian), 29.9% of the participants had DR, while 20.7% had DKD. Over a
management of patients with both
median (interquartile range) follow-up of 8.8 (7.2-11.0) years, 610 deaths occurred (20.6%), of which
conditions may reduce the risk of
267 (9.0%) were due to CVD. In separate models, the multivariable hazard ratios for all-cause and
mortality.
CVD mortality were 1.54 (95% CI, 1.24-1.91) and 1.74 (95% CI, 1.27-2.40), respectively, for DR and 2.04
(95% CI, 1.64-2.56) and 2.29 (95% CI, 1.64-3.19), respectively, for DKD. In models including both DR
and DKD, the subgroup with DKD alone (27.1% and 12.6%) followed by DR alone (6.5% and 5.2%) + Supplemental content
contributed substantially to the excess risk of all-cause and CVD mortality. Compared with those with Author affiliations and article information are
no DR and DKD, the hazard ratios of all-cause and CVD mortality were 1.89 (95% CI, 1.40-2.57) and listed at the end of this article.
2.26 (95% CI, 1.42-3.61), respectively, for DKD alone and 1.38 (95% CI, 1.03-1.86) and 1.64 (95% CI,
1.06-2.56), respectively, for DR alone. Hazard ratios for all-cause and CVD mortality were 2.76 (95%
CI, 2.05-3.72) and 3.41 (95% CI, 2.19-5.32), respectively, for those with both DKD and DR. The relative
excess risk associated with the interaction was 0.49 (95% CI, −0.29 to 1.27; P = .20) for all-cause
mortality and 0.51 (95% CI, −0.83 to 1.85; P = .50) for CVD mortality.
CONCLUSIONS AND RELEVANCE These results suggest that risks of all-cause and CVD mortality
were significantly higher in those with DKD and DR, but DKD was more strongly associated with
(continued)
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2019;2(3):e191540. doi:10.1001/jamanetworkopen.2019.1540 (Reprinted) March 29, 2019 1/11
Downloaded From: https://jamanetwork.com/ on 03/31/2019

JAMA Network Open | Diabetes and Endocrinology Diabetic Retinopathy, Kidney Disease, and Mortality in a Multiethnic Asian Population
Abstract (continued)
excess risk. The findings underscore the importance of early identification and close monitoring and
management of patients with DR and DKD to reduce the risk of death.
JAMA Network Open. 2019;2(3):e191540. doi:10.1001/jamanetworkopen.2019.1540
Introduction
Diabetes affected an estimated 415 million people worldwide in 2015, and the number is expected to
increase to 642 million by 2040, with the greatest increase expected in Asia, in particular, India and
China.1 Diabetes is a major risk factor for cardiovascular disease (CVD) and it is well known that
diabetes is associated with an increased risk of both all-cause and CVD mortality.2,3 With the
increasing prevalence of diabetes and the aging of the population, the prevalence of diabetic
microvascular complications such as diabetic retinopathy (DR) and diabetic kidney disease (DKD) is
likely to increase in parallel. Diabetic kidney disease has been shown to be associated with an excess
risk of premature death, in particular CVD death, in 2 recent studies conducted in the United States4
and Europe.5 Likewise, DR, a leading cause of preventable blindness, has been shown to increase the
risk of all-cause and CVD death.6-8 A study9 in the United States that examined the concurrent
association of diabetes and DKD with mortality reported that coexistence of diabetes and DKD was
associated with a substantially increased mortality risk; in the absence of DKD, diabetes alone was
not associated with a large increase in mortality in the US population. Tong et al10 reported that those
with both DR and macroalbuminuria had excess risk of mortality compared with either one alone in
patients with type 2 diabetes. However, it is not clear whether DR is associated with greater risk of
mortality independent of DKD and whether the joint association of DR and DKD with mortality is
greater than the sum of the individual associations of the two. Given the increasing prevalence of
diabetes in Asia, it is imperative to understand the associations of DKD and DR with mortality and the
interaction between DKD and DR and its association with mortality, in particular, mortality due
to CVD.
Methods
Study Cohort
Data for this study were derived from the Singapore Epidemiology of Eye Diseases (SEED) study, a
population-based prospective study of eye diseases in 10 033 Chinese, Malay, and Indian adults aged
40 to 80 years in Singapore. Baseline data collection started with Malay individuals (2004-2007;
n = 3280),11 followed by Indian individuals (2007-2009; n = 3400) and Chinese individuals (2009-
2011; n = 3353).12 Response rates for the 3 studies were 78.7%, 75.6%, and 72.8%, respectively. The
detailed methods of the SEED study have been published elsewhere.13 As all 3 studies followed the
same methods and were conducted in the same study clinic, we combined the 3 populations and
included only those with diabetes (n = 2964) for the present study. Diabetes was defined as random
glucose level greater than or equal to 200 mg/dL (to convert to millimoles per liter, multiply by
0.0555), glycated hemoglobin (HbA1c) greater than or equal to 6.5% of total hemoglobin, self-
reported physician-diagnosed diabetes, or use of antidiabetic medication. We defined type 1
diabetes as development of diabetes before the age of 30 years. For DR analysis, after excluding
those who had missing data for fundus photography and other covariates, the final sample size was
2880; for DKD, after excluding those with missing estimated glomerular filtration rate (eGFR) and
other covariates, 2858 were included in the final analysis. We assessed diabetic nephropathy (DN)
separately based on albuminuria; however, data on albuminuria were not available in two-thirds of
Malay participants. Hence, we did not include albuminuria in the current analysis. This study was
performed in accordance with the tenets of the Declaration of Helsinki14 and ethics approval was
obtained from the Singapore Eye Research Institute institutional review board. Written informed

consent was provided by participants. This study followed the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
Assessment of Outcomes
Information on all-cause and CVD-related mortality was obtained by linkage of SEED baseline data to
the National Registry of Births and Deaths. Outcomes were assessed up to the date of death or May
31, 2017, whichever occurred first. As it is mandatory to report all deaths occurring in Singapore, the
registry was 100% accurate in capturing all reported deaths. Deaths related to CVD included death
due to cardiovascular causes, including acute myocardial infarction, coronary heart disease,
hypertensive and other heart disease, heart failure, and stroke (International Classification of
Diseases, Ninth Revision, codes 390-459 and International Classification of Diseases, Tenth Revision,
codes I00-I99).
Assessment of DR
After pupil dilation, 2-field color photographs (Early Treatment for Diabetic Retinopathy Study
[ETDRS] field 1, centered on the optic disc, and field 2, centered on the fovea) for both eyes of all
participants were obtained using a digital retinal camera (Canon CR-1 Mark-II Non-mydriatic Digital
Retinal Camera). We considered DR to be present if any characteristic lesion was present, including
microaneurysms, hemorrhages, cotton wool spots, intraretinal microvascular abnormalities, hard
exudates, venous beading, and new vessels. Severity of DR was graded by trained graders at the
University of Sydney, Australia, according to the modified Airlie House classification system15 and
categorized into minimal nonproliferative DR (NPDR) (level 20), mild NPDR (level 35), moderate
NPDR (levels 43-47), severe NPDR (level 53), and proliferative DR (PDR) (levels >60).13 Based on the
severity score of the worse eye, a level greater than or equal to 20 was defined as any DR.
Assessment of DKD
We defined DKD as an eGFR of less than 60 mL/min/1.73 m2 as recommended by the National Kidney
Foundation’s Kidney Disease Outcomes Quality Initiative guidelines.16 We estimated GFR based on
plasma creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation.17 Serum
creatinine was measured by the Jaffe method on the Beckman DXC800 analyzer calibrated to the
isotope dilution mass spectrometry method using the National Institute of Standards and
Technology reference material. Based on eGFR, DKD severity was classified into 4 groups: eGFR
greater than or equal to 60 mL/min/1.73 m2 (reference representing normal high or mild decrease in
kidney function), mild to moderate (eGFR 45-59 mL/min/1.73 m2), moderate to severe (eGFR 30-44
mL/min/1.73 m2), and severe or renal failure (eGFR <30 mL/min/1.73 m2).18
Assessment of Other Factors Associated With Mortality

An interviewer-administered questionnaire was used to collect participants’ demographic data (age,
sex, ethnicity, and education level); lifestyle characteristics (cigarette smoking and alcohol
consumption); and personal history of diabetes, hypertension, and CVD (defined as self-reported
myocardial infarction, angina, or stroke). Physical examination included height, weight, and blood
pressure (BP) measurements. We calculated body mass index (BMI) as weight in kilograms divided by
height in meters squared. Hypertension was defined as systolic BP greater than or equal to 140 mm
Hg, diastolic BP greater than or equal to 90 mm Hg, or self-reported physician-diagnosed
hypertension or use of BP-lowering medication. Laboratory measurements included random plasma
glucose level, HbA1c percentage, serum creatinine level, and total and high-density lipoprotein (HDL)
cholesterol values.
Statistical Analysis
We compared the baseline characteristics of the participants stratified by ethnicity. To examine the
association of the interaction between DR and DKD with mortality (DN was not included in the main

joint association model owing to a large number of missing data), we created 4 categories by
combining DR and DKD: no DR and no DKD, representing background risk (reference, − −), DR only
(+ −), DKD only (− +), and both DR and DKD (+ +). We plotted the incidence of all-cause and CVD
mortality with 1 minus Kaplan-Meier failure function and compared survival distributions across
categories of DR and DKD using log-rank tests. We calculated the absolute mortality rates in each of
the 4 categories and the hazard ratio (HR) and 95% confidence intervals associated with each
category compared with the reference group. We examined for interaction on additive scale using
relative excessive risk due to interaction (RERI) and on the multiplicative scale using cross-product
interaction terms.19 Additive interaction is present when the combined associations of DR and DKD
alone are more than the sum of the individual associations. We calculated RERI using the formula
(HR+ +) – (HR+ −) – (HR− +) + 1. Estimates of RERI were considered significant when 95% confidence
intervals of RERI did not contain zero. We examined the risks of all-cause and CVD mortality by
presence and severity of DR and DKD separately and jointly using Cox proportional hazards
regression models adjusted for age, sex, and ethnicity and a multivariable model that additionally
adjusted for primary school education or less, current smoking, alcohol consumption, history of CVD,
BMI, hypertension, HbA1c level, duration of diabetes, and total and HDL cholesterol measurements.
In a supplementary analysis, we examined the risks of all-cause and CVD mortality in those without
diabetes (n = 6621) and presence or absence of DR and/or DKD in those with diabetes (n = 2775). For
this analysis, we compared mortality risks across 4 categories: normal glucose level (reference,
defined as HbA1c <5.7% and random plasma glucose <140 mg/dL in those with no history of
diabetes), prediabetes (HbA1c of 5.7%-6.4% and/or random plasma glucose of 140-200 mg/dL in
those with no history of diabetes), diabetes without DR or DKD, and diabetes with DR and/or DKD.
All analyses were performed using Stata statistical software version 13.0 (StataCorp LLC).
Results
Of the 2964 adults with diabetes aged 40 to 80 years (mean [SD] age, 61.8 [10.0] years), 49.4%
(1464) were women, 1.8% (53) had type 1 diabetes, and 98.2% (2911) had type 2 diabetes. Indian
individuals were significantly greater in number (44.5% [1320 participants]) compared with Malay
individuals (35.5% [1052 participants]) (difference for Indian vs Malay, 9.0%; 95% CI, 6.5%-11.5%;
P < .001) and Chinese individuals (20.0% [592 participants]) (difference for Indian vs Chinese,
24.5%; 95% CI, 21.7%-26.3%; P < .001). Table 1 shows the characteristics of the participants
stratified by ethnicity. In general, Malay participants were more likely to be female and had higher
prevalence of primary education or less, smoking, hypertension, and DKD, including severe DKD
(eGFR <30 mL/min/1.73 m2); lower prevalence of drinking; higher BMI, systolic and diastolic BP, HbA1c
levels, and total cholesterol levels; and lower eGFR. Indian participants had higher prevalence of
drinking, history of CVD (including prior heart attacks), and antidiabetic medication use; higher BMI;
longer duration of diabetes; and lower levels of HDL cholesterol. In addition, Indian participants had
higher prevalence of any DR but lower prevalence of moderate and severe DR compared with the
other 2 ethnic groups; they also had had higher prevalence of normal kidney function (eGFR >60
mL/min/1.73 m2) and lower prevalence of severe DKD (eGFR <30 mL/min/1.73 m2 occurred in 1.5% of
Indian vs 3.5% of Chinese vs 5.1% of Malay individuals). Chinese participants were older, had lower
prevalence of history of CVD (including prior heart attacks), and had lower BMI measurements. Over
a median (interquartile range) follow-up of 8.8 (7.2-11.0) years, 610 participants (20.6%) died; 267
(9.0%) of these deaths were due to CVD (data not shown).
eTable 1 in the Supplement presents characteristics of participants across the 4 disease groups
(no DR and no DKD, DR only, DKD only, and both DR and DKD). Of the 2775 participants with
information on both DR and DKD, 21.0% had DR alone, 11.8% had DKD alone, and 8.3% had both DR
and DKD. Of the 4 groups, the group with both DR and DKD had higher prevalence of primary
education or less, antidiabetic medication use, hypertension, and history of CVD (including heart
attacks); higher levels of systolic BP; and longer duration of diabetes but lower levels of diastolic BP

and lower eGFR. Those with DKD alone were older and had lower levels of random blood glucose.
Those with DR alone had lower BMI, higher levels of random blood glucose, and higher HbA1c
percentage compared with the other 3 groups. Compared with the DKD-only group (11.6%), those
with DR and DKD had significantly higher prevalence of severe DKD (20.3%) (P < .001). Similarly,
compared with the DR-only group (11.8%), those with DR and DKD had higher prevalence of severe
NPDR and PDR (30.3%).
In participants with diabetes, 29.9% (862) had DR, while 20.7% (579) had DKD. Incidence of
all-cause and CVD death was significantly higher in those with DR or DKD compared with those
without (Table 2). Risks increased significantly with increasing severity of DR and DKD. In separate
multivariable models, DR and DKD were independently associated with both all-cause and CVD
mortality. Hazard ratios for all-cause and CVD mortality were 1.54 (95% CI, 1.24-1.91) and 1.74 (95%
CI, 1.27-2.40), respectively, for DR and 2.04 (95% CI, 1.64-2.56) and 2.29 (95% CI, 1.64-3.19),
respectively, for DKD. In severity analyses, moderate DR (HR, 1.78; 95% CI, 1.26-2.52) and severe
NPDR and PDR (HR, 2.75; 95% CI, 1.93-3.92) were significantly associated with all-cause mortality;
corresponding HRs for CVD mortality were 1.95 (95% CI, 1.20-3.19) for moderate DR and 3.41 (95%
CI, 2.11-5.5) for severe NPDR and PDR. With DKD, all severity categories were significantly associated
with both outcomes. Hazard ratios of all-cause and CVD mortality were 1.51 (95% CI, 1.15-1.99) and
1.57 (95% CI, 1.04-2.38) for mild to moderate DKD and 6.47 (95% CI, 4.65-9.01) and 7.84 (95% CI,
Table 1. Baseline Characteristics of 2964 Singapore Epidemiology of Eye Diseases Participants With Diabetes
Malay Indian Chinese
Characteristic (n = 1052) (n = 1320) (n = 592) P Value
Age, mean (SD), y 62.6 (9.9) 60.4 (10.0) 63.5 (9.6) <.001
Female, No. (%) 568 (54.0) 622 (47.1) 274 (46.3) .001
Primary education or less, No. (%) 859 (82.0) 813 (61.8) 389 (65.7) <.001
Current smoker, No. (%) 156 (14.9) 159 (12.1) 83 (14.0) .12
Ever consume alcohol, No. (%) 5 (0.5) 160 (12.1) 51 (8.6) <.001
Duration of diabetes, mean (SD) y 5.9 (8.2) 8.5 (9.4) 7.7 (9.0) <.001
Antidiabetic medication use, No. (%) 562 (53.5) 863 (68.0) 367 (62.7) <.001
Hypertension, No. (%) 880 (84.0) 939 (71.4) 463 (78.2) <.001
History of cardiovascular disease, No. (%) 187 (17.9) 285 (21.7) 86 (14.5) .001
History of heart attacks, No. (%) 112 (10.7) 184 (14.0) 56 (9.5) .006
Body mass index, mean (SD)a 27.6 (4.9) 27 (5.0) 25.2 (3.8) <.001
Systolic blood pressure, mean (SD), mm Hg 154.2 (23.4) 140.1 (19.8) 142.6 (19.5) <.001
Diastolic blood pressure, mean (SD), mm Hg 80.1 (11.4) 77.3 (10.2) 76.7 (9.4) <.001
Random blood glucose, mean (SD), mg/dL 178.2 (90.0) 174.6 (81.0) 176.4 (88.2) .64
Glycated hemoglobin, mean (SD), % 8.0 (1.9) 7.6 (1.6) 7.4 (1.4) <.001
Serum total cholesterol, mean (SD), mg/dL 216.6 (50.3) 189.5 (46.4) 193.3 (46.4) <.001
Serum high-density lipoprotein cholesterol,
50.3 (11.6) 38.7 (11.6) 46.4 (11.6) <.001
mean (SD), mg/dL
eGFR, mean (SD), mL/min/1.73 m2 69.4 (23.4) 84.0 (20.2) 82.9 (23.7) <.001
Chronic kidney disease, No. (%) 347 (34.2) 170 (13.3) 76 (13.5) <.001
Diabetic kidney disease severity, No. (%)
eGFR >60 mL/min/1.73 m2 669 (65.9) 1107 (86.7) 489 (86.5)
eGFR 45-60 mL/min/1.73 m2 184 (18.1) 109 (8.5) 37 (6.6)
<.001
eGFR 30-44 mL/min/1.73 m2 111 (10.9) 42 (3.3) 19 (3.4)
Abbreviation: eGFR, estimated glomerular
eGFR <30 mL/min/1.73 m2 52 (5.1) 19 (1.5) 20 (3.5)
filtration rate.
Diabetic retinopathy severity, No. (%)
SI conversion factors: To convert random blood
None 716 (71.0) 870 (67.6) 432 (74.4)
glucose to mmol/L, multiply by 0.0555; total and high-
Minimal or mild 166 (16.5) 281 (21.8) 84 (14.5) density lipoprotein cholesterol to mmol/L, multiply
Moderate 70 (6.9) 71 (5.5) 34 (5.9) .003 by 0.0259.
Severe nonproliferative diabetic retinopathy or a
56 (5.6) 66 (5.1) 31 (5.3) Calculated as weight in kilograms divided by height
proliferative diabetic retinopathy
in meters squared.

4.90-12.57) for severe DKD. There was no significant interaction by ethnicity between the risks of
DKD or DR and mortality (P for interaction >0.5 for both DKD and DR).
Figure 1 shows the joint association of DR and DKD with all-cause and CVD mortality. Compared
with controls, those with either DKD or DR had lower survival and those with both DR and DKD had
the lowest survival for both all-cause and CVD mortality. Figure 2 shows the additive interaction
between DR and DKD and its association with absolute rates of all-cause and CVD mortality. Of the
Table 2. All-Cause and CVD Mortality by Presence and Severity of DR and DKD in Those With Diabetes
All-Cause Mortality CVD Mortality

Age-, Sex-, and Age-, Sex-, and
No. at Risk Ethnicity-Adjusted Multivariable No. at Risk Ethnicity-Adjusted Multivariable
Characteristics (No. of Cases) Incidence, % HR (95% CI) HR (95% CI)a (No. of Cases) Incidence, % HR (95% CI) HR (95% CI)a
DRb
No 2018 (338) 16.8 1 [Reference] 1 [Reference] 2018 (128) 6.3 1 [Reference] 1 [Reference]
Yes 862 (242) 28.1 1.94 (1.64-2.29) 1.54 (1.24-1.91) 862 (126) 14.6 2.65 (2.07-3.40) 1.74 (1.27-2.40)
DKDc
No 2265 (314) 13.9 1 [Reference] 1 [Reference] 2265 (128) 5.7 1 [Reference] 1 [Reference]
Yes 593 (265) 44.7 2.09 (1.75-2.50) 2.04 (1.64-2.56) 593 (126) 21.3 2.67 (2.04-3.49) 2.29 (1.64-3.19)
DR severity
None 2018 (338) 16.8 1 [Reference] 1 [Reference] 2018 (128) 6.3 1 [Reference] 1 [Reference]
Minimal or mild 532 (118) 22.2 1.40 (1.14-1.73) 1.25 (0.96-1.62) 532 (53) 10.0 1.65 (1.20-2.28) 1.33 (0.90-1.96)
Moderate 175 (55) 31.4 2.38 (1.78-3.17) 1.78 (1.26-2.52) 175 (32) 18.3 3.66 (2.47-5.40) 1.95 (1.20-3.19)
Severe NPDR 155 (69) 44.5 4.12 (3.16-5.35) 2.75 (1.93-3.92) 155 (41) 26.5 6.46 (4.52-9.25) 3.41 (2.11-5.51)
or PDR
DKD severity
eGFR >60 2265 (314) 13.9 1 [Reference] 1 [Reference] 2265 (128) 5.7 1 [Reference] 1 [Reference]
mL/min/1.73 m2
eGFR 45-60 330 (114) 34.6 1.55 (1.24-1.93) 1.51 (1.15-1.99) 330 (49) 14.9 1.77 (1.26-2.50) 1.57 (1.04-2.38)
mL/min/1.73 m2
eGFR 30-44 172 (78) 45.4 1.96 (1.51-2.54) 1.82 (1.31-2.53) 172 (38) 22.1 2.63 (1.79-3.86) 2.11 (1.31-3.40)
mL/min/1.73 m2
eGFR <30 91 (73) 80.2 6.08 (4.65-7.96) 6.47 (4.65-9.01) 91 (39) 42.9 9.03 (6.15-13.27) 7.84 (4.90-12.57)
mL/min/1.73 m2
b
Abbreviations: CVD, cardiovascular disease; DR, diabetic retinopathy; DKD, diabetic P value for interaction for DR × ethnicity = .40.
kidney disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio; NPDR; c
P value for interaction for DKD × ethnicity = .30.
nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy.
a
Adjusted for age, sex, ethnicity, primary education or less, history of CVD, current
smoking, alcohol consumption, body mass index, hypertension, total and high-density
lipoprotein cholesterol, glycated hemoglobin, and diabetes duration.
Figure 1. Joint Association of Diabetic Retinopathy (DR) and Diabetic Kidney Disease (DKD) With All-Cause and Cardiovascular Disease (CVD) Mortality
A All-cause mortality B Mortality from CVD

1.0 1.0
0.8 0.8
Survival Proportion
Survival Proportion
0.6 0.6
0.4 0.4
No DR or DKD
DR alone
0.2 DKD alone 0.2
DR and DKD
0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
Time, y Time, y
No. at risk No. at risk
No DR or DKD 1633 1602 1570 1468 1147 422 141 No DR or DKD 1633 1602 1570 1468 1147 422 141
DR alone 584 574 553 504 394 117 35 DR alone 584 574 553 504 394 117 35
DKD alone 327 303 277 247 190 120 35 DKD alone 327 303 277 247 190 120 35
DR and DKD 231 208 183 160 126 63 22 DR and DKD 231 208 183 160 126 63 22

2775 participants with diabetes and data on DR and DKD, 58.9% had neither DR nor DKD, 21% had
DR alone, 11.8% had DKD alone, and 8.3% had both DR and DKD. The absolute all-cause mortality
was lowest in those without DR or DKD (background rate of 12%). The mortality rate in participants
with DR was slightly increased (18.5%, ie, background rate plus additional 6.5% associated with DR),
but was substantially increased in those with DKD (39.1%, ie, background rate plus additional 27.1%
associated with DKD). On top of the combined mortality rate associated with diabetes, DR, and DKD,
an additional 5.1% (50.7% − 12.0% − 6.5% − 27.1%) was associated with the interaction between DR
and DKD. For absolute CVD mortality, the background rate was 4.2%, an additional 5.2% was
associated with DR, an additional 12.6% was associated with DKD, and an additional 5.3% was
associated with the interaction between DR and DKD.
In multivariable models examining the joint association of DR and DKD with mortality (Table 3),
compared with those without either condition, the HRs of all-cause and CVD mortality were 1.89
(95% CI, 1.40-2.57) and 2.26 (95% CI, 1.42-3.61), respectively, for DKD alone; 1.38 (95% CI, 1.03-1.86)
and 1.64 (95% CI, 1.06-2.56), respectively, for DR alone; and 2.76 (95% CI, 2.05-3.72) and 3.41 (95%
CI, 2.19-5.32), respectively, for those with both DKD and DR. Other risk factors that were significant
for both outcomes in the multivariable model were age, male sex, history of CVD, and HbA1c
percentage. In addition, Indian ethnicity was inversely associated with all-cause mortality (eTable 2
in the Supplement). No substantial additive interaction was observed for either mortality outcome
with a RERI estimate of 0.49 (95% CI, −0.29 to 1.27; P = .20) for all-cause mortality and 0.51 (95% CI,
−0.83 to 1.85; P = .50) for CVD mortality. Interaction between DR and DKD on a multiplicative scale
was also not significant for either outcome. It is possible that the lack of additive and multiplicative
association of both variables with mortality might be due to pooling together all cases of DKD and DR
Figure 2. Additive Interaction of Diabetic Retinopathy (DR) and Diabetic Kidney Disease (DKD) on Absolute All-Cause and Cardiovascular Disease (CVD) Mortality
Rates
Background rate Mortality associated with DKD Mortality associated with DR Excess mortality (interaction effect)
A All-cause mortality B Mortality from CVD

20 20
Absolute Incidence, %
Absolute Incidence, %
15 15
10 10
5 5
0 0
Background DR DKD DK and DKD Background DR DKD DK and DKD
Table 3. Joint Association of DR and DKD With Adjusted All-Cause and CVD Mortality Risk
All-Cause Mortality CVD Mortality

No. at Risk No. at Risk
Diagnosis (No. of Cases) Incidence, % Multivariable HR (95% CI)a (No. of Cases) Incidence, % Multivariable HR (95% CI)a
No DR and no DKD 1633 (196) 12.0 1 [Reference] 1633 (68) 4.2 1 [Reference]
DR alone 584 (108) 18.5 1.38 (1.03-1.86) 584 (55) 9.4 1.64 (1.06-2.56)
DKD alone 327 (128) 39.1 1.89 (1.40-2.57) 327 (55) 16.8 2.26 (1.42-3.61)
Both DR and DKDb 231 (117) 50.7 2.76 (2.05-3.72) 231 (63) 27.3 3.41 (2.19-5.32)
b
Abbreviations: CVD, cardiovascular disease; DR, diabetic retinopathy; DKD, diabetic P value for interaction (DR × DKD) for all-cause mortality = .80; P value for interaction
kidney disease; HR, hazard ratio. (DR × DKD) for CVD mortality = .78
a
Adjusted for age, sex, ethnicity, primary education or less, history of CVD, current
smoking, alcohol consumption, body mass index, hypertension, total and high-density
lipoprotein cholesterol, glycated hemoglobin, and diabetes duration.

without regard for the disease severity. To account for severity, in a sensitivity analysis, we assessed
interaction between severity categories of DR and DKD in association with all-cause mortality. Similar
to the main analysis (DR and DKD) presented in Table 3, there was no significant interaction between
severity of DR and DKD in association with all-cause mortality.
In a supplementary analysis, we compared the association of presence of diabetes and DR and
DKD with absence of diabetes on mortality. In survival analysis, 5-year survival ranged from 97% in
the reference group to 96% in the group with prediabetes and 95% in the group with diabetes
without DR and DKD (log-rank P > .10) but was significantly lower in those with DR and/or DKD (84%;
log-rank P < .001). In regression models, compared with controls, the multivariable HRs of all-cause
and CVD mortality in those with DR and/or DKD were 2.12 (95% CI, 1.76-2.56) and 2.65 (95% CI,
1.97-3.58), respectively. Hazard ratios of all-cause and CVD deaths in prediabetes (HR, 0.95; 95% CI,
0.80-1.14 and HR, 0.93; 95% CI, 0.69-1.25, respectively) and diabetes without DR or DKD (HR, 1.12;
95% CI, 0.91-1.38 and HR, 1.03; 95% CI, 0.73-1.47) were not significant.
Discussion
In a population-based sample of multiethnic Asian adults, we found that (1) the presence of DR and
DKD in those with diabetes was independently associated with increased risk of all-cause and CVD
mortality; (2) risk increased with increasing severity, with even mild or minimal DR and moderate
DKD associated with increased risks; and (3) in joint association models, although those with both DR
and DKD had the highest rate of all-cause and CVD mortality (50.7% and 27.3%, respectively), DKD
alone contributed to a substantial amount of excess all-cause and CVD mortality (27.1% and 12.6%,
respectively) followed by DR alone (6.5% and 5.2%, respectively), but there were no significant
interactions either on additive or multiplicative scale between DR and DKD on all-cause or CVD
mortality. To our knowledge, this is the first study in an Asian population that assessed the
association of DR and DKD with all-cause and CVD mortality.
The mortality rate reported in the current study of 20.6% over a median follow-up of 8.8 years
was high. This is consistent with a previous study20 that reported a higher prevalence of
cardiovascular risk factors and premature deaths in rapidly transitioning Southeast Asian countries
compared with countries experiencing long-standing affluence such as Japan and South Korea. It is
also consistent with the 2014 World Health Organization global status report that showed premature
deaths from noncommunicable diseases to be 19.6% in Malaysia, 23.1% in Indonesia, and 27.9% in
the Philippines compared with 12.0% in the United Kingdom.21
In the current study, we found both presence and severity of DKD to be significantly associated
with both all-cause and CVD mortality. Compared with participants with eGFR greater than 60
mL/min/1.73 m2, even those with eGFR from 45 to 60 mL/min/1.73 m2 had 1.51 times increased risk
of all-cause mortality and 1.57 times increased risk of CVD mortality. With moderate or severe DKD,
the risk increased to 6.47 times for all-cause mortality and to 7.84 times for CVD mortality. Few
studies conducted in the United States and Europe have shown increased risk of all-cause and CVD
mortality in those with diabetes and DKD.4,5,9 In a US study including insurance enrollees, Nichols
et al4 showed that the adjusted incidence of all-cause mortality increased with increasing severity of
DKD (decreasing levels of eGFR), similar to our study finding. In the MADIABETES Study5 in Europe,
DKD was associated with 2.11 times increased risk of all-cause mortality and 1.82 times increased risk
of CVD mortality.
We found severe NPDR and PDR to be associated with 2.75 times higher risk of all-cause
mortality and 3.41 times higher risk of CVD mortality. A meta-analysis8 of published prospective
studies showed the risk of all-cause mortality associated with NPDR was 1.38 (95 % CI, 1.11-1.70) and
the risk associated with PDR was 2.32 (95% CI, 1.75-3.06). In the same study, participants with DR
had 1.74 times increased risk of all-cause mortality for stroke. In the Reykjavik Study,6 those with both
DR and DN had 2 times increased risk of all-cause mortality (95% CI, 1.22-3.31).

In the current study, in joint association models, beyond the background risk, substantial excess
mortality was associated with DKD (27.1% for all-cause mortality and 12.6% for CVD mortality) and
to some extent with DR (6.5% for all cause and 5.2% for CVD), but there was no significant excess risk
associated with the interaction of DR and DKD. Furthermore, our results suggest that risk of death
(including CVD deaths) in those with diabetes but without DR and/or DKD were similar to those
without diabetes but increased substantially when there was DKD and/or DR. These findings are
consistent with several previous studies including both type 122,23 and type 29,24 diabetes. In the
Pittsburgh Epidemiology of Diabetes Complications Study,22 the 20-year risk of mortality in those
with type 1 diabetes but without renal impairment during follow-up was similar to that of the general
population. Similarly, in the FinnDiane Study23 mortality rates in individuals with normoalbuminuric
type 1 diabetes were not significantly different from those of the general population. A Swedish
registry-based study24 reported that mortality in persons with type 2 diabetes varied greatly from
substantial to lower risks of death depending on age, glycemic control, and renal complications.
Subgroups that were younger, had poor glycemic control, and had renal complications had excess
risk. Afkarian et al9 found that, on the absolute scale, compared with those without diabetes and
DKD (background risk = 7.7%), those with diabetes alone had 3.9% increased risk, those with DKD
alone had 9.5% increased risk, and those with both diabetes and DKD had a 23% increased risk of
mortality. Authors concluded that DKD in diabetes was associated with substantially increased
mortality risk and, in the absence of DKD, diabetes was not associated with a large increase in
mortality risk.9 Our findings of excess mortality in those with diabetes and DKD support results from
the Swedish study24 and Afkarian et al9 and extend the previous works by evaluating the influence
of DR in addition to DKD.
Strengths of our study include a multiethnic Asian population with long follow-up and
information on both all-cause and CVD mortality and information on microvascular complications,
including DR and DKD, which were assessed using objective measures. Our study sample is fairly
representative of Singapore’s general population in terms of age distribution, housing type, and
socioeconomic status according to the 2000 Singapore census.11,12
Limitations
Our study has some limitations. First, our definition of diabetes was based on random glucose level,
and prediabetes was based on HbA1c level alone. This would have resulted in some misclassification,
but the bias would be nondifferential and would be similar across both outcomes. Second,
information on albuminuria, another important indicator of DKD, was missing in most of the Malay
participants. Therefore, we were unable to study the association of albuminuria with risk of mortality.
Third, differences in risk factor profile and follow-up duration among the 3 ethnic groups may have
also influenced the association of DR and DKD with mortality. Fourth, although our sample size of
2880 participants with 580 deaths had greater than 99% power to detect HRs of 1.54 and 2.04 for
association of DR and DKD, respectively, with all-cause mortality, the power to detect interaction
between DR and DKD was limited.
Conclusions
Our study findings showed that the risk of all-cause and CVD mortality was substantially higher in
participants with DKD, and to some extent in those with DR. Our findings suggest that regular
screening of diabetic participants for DR and DKD and close monitoring and management of these
conditions may reduce the risk of all-cause and CVD death in this Asian population.

ARTICLE INFORMATION
Accepted for Publication: February 12, 2019.
Published: March 29, 2019. doi:10.1001/jamanetworkopen.2019.1540
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Sabanayagam
C et al. JAMA Network Open.
Corresponding Author: Tien Y. Wong, MD, PhD, Singapore National Eye Centre, 11 Third Hospital Ave, Singapore
168751 (ophwty@nus.edu.sg).
Author Affiliations: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore (Sabanayagam,
Chee, Banu, Cheng, Wong); Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical
School, Singapore (Sabanayagam, Cheng, Wong); Khoo Tech Puat Hospital, Singapore (Lim); Department of
Medicine, Yong Loo Lin School of Medicine, Singapore, National University of Singapore, Singapore (Tai);
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (Coffman).
Author Contributions: Dr Sabanayagam had full access to all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.
Concept and design: Sabanayagam, Wong.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Sabanayagam, Chee, Banu.
Critical revision of the manuscript for important intellectual content: Sabanayagam, Cheng, Lim, Tai,
Coffman, Wong.
Statistical analysis: Chee.
Obtained funding: Cheng, Coffman.
Administrative, technical, or material support: Banu, Cheng.
Supervision: Sabanayagam, Wong.
Conflict of Interest Disclosures: Dr Wong reported personal fees from Allergan, Bayer, Boehringer Ingelheim,
Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), and Roche outside the submitted work; and
serving as cofounder of plano and EyRiS. No other disclosures were reported.
Funding/Support: This study was supported by the National Medical Research Council (grants OFLCG/001/2017,
0796/2003, 1149/2008, and STaR/0003/2008) and the Biomedical Research Council (grant 08/1/35/19/550).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Additional Information: As the study involves human participants, the data cannot be made freely available in the
article, the supplemental files, or a public repository owing to ethical restrictions. Nevertheless, the data are
available from the Singapore Eye Research Institutional Ethics Committee for researchers who meet the criteria for
access to confidential data. Interested researchers can send data access requests to the Singapore Eye Research
Institute at seri@seri.com.sg.
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SUPPLEMENT.
eTable 1. Baseline Characteristics of SEED Participants Across the 4 Disease Groups
eTable 2. Association of Risk Factors With All-Cause and CVD Mortality (Joint Effect of DR and DKD Model)

Diabetic Retinopathy

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Original Investigation | Diabetes and Endocrinology

Association of Diabetic Retinopathy and Diabetic Kidney Disease

Abstract Key Points

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JAMA Network Open. 2019;2(3):e191540. doi:10.1001/jamanetworkopen.2019.1540

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Assessment of Other Factors Associated With Mortality

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All-Cause Mortality CVD Mortality

A All-cause mortality B Mortality from CVD

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A All-cause mortality B Mortality from CVD

All-Cause Mortality CVD Mortality

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