Global_Prevalence_and_Major_Risk_Factors_of_Diabetic_Retinopathy

Global Prevalence and Major Risk Factors of Diabetic Retinopathy

J OANNE W.Y.Y AU ,MBBS 1S OPHIE L.R OGERS ,MEPID 1R YO K AWASAKI ,PHD 1

E COSSE L.L AMOUREUX ,PHD 1,2

J ONATHAN W.K OWALSKI ,PHARMD 3T OKE B EK ,PHD 4

S HIH -J EN C HEN ,PHD 5

J ACQUELINE M.D EKKER ,PHD 6A STRID F LETCHER ,PHD 7J AKOB G RAUSLUND ,MD 8S TEVEN H AFFNER ,PHD 9

R ICHARD F.H AMMAN ,PHD 10M.K AMRAN I KRAM ,PHD 11T AKAMASA K AYAMA ,MD 12B ARBARA E.K.K LEIN ,PHD 13R ONALD K LEIN ,PHD 13

S ANNAPANENI K RISHNAIAH ,MD 14K ORAPAT M AYURASAKORN ,MD 15J OSEPH P.O ’H ARE ,MD 16

T REVOR J.O RCHARD ,MD 17M ASSIMO P ORTA ,PHD 18M OHAN R EMA ,MD 19M ONIQUE S.R OY ,MD 20T ARUN S HARMA ,MD 21J ONATHAN S HAW ,PHD 22H UGH T AYLOR ,AC 23

J AMES M.T IELSCH ,PHD 24R OHIT V ARMA ,MD 25J IE J IN W ANG ,PHD 26N INGLI W ANG ,MD 27S HEILA W EST ,PHD 28L IANG X U ,PHD 29

M IHO Y ASUDA ,PHD 30X INZHI Z HANG ,PHD 31P AUL M ITCHELL ,PHD 26T IEN Y.W ONG ,PHD 1,2,32

FOR THE M ETA -A NALYSIS FOR E YE

D ISEAS

E (META-EYE)S TUDY G ROUP *

OBJECTIVE d To examine the global prevalence and major risk factors for diabetic retino-pathy (DR)and vision-threatening diabetic retinopathy (VTDR)among people with diabetes.RESEARCH DESIGN AND METHODS d A pooled analysis using individual participant data from population-based studies around the world was performed.A systematic literature review was conducted to identify all population-based studies in general populations or indi-viduals with diabetes who had ascertained DR from retinal photographs.Studies provided data for DR end points,including any DR,proliferative DR,diabetic macular edema,and VTDR,and also major systemic risk factors.Pooled prevalence estimates were directly age-standardized to the 2010World Diabetes Population aged 20–79years.

RESULTS d A total of 35studies (1980–2008)provided data from 22,896individuals with diabetes.The overall prevalence was 34.6%(95%CI 34.5–34.8)for any DR,6.96%(6.87–7.04)for proliferative DR,6.81%(6.74–6.89)for diabetic macular edema,and 10.2%(10.1–10.3)for VTDR.All DR prevalence end points increased with diabetes duration,hemoglobin A 1c ,and blood pressure levels and were higher in people with type 1compared with type 2diabetes.CONCLUSIONS d There are approximately 93million people with DR,17million with proliferative DR,21million with diabetic macular edema,and 28million with VTDR worldwide.Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR.These data highlight the substantial worldwide public health burden of DR and the importance of modi ?able risk factors in its occurrence.This study is limited by data pooled from studies at different time points,with different methodologies and population characteristics.

Diabetes Care 35:556–564,2012

D

iabetic retinopathy (DR)is the lead-ing cause of blindness among working-aged adults around the world (1).Despite the signi ?cance of this problem,and the rising prevalence of diabetes no-tably in emerging Asian countries such as India and China (2,3),there are few precise contemporary estimates of the worldwide prevalence of DR,particularly severe vision-threatening stages of the dis-ease,including proliferative DR (PDR)and diabetic macular edema (DME).

Previous individual studies have shown considerable variability in DR prevalence estimates among individuals with both diagnosed and undiagnosed diabetes,with rates ranging from 17.6%in a study in India (4)to 33.2%in a large U.S.study (5).Differences in study meth-odologies,population characteristics,and ascertainment and classi ?cation of DR have made direct comparisons between studies dif ?cult.A meta-analysis summa-rized the U.S.prevalence of DR (6),but this study was limited to individuals with type 2diabetes aged 40years and older,and the data were largely derived from individuals of Caucasian background,with limited data on other racial groups.More important,this study did not in-clude Asians,and an estimated 100mil-lion people in China and 80million in India have diabetes (2,3).

Although the major risk factors for DR (e.g.,hyperglycemia,hypertension,dyslipidemia)have been examined in many epidemiologic studies and clinical trials (1),there is considerable variation in the consistency,pattern,and strength of these risk factors.This is particularly so with respect to severe stages of DR,be-cause individual studies generally lack

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From the 1Centre for Eye Research Australia,Uni-versity of Melbourne,Royal Victorian Eye and Ear Hospital,Melbourne,Victoria,Australia;the 2

Singapore Eye Research Institute,Singapore National Eye Centre,Singapore,Singapore;3

Global Health Outcomes Strategy and Research,Allergan Inc.,Irvine,California;the 4Department of Ophthalmology,Aarhus University Hospital,Aarhus,Denmark;the 5Department of Ophthal-mology,Taipei Veterans General Hospital,Na-tional Yang-Ming University,Taipei,Taiwan;the 6

Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care

Research,VU University Medical Center,Am-sterdam,the Netherlands;the 7Department of Ep-idemiology and Population Health,London School of Hygiene and Tropical Medicine,London,U.K.;the 8Department of Ophthalmology,Odense University Hospital,Odense,Denmark;9

Shavano Park,Texas;the 10Department of Epi-demiology,Colorado School of Public Health,Aurora,Colorado;the 11Departments of Epidemi-ology and Ophthalmology,Erasmus Medical Cen-ter,Rotterdam,the Netherlands;the 12National Cancer Center/Department of Neurosurgery,Ad-vanced Molecular Epidemiology Research Institute,Faculty of Medicine,Yamagata University,Yama-gata,Japan;the 13Department of Ophthalmology and Visual Sciences,University of Wisconsin,Madison,Wisconsin;the 14Center for Clinical Epidemiology and Biostatistics,L V Prasad Eye Institute,Hyderabad,India;the 15Department of Social Medicine,Samutsakhon General Hospital,Samutsakhon,Thailand;the 16Clinical Sciences Research Institute,Warwick Medical School,University of Warwick,Coventry,U.K.;the 17

Department of Epidemiology,Graduate School of Public Health,University of Pittsburgh,Pittsburgh,Pennsylvania;the 18Department of Internal

556D IABETES C ARE ,VOLUME 35,M ARCH https://www.wendangku.net/doc/0512504868.html,

E p i d e m i o l o g y /H e a l t h S e r v i c e s R e s e a r c h

O R I G I N A L

A R T I C L E

power to detect signi?cant associations for PDR and DME.Thus,the importance of modi?able risk factors for these vision-threatening stages of DR remains unclear.

Generating a broader and more pre-cise estimate of the prevalence of DR and its relationship with major modi?able risk factors,speci?cally for vision-threatening DR(VTDR),is crucial for guiding public health education and optimal clinical man-agement of diabetes.We therefore con-ducted an individual participant analysis pooling population-based studies from the U.S.,Australia,Europe,and Asia to de-termine the prevalence of DR and its sight-threatening end points(PDR and DME)as well as their relationship to key risk factors.

RESEARCH DESIGN AND METHODS

Study selection and

inclusion criteria

We?rst performed a systematic literature review to identify all population-based studies that had ascertained DR from fundus(retinal)photographs.English-language articles were retrieved using Medline,EMBASE,Current Contents, EBSCO,JSTOR,and Science Direct using the following search terms:“diabetes”and “retinopathy”or“diabetic macular edema”and“population.”We identi?ed 3,539citations identi?ed to10February 2010.Irrelevant and duplicate citations were excluded after a review of the titles and abstracts.The full texts of the remain-ing articles were reviewed to ensure stud-ies met inclusion and exclusion criteria. In addition,we manually reviewed bib-liographies of included articles and con-sulted with colleagues to identify other potentially relevant population-based studies that had assessed DR from fundus

photographs but which may not have

published results or in which grading for

DR was still ongoing.

Studies were excluded if they were

not population-based and/or if fundus

photographs were not undertaken to

ascertain DR.Two investigators(J.Y.,

R.Kaw.)independently selected the studies

for inclusion.Disagreements between the

two were resolved by adjudication with

two additional reviewers(S.R.,T.Y.W.).

We identi?ed58population-based

studies in which fundus photographs

were potentially assessed for DR.Princi-

pal investigators of these identi?ed stud-

ies were then invited for collaboration in

this individual participant meta-analysis.

We requested individual participant data

regarding presence and severity of DR,

DME status,age,sex,ethnicity,diabetes

type and duration,hemoglobin A1c

(HbA1c),systolic and diastolic blood pres-

sure,lipid pro?le,cigarette smoking sta-

tus,BMI,and current use of diabetes,

antihypertensive,and lipid-lowering

medications.

Investigators from35of the58iden-

ti?ed studies provided data for this analysis

(Table1).Investigators of the remaining23

studies could not or did not want to partic-

ipate,or did not respond to repeated invi-

tations.All studies had institutional board

review approval and provided appropri-

ately deidenti?ed data for analysis.

DR assessment and de?nition

Retinal photography was performed in

all35studies according to standardized

protocols.Most of the studies graded for

DR using the Early Treatment Diabetic

Retinopathy Scale(ETDRS)and its mod-

i?cation or the American Academy of

Ophthalmology(AAO)International

Clinical Diabetic Retinopathy Disease Se-

verity Scale(Table1).

DR severity was categorized as non-

PDR(NPDR;level20through level53)

and PDR(level$60).DME was de?ned as

absent or present.The four primary out-

comes for this study were based on the

severity in the worse eye or of the single

eye that was photographed.Any DR was

de?ned as the presence of NPDR,PDR,

DME,or any combination thereof;and

VTDR was de?ned as the presence of

PDR and/or DME.These composite out-

comes serve as the primary outcomes for

this report,which respectively,indicate

presence of any DR and severe DR likely

to result in vision loss if left untreated.

De?nition of diabetes and major

risk factors

Not all studies reported information on

diabetes type.If data on age at diagnosis of

diabetes were available in these studies,

participants were classi?ed as type1if

they were diagnosed before age30years

and as type2if they were diagnosed with

diabetes after age30years,as previously

used in one study(7).Hypertension was

de?ned in subjects with a blood pressure

.140/90or who reported being on treat-

ment for hypertension.Serum cholesterol

was categorized into levels,4.0or$4.0

mmol/L.

Appraisal of study methodology

and heterogeneity

Study methodology and heterogeneity

were assessed independently by two inves-

tigators(J.Y.,R.Kaw.).Any disagreement

was settled by consensus or adjudication

with a third reviewer(S.R.).Studies were

assessed for a list of attributes as de?ned

in Supplementary Table1.Studies with

similar methodologies and rigorous

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Medicine,University of Turin,Turin,Italy;the 19Department of Ophthalmology,Madras Di-abetes Research Foundation,Chennai,India;the 20Institute of Ophthalmology and Visual Science, University of New Jersey,Newark,New Jersey; 21Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya,Chennai,Tamil Nadu,India; the22Baker IDI Heart and Diabetes Institute, Melbourne,Victoria,Australia;the23Melbourne School of Population Health,University of Mel-bourne,Melbourne,Victoria,Australia;the24De-partment of International Health,Johns Hopkins Bloomberg School of Public Health,Baltimore, Maryland;the25Doheny Eye Institute,Keck School of Medicine,University of Southern California,Los Angeles,California;the26Centre for Vision Research,Westmead Millennium Institute, University of Sydney,Sydney,New South Wales, Australia;27Beijing Tongren Hospital,Capital

Medical University,Beijing,China;the28Wilmer

Eye Institute,Johns Hopkins Hospital,Baltimore,

Maryland;the29Beijing Institute of Ophthalmology,

Beijing Tongren Hospital,Capital Medical

University,Beijing,China;the30Department of

Ophthalmology,Graduate School of Medical

Sciences,Kyushu University,Fukuoka,Japan;the

31Division of Diabetes Translation,National

Center for Chronic Disease Prevention and Health

Promotion,Centers for Disease Control and Pre-

vention,Atlanta,Georgia;and the32Department

of Ophthalmology,Yong Loo Lin School of

Medicine,National University of Singapore,

Singapore,Singapore.

Corresponding author:Tien Y.Wong,ophwty@nus

.edu.sg.

Received25October2011and accepted5December

2011.

DOI:10.2337/dc11-1909

This article contains Supplementary Data online at

https://www.wendangku.net/doc/0512504868.html,/lookup/suppl/

doi:10.2337/dc11-1909/-/DC1.

*A complete list of the study group can be found in

the Supplementary Data online.

The content is solely the responsibility of the au-

thors and does not necessarily re?ect the of?cial

views of the National Eye Institute or the Na-

tional Institutes of Health.The?ndings and

conclusions in this article are those of the au-

thors and do not necessarily represent the of-

?cial position of the Centers for Disease Control

and Prevention.

?2012by the American Diabetes Association.

Readers may use this article as long as the work is

properly cited,the use is educational and not for

pro?t,and the work is not altered.See http://

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T a b l e 1d C h a r a c t e r i s t i c s o f d i a b e t i c p a r t i c i p a n t s i n e a c h s t u d y p o p u l a t i o n (N =35)

S t u d y C o u n t r y

Y e a r o f p h o t o T 2D M (%)M a l e (%)M e a n a g e (r a n g e )

E t h n i c i t y (%)

F u n d u s p h o t o g r a p h y

G r a d i n g m e t h o d

E y e s /s u b D i l a t e d M y d r i a s i s

F i e l d D e g S t e r e o D R D M E

T 1D M o n l y E D C U .S .1986–1988050.627.6(8–48)98E U ,2A A 2!!330!E T D R S C S M E F y n D e n m a r k 2007–2008059.858.6(37–88)100E U 2!!945X E T D R S C S M E N e w J e r s e y 725U .S .1993–1998040.427.5(3–60)100A A 2!!730!E D T R S O t h e r 1

T u r i n I t a l y

2006–2008

053.029.5(7–68)100E U 2!X 245X A A O

N o d a t a

T 2D M o n l y A a r h u s D e n m a r k 200010056.565.0(32–90)100E U 2!!260X E D T R S C S M E A D D I T I O N D e n m a r k 200310056.563.8(43–78)100E U 2!!260X E T D R S ?C S M E C U R E S E S I n d i a 2001–200210044.850.8(20–85)100A S 2!!430!E T D R S C S M E F u n a g a t a J a p a n 2000–200210057.367.1(37–92)100A S 1X X 145X E T D R S C S M E H o o r n N e t h e r l a n d s 1989–199210045.964.9(50–76)100E U 2!!245X E u r o d i a b N o d a t a S a m u t s a k h o n T h a i l a n d 200710028.359.2(27–86)100A S 2X X 730!O t h e r 2

N o d a t a S a n L u i s V a l l e y U .S .1984–198810043.358.6(22–75)66H I ,34E U 2!!330!E T D R S C S M E U K A D S U .K .

2004–2007

10053.164.3(17–96)59E U ,41A S 2!X 245!

U K N S C G

U K N S C G

T 1D M a n d T 2D M A u s D i a b A u s t r a l i a 1999–200096.551.463.0(25–91)92E U ,5A S 2X X 2.45X E T D R S O t h e r 3

B D E S U .S .1988–199088.344.465.8(44–86)99E U 2!!730!E T D R S

C S M E H a n d a n C h i n a 2006–200799.735.957.6(30–83)100A S 2!!245X E T

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E L A L E S U .S .2000–200397.643.858.5(40–90)100H I 2!!730!E T D R S C S M E S a n A n t o n i o U .S .1985–198697.840.654.4(31–70)82H I ,18E U 2!!730!E T D R S N o d a t a W E S D R U .S .

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https://www.wendangku.net/doc/0512504868.html,

Global prevalence and risk factors of DR

ophthalmologic de ?nitions were de ?ned as those with a score of $9(maximum,11).

Statistical analysis

Data from each study were checked for consistency in variable de ?nition before pooling,and where appropriate,data were recategorized according to a common de ?nition.Race/ethnicity was categorized as Caucasian (Europeans and those of European origin),Asian (Chinese,Chinese American,Japanese,Malay,Indian,or peo-ple of Asian origin),African American,and Hispanic (Mexican Americans).Asians were further subdivided into Chinese or Japanese origin,and South Asian (Indian,Malay,South Indian,Thai,etc).Study-speci ?c and pooled-data estimates of the prevalence of any DR,PDR,DME,and VTDR were directly age-standardized to the 2010world diabetes population aged 20–79years (8)using age strata 20–39,40–59,and 60–79years.We calculated 95%CIs for standardized prevalence rates using a normal approximation and Breslow-Day standard errors,after being modi ?ed to use a binomial assumption for the variance of the crude stratum-speci ?c rates (9).

Initial analyses included data from all 35studies,and subsequent analyses were performed using only data from studies with similar methodologies and outcome de ?nitions (i.e.,studies with a score of $9).Results from the latter analyses are presented throughout this report because of their similar methodologies.

Poisson regression models with ro-bust error variance were used to estimate relative risks for DR,PDR,DME,and VTDR by categories of risk factors (e.g.,hypertension,duration),adjusting for age (continuous,from 20–79years),race (?ve categories),hypertension (yes/no),HbA 1c (four categories)and study,as ap-propriate.We also performed supple-mentary analyses on the interaction between diabetes type and duration,us-ing people with type 2diabetes for ,10years as the reference group.Including sex in regression models generally did not improve the model ?t and did not appreciably alter the results.

Global estimates

The total number of patients with diabe-tes with DR aged between 20and 79years was estimated by multiplying the 2010country-speci ?c totals of people with di-abetes (sourced from Diabetes Atlas)by our pooled racial group –speci ?c rates of DR using the most predominant racial

T a b l e 1d C o n t i n u e d

S t u d y C o u n t r y

Y e a r o f p h o t o T 2D M (%)M a l e (%)M e a n a g e (r a n g e )E t h n i c i t y (%)F u n d u s p h o t o g r a p h y

G r a d i n g m e t h o d

E y e s /s u b D i l a t e d M y d r i a s i s

F i e l d D e g S t e r e o D R D M E

D M t y p e n o t r e p o r t e d a n d c o u l d n o t b e d e d u c e d A R I C U .S .1993–1995N R 47.560.8(50–71)64

E U ,36A A 1X X 145X E T D R S C S M E B M E S A u s t r a l i a 1992–1994N R 53.067.9(51–96)97E U ,2A S 2!!630!E T D R S C S M E M E S A

U .S .2002–2004

N R 52.065.5(46–86)36A A ,30H I ,22E U ,12A S 2X X 245X E D T R S

O t h e r 7

R o t t e r d a m N e t h e r l a n d s 1990–1993N R 39.472.9(55–96)96E U ,4O 2!!135!O t h e r 5

N o d a t a S h i h p a i T a i w a n 1999–2000N R 61.171.7(65–90)100A S 2!!235X A A O C S M E S i M E S S i n g a p o r e

2004–2006N R 43.362.6(40–80)100A S

2!X 245X

E T D R S

O t h e r 6

A A ,A f r i c a n A m e r i c a n ;A A O ,A m e r i c a n A c a d e m y o f O p h t h a l m o l o g y ;A S ,A s i a n ;C S M E ,c l i n i c a l l y s i g n i ?c a n t m a c u l a r e d e m a ;D M ,d i a b e t e s m e l l i t u s ;E T D R S ,E a r l y T r e a t m e n t D i a b e t i c R e t i n o p a t h y S t u d y ;E U ,C a u c a s i a n ,E u r o p e a n a n c e s t r y ;E y e s /s u b ,e y e s p e r s u b j e c t ;H I ,H i s p a n i c ;N R ,n o t r e p o r t e d a n d c o u l d n o t b e d e d u c e d ;O ,o t h e r s ;U K N S C G ,U n i t e d K i n g d o m N a t i o n a l S c r e e n i n g C o m m i t t e e g u i d e l i n e s .A D D I T I O N ,A n g l o -D a n i s h -D u t c h s t u d y o f I n t e n s i v e T r e a t m e n t i n P e o p l e w i t h S c r e e n -d e t e c t e d D i a b e t e s i n P r i m a r y C a r e ;A R I C ,A t h e r o s c l e r o s i s R i s k i n C o m m u n i t i e s S t u d y ;A n d h r a P r a d e s h ,A n d h r a P r a d e s h E y e D i s e a s e S t u d y ;A u s D i a b ,A u s t r a l i a n D i a b e t e s ,O b e s i t y a n d L i f e s t y l e S t u d y ;

B D E S ,B e a v e r D a m E y e S t u d y ;B E S ,B a l t i m o r e E y e S u r v e y ;B M E S ,B l u e M o u n t a i n s E y e S t u d y ;B e i j i n g ,B e i j i n g E y e S t u d y ;

C H S ,C a r d i o v a s c u l a r H e a l t h S t u d y ;C U R E S E S ,C h e n n a i U r b a n R u r a l E p i d e m i o l o g y S t u d y (E y e S t u d y );E

D C ,P i t t s b u r g h

E p i d e m i o l o g y o f D i a b e t e s C o m p l i c a t i o n s S t u d y ;E U R E Y E ;E u r o p e a n E y e S t u d y ;

F u n a g a t a ,F u n a g a t a S t u d y ;H a n d a n ,H a n d a n E y e S t u d y ;H i s a y a m a ,H i s a y a m a S t u d y ;H o o r n ,H o o r n S t u d y ;L A L E S ,L o s A n g e l e s L a t i n o E y e S t u d y ;M E S A ,M u l t i e t h n i c S t u d y o f A t h e r o s c l e r o s i s ;M V I P ,M e l b o u r n e V i s i o n I m p a i r m e n t P r o j e c t ;N H A N E S ,N a t i o n a l H e a l t h a n d N u t r i t i o n E x a m i n a t i o n S u r v e y ;P r o y e c t o V E R ,P r o y e c t o V i s i o n a n d E y e R e s e a r c h ;R o t t e r d a m ,R o t t e r d a m S t u d y ;S i M E S ,S i n g a p o r e M a l a y E y e S t u d y ;S I N D I ,S i n g a p o r e I n d i a n E y e S t u d y ;S N D R E A M S ,S a n k a r a N e t h r a l a y a D i a b e t i c R e t i n o p a t h y E p i d e m i o l o g y a n d M o l e c u l a r

G e n e t i c s S t u d y ;T 1D M ,t y p e 1d i a b e t e s ;T 2D M ,t y p e 2d i a b e t e s ;U K A D S ,U K A s i a n D i a b e t e s S t u d y ;W E S D R ,W i s c o n s i n E p i d e m i o l o g i c S t u d y o f D i a b e t i c R e t i n o p a t h y .*D M t y p e n o t r e p o r t e d b y s t u d y b u t c o u l d b e d e d u c e d f r o m p r o v i d e d i n f o r m a t i o n r e g a r d i n g s u b j e c t ’s a g e a n d d u r a t i o n o f d i a b e t e s :T y p e 1d i a b e t e s w a s a s s u m e d i f s u b j e c t w a s a g e d l e s s t h a n 30y e a r s a t d i a g n o s i s ;t y p e 2d i a b e t e s w a s a s s u m e d i f s u b j e c t w a s a g e d 30y e a r s o r o l d e r a t d i a g n o s i s .?E T D R S i n c l u d e s m o d i ?e d W E S D R ,m o d i ?e d A i r l i e

H o u s e ,m o d i ?e d E T D R S .?7E u r o p e a n c o u n t r i e s :N o r w a y ,E s t o n i a ,U K ,F r a n c e ,

I t a l y ,G r e e c e ,S p a i n .1O t h e r :M a c u l a r e d e m a (M E )=r e t i n a l t h i c k e n i n g w i t h i n 1d i s c d i a m e t e r o f c e n t e r o f m a c u l a o r h i s t o r y o f M E w i t h h i s t o r y o f p h o t o c o a g u l a t i o n c o n ?r m e d b y t r e a t i n g p h y s i c i a n .2O t h e r :N o t r e p o r t e d .3O t h e r :H a r d e x u d a t e s (H E )w i t h i n 1d i s c d i a m e t e r o f m a c u l a .4O t h e r :A d a p t e d f r o m O l k R

J ,L e e C M .D i a b e t i c R e t i n o p a t h y :P r a c t i c a l M a n a g e m e n t .P h i l a d e l p h i a :J B L i p p i n c o t t ,1993:3–20.5O t h e r :G r a d e d f o r p r e s e n c e o f m i c r o -a n e u r y s m s (M A )a n d /o r d o t h e m o r r h a g e s w i t h I C D c o d e s .6O t h e r :M E =H E i n t h e p r e s e n c e o f M A a n d b l o t h e m o r r h a g e w i t h i n 1d i s c d i a m e t e r f r o m f o v e a l c e n t e r o r p r e s e n c e o f f o c a l p h o t o c o a g u l a t i o n s c a r s i n t h e m a c u l a r a r e a .7O t h e r :C l i n i c a l l y s i g n i ?c a n t m a c u l a r e d e m a (C S M E )=m a c u l a r e d e m a w i t h i n 500m m o f f o v e a l c e n t e r ,o r i f p h o t o c o a g u l a t i o n s c a r s w e r e p r e s e n t i n t h e m a c u l a r a r e a .

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group per country;for example,in Brazil, where53.7%of country is“white”(ac-cording to2000census results listed in Central Intelligence Agency,The World Factbook)(10),our pooled Caucasian rate was applied,and in countries where the predominant racial group did not eas-ily align with our limited pooled racial groups(e.g.,Melanesians in Papua New Guinea),the overall pooled world rate was applied.

All analyses were undertaken using Stata Intercooled11.1software(StataCorp LP,College Station,TX).

RESULTS d Data were collated from 22,896individuals from35studies in the U.S.,Australia,Europe,and Asia.Of these, 52%were female,44.4%were Caucasian, 30.9%were Asian,13.9%were Hispanic, and8.9%were African American.The mean age was58.1years(range3–97),median

diabetes duration was7.9years(interquar-tile range[IQR]3–16),and median HbA1c was8.0%(6.7–9.9%).Summary character-istics of the diabetic participants from each of the included studies are presented in Ta-ble1and Supplementary Table2.

Analyses of these35studies showed that the overall age-standardized preva-lence of any DR was34.6%(95%CI34.5–34.8),PDR was6.96%(6.87–7.04),DME was6.81%(6.74–6.89),and VTDR was 10.2%(10.1–10.3;data not shown). Analyses con?ned to studies with similar methodologies and rigorous outcome def-initions showed that the age-standardized prevalence was35.4%(35.2–35.6)for any DR,7.24%(7.15–7.33)for PDR, 7.48%(7.39–7.57)for DME,and11.7% (11.6–11.8)for VTDR(Table2).There was no discernible sex difference in the prevalence of any DR or for PDR,DME, or VTDR.Extrapolating these prevalence rates to the2010world diabetes popula-tion,we estimate that92.6million(91.2–94.0)adults had any DR,17.2million (16.6–17.7)had PDR,20.6million(19.6–21.6)had DME,and28.4million(27.6–29.2)had VTDR.

Table3reports the age-standardized prevalence of any DR by retinopathy risk factors and other subgroups of interest. The prevalence of any DR varied across ethnic groups and was highest among Af-rican Americans and lowest among Asians.The prevalence of any DR increased with diabetes duration(21.1vs.76.3%, comparing,10with$20years),HbA1c (18.0vs.51.2%,comparing levels#7.0 with.9.0%),and blood pressure(30.8 vs.39.6%,comparing blood pressure #140/90or.140/90),and was higher in

people with type1than type2diabetes

(77.3vs.25.2%).Similar relationships

were also evident in the prevalence patterns

of PDR,DME,and VTDR.There was a

trend toward a higher prevalence of

VTDR stages,but not any DR,in people

with cholesterol levels$4.0mmol/L.Anal-

ysis by year/period of fundus photography

suggests a decline in the prevalence of any

DR in the post-2000era(Table3).

After adjusting for known risk factors,

individuals with type1diabetes for$20

years were2.7times more likely to have

any DR(relative risk2.69[96%CI2.47–

2.93]),15times more likely to have PDR

(15.3[11.3–20.8]),5times more likely to

have DME(4.83[3.71–6.30]),and8.7

times more likely to have VTDR(8.69

[7.10–10.63])compared with those with

type2diabetes for,10years(Table4).

CONCLUSIONS d This study pro-

vides a global estimate of the prevalence

of DR and the severe stages of DR(PDR,

DME)using individual-level data from

population-based studies worldwide.On

the basis of the data from all35studies on

more than20,000participants with di-

abetes,we estimated that among individ-

uals with diabetes,the overall prevalence

of any DR was34.6%,PDR was7.0%,DME

was6.8%,and VTDR was10.2%.Analyses

con?ned only to studies with similar metho-

dologies and ophthalmologic de?nitions

showed that the age-standardized prev-

alence of any DR was35.4%,PDR was

7.2%,DME was7.4%,and VTDR was

11.7%,among individuals with diabetes.

The prevalence estimates of any DR and

VTDR were similar in men and women

and were highest in African Americans and

lowest in Asians.Prevalence rates were

substantially higher in those with type1

diabetes and increased with duration of

diabetes,and values for HbA1c,blood pres-

sure,and cholesterol.Extrapolated to the

world diabetes population in2010,we es-

timate that approximately93million may

have some DR,and28million may have

sight-threatening stages of DR.

The prevalence of DR has been pre-

viously reported in a number of population-

based samples(11–16).However,

prevalence estimates varied considerably

across some studies,depending on the pop-

ulation and study methodology.For exam-

ple,variable prevalence rates were reported

between populations of different ethnicities

(e.g.,32.4%in an Australian Caucasian co-

hort(14)vs.48.0%in a Mexican American

cohort(15))as well as between different

populations of the same ethnicity(e.g.,

35%in a U.S.Caucasian cohort(13)

and15.3%in a more recent Australian

Caucasian cohort).More important,prev-

alence estimates for the more severe and

vision-threatening end points,such as

PDR and DME,are scarce,due to the small

numbers of these cases from individual

population-based studies.Published esti-

mates for VTDR prevalence(17–20),for

example,ranges widely,from1.2(17)to

32.2%(18).Our study provides the?rst

precise estimates for these important

clinical subgroups of DR.

The most comparable study to ours is

the pooled analysis for prevalence of DR Table2d Age-standardized prevalence of DR in diabetic subjects aged20–79years,using studies with similar methodologies and ophthalmologic de?nitions

Overall

Studies

included

(n)

Total

(N)

Cases

(n)

Age-standardized

prevalence

per100(95%CI) Any DR1812,6204,48735.36(35.17–35.56) PDR2113,4369577.24(7.15–7.33) DME2014,5541,0397.48(7.39–7.57) VTDR1812,7101,48111.72(11.61–11.83) Men

Any DR186,2522,26336.27(35.99–36.55) PDR216,3764697.53(7.39–7.66) DME207,0104867.44(7.30–7.57) VTDR186,05170411.74(11.57–11.90) Women

Any DR186,3682,22434.46(34.19–34.73) PDR217,060488 6.98(6.86–7.10) DME207,5445537.54(7.42–7.66) VTDR186,65977711.70(11.55–11.86)

560D IABETES C ARE,VOLUME35,M https://www.wendangku.net/doc/0512504868.html, Global prevalence and risk factors of DR

Table 3d Age-standardized prevalence of DR by subgroups of interest,in diabetic subjects aged 20–79years,using studies with similar methodologies and ophthalmologic de ?nitions

Any DR (cases/total)PDR (cases/total)DME (cases/total)VTDR (cases/total)

Age-standardized prevalence per 100(95%CI)Any DR

PDR

DME VTDR

Sex Male 2,263/6,252469/6,376486/7,010704/6,05136.27(35.99–36.55)7.53(7.39–7.66)7.44(7.30–7.57)11.74(11.57–11.90)Female 2,224/6,368

488/7,060553/7,544777/6,659

34.46(34.19–34.73)

6.98(6.86–

7.1)

7.54(7.42–7.66)11.7(11.55–11.86)

Race Caucasian 2,814/6,021666/5,573453/5,345856/5,51645.76(45.44–46.07)12.04(11.87–12.21)8.42(8.28–8.57)15.45(15.25–15.64)Chinese 202/75126/1,02531/56842/75125.08(24.25–25.91)2.67(2.26–3.07)8.12(6.88–9.36)6.14(5.55–6.73)South Asian 886/4,46340/3,196270/5,220165/3,10019.12(18.88–19.35)1.29(1.22–1.36)4.93(4.82–5.04)5.2(5.05–5.34)African Americans 378/67861/67070/673111/67849.56(48.59–50.52)8.99(8.58–9.40)10.35(9.90–10.79)16.89(16.32–17.46)Hispanic 151/448159/2,830209/2,490301/2,52334.56(33.24–35.87)5.10(4.91–5.29)7.15(7.0–7.3)10.85(10.44–11.25)Asian (combined)1,088/5,214

66/4,221

301/5,788

207/3,851

19.92(19.7–20.14)

1.54(1.48–1.61)

5.0(4.89–5.12)5.25(5.12–5.39)

Diabetes type*Type 11,740/2,277594/2,314305/1,864716/2,31577.31(76.34–78.28)32.39(31.76–33.01)14.25(13.86–14.64)38.48(37.80–39.16)Type 22,633/9,666

356/1,0464671/1,1244742/9,814

25.16(24.96–25.36)

2.97(2.91–

3.02)

5.57(5.48–5.66)

6.92(6.83–

7.02)

Diabetes duration ,10years 1,394/6,74788/7,207243/7,685238/6,77121.09(20.87–21.30)1.23(1.18–1.28)3.15(3.08–3.23)3.53(3.45–3.62)10to ,20years 1,544/2,702278/2,852368/2,842479/2,69854.22(53.73–54.71)9.06(8.86–9.25)13.43(13.19–13.66)17.78(17.5–18.05)$20years 1,338/1,752

582/1,840344/1,734

727/1,789

76.32(75.61–77.04)

31.66(31.21–32.11)

19.96(19.58–20.34)40.87(40.35–41.38)

HbA 1c #7.0%562/3,29085/3,285125/3,975147/3,03817.99(17.64–18.33)3.1(2.93–3.26)3.59(3.42–3.76)5.40(5.19–5.60)7.1–8.0%624/1,856129/1,896133/2,344202/1,86033.13(32.64–33.62)6.87(6.63–7.10)6.30(6.06–6.54)10.82(10.53–11.10)8.1–9.0%701/1,546168/1,652141/1,843230/1,62643.1(42.53–43.66)9.64(9.37–9.90)7.69(7.46–7.93)13.64(13.33–13.95).9.0%1,995/3,700

485/4,098546/4,346

773/4,076

51.2(50.8–51.6)

10.93(10.76–11.11)

12.49(12.31–12.67)18.35(18.13–18.58)

Blood pressure Normal 2,037/5,900307/6,243369/6,516521/6,12230.84(30.59–31.09)4.16(4.07–4.25)5.45(5.35–5.55)7.60(7.48–7.72)Hypertensive ?2,407/6,583

632/6,791

661/7,900

958/6,568

39.55(39.19–39.91)

12.32(12.08–12.57)

10.59(10.37–10.81)17.63(17.36–17.9)

Total cholesterol ,4mmol/L 503/1,61956/1,06469/1,62489/1,05631.64(31.11–32.17)5.12(4.87–5.36)4.60(4.37–4.83)8.09(7.78–8.40)$4.0mmol/L 2,491/8,074

409/7,072

534/8,289

664/6,798

31.06(30.82–31.29)

5.67(5.56–5.78)

6.78(6.67–6.9)9.55(9.42–9.69)

Era of study ?Pre-20002,502/4,645692/6,162505/5,139907/5,53049.57(49.21–49.93)10.58(10.43–10.73)9.28(9.14–9.43)15.62(15.43–15.81)Post-2000

1,985/7,975

265/7,274

534/9,415

574/7,180

24.79(24.57–25.00)

3.47(3.40–3.55)

5.46(5.35–5.56)7.86(7.74–7.98)

Data are n /n unless otherwise indicated.Note:Data in this table come from high-quality studies only.High-quality studies were those that scored $9/11on our score,and,for “Any DR ”outcome,the DR grading could distinguish $level 20and the study provided DME data;for “PDR outcome,”the DR grading could distinguish $level 60;for DME outcome the study provided DME data;for “VTDR outcome,”the DR grading could distinguish $level 60and the study provided DME data.*Diabetes type includes the diabetes type information provided by each study plus the calculated diabetes type based on the age at diagnosis assumption.Type is missing if this information was not provided,and/or age at diagnosis could not be determined.?Hypertension was de ?ned in subjects with a blood pressure .140/90mmHg or who reported being on treatment for hypertension.?Era of study was the period during which the fundus photography was undertaken.

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in the U.S.(6).On the basis of eight pop-ulation studies derived from the U.S.and Australia,an overall prevalence of40% for any DR and8%for VTDR was repor-ted(6).These estimates,however,repre-sented?ndings limited to individuals aged older than40years and only with type2diabetes,were largely derived from individuals of Caucasian back-ground,did not evaluate PDR and DME separately,and did not include studies from Asia.Ours is the?rst synthesis of individual-level data from all eligible population-based studies worldwide with a suf?ciently large sample to allow a more precise estimation of the prevalence of PDR and DME.

Some of the differences in DR preva-lence between individual studies may be partly attributed to the differing periods of the studies(Table1and Supplemen-tary Table3).Improvements in the management of DR and diabetes,and in-

creased screening for diabetes,may have

led to lower DR incidence and prevalence

over time(21).Furthermore,DR suscep-

tibility may also vary among ethnic

groups.In support of the latter hy-

pothesis,a number of multiethnic cohort

studies have reported a higher DR preva-

lence among Mexican Americans than in

non-Hispanic whites(5,22,23).Others,

however,showed a similar or lower prev-

alence of DR in African Americans(18)

and Mexican Americans(24)than in

non-Hispanic whites.In some studies

(5),after adjusting for putative DR risk

factors,racial differences in the preva-

lence of DR was attributed to differing

levels of risk factors for DR,but in others,

the excess risk was unexplained(22,23,25).

Differences in socioeconomic factors,in-

cluding access to and the level of diabetes

care,and possibly genetic susceptibility

(26),may also possibly explain some of

the disparities in rates and severity of DR

in the different ethnic groups.In addition,

racial differences in the effect of DR risk

factors could also have accounted for some

of these variations(23,27).Population-

based studies incorporating host and en-

vironmental data are needed to further

clarify the effect of race and ethnicity on

DR prevalence.

We highlight several key points re-

garding the major risk factors for DR:

First,we con?rm the importance of the

three major risk factors for DR d diabetes

duration(17,19,28),HbA1c(17,28–32),

and blood pressure(17,28,33)d and sug-

gest that they apply broadly across the

mild to vision-threatening stages of DR.

Second,we establish that higher total

serum cholesterol was associated with a

higher prevalence of DME,bringing clar-

ity to previously con?icting reports about

this risk factor(19).This is particularly

relevant to recent reports from trials sug-

gesting that feno?brate,a lipid-altering

agent,may slow the development and

progression of DR(34).Feno?brate,how-

ever,acts mostly on triglycerides,and its

effects on retinopathy in those trials were

independent of lipid levels achieved.Sta-

tins,however,did not affect DR severity

in the few studies in which this was eval-

uated,although not as a primary outcome

(35,36).

Third,we provide estimates of risk of

DR by diabetes type,in which studies in

individuals with type1diabetes are cur-

rently scarce.We showed that the prev-

alence of DR is substantially higher in type

1than in type2diabetes(11,37),an out-

come independent of diabetes duration.

However,because we classi?ed type of di-

abetes by age of onset(younger or older

than age30years),in some studies there

may be potential misclassi?cation(e.g.,

some people with type2diabetes will be

younger than30years).

The strengths of our study include a

large sample size to determine prevalence

and risk factor associations for sight-

threatening end points(PDR,DME),the

inclusion of diverse ethnic population

samples from around the world,and

studies that had used photographic doc-

umentation of DR.

Our study has limitations.Pooling of

data from various sources introduces

many potential sources of heterogeneity

that could in?uence accuracy;thus,although

our estimates are highly precise,their

accuracy is unknown.Samples of different

study designs could have considerably

Table4d Age-standardized prevalence of DR by diabetes type and duration,in diabetic subjects aged20–79years,using studies with similar methodologies and ophthalmologic de?nitions

DM type DM duration

(years)

Total

(N)

Cases

(n)

Age-standardized

prevalence per

100(95%CI)

Adjusted

relative risk*

(95%CI)

Any DR

Type1,1045620220.53(18.73–22.34) 1.38(1.19–1.59)

Type110to,2079462455.55(51.34–59.76) 2.43(2.19–2.69)

Type120+1,02691486.22(85.07–87.37) 2.69(2.47–2.93)

Type2,106,2911,19218.11(17.91–18.31) 1.0

Type210to,201,90892051.10(49.53–52.66) 2.06(1.91–2.23)

Type220+72642452.15(51.12–53.19) 2.45(2.24–2.68)

PDR

Type1,10458100.37(0.31–0.43)0.90(0.44–1.86)

Type110to,2080314119.46(16.38–22.53) 6.72(4.70–9.61)

Type120+1,05244340.36(39.60–41.12)15.33(11.29–20.80)

Type2,106,74978 1.06(1.02–1.10) 1.0

Type210to,202,049137 6.92(6.41–7.42) 4.32(3.16–5.91)

Type220+78813915.13(14.64–15.63)9.79(7.14–13.43)

DME

Type1,10399130.55(0.48–0.63)0.59(0.32–1.07)

Type110to,205879112.27(11.43–13.1) 2.50(1.77–3.52)

Type120+87720117.31(16.83–17.8) 4.83(3.71–6.30)

Type2,107,286230 3.07(2.99–3.16) 1.0

Type210to,202,25527711.94(11.42–12.47) 3.22(2.68–3.87)

Type220+85714316.47(15.93–17.01) 4.56(3.67–5.67)

VTDR

Type1,10456200.74(0.65–0.82)0.85(0.52–1.38)

Type110to,2080417814.29(13.61–14.97) 3.97(3.08–5.12)

Type120+1,05451847.2(46.38–48.03)8.69(7.10–10.63)

Type2,106,315218 3.37(3.28–3.47) 1.0

Type210to,201,89430116.14(15.41–16.87) 3.73(3.10–4.49)

Type220+73520925.95(25.26–26.65) 6.27(5.14–7.65)

DM,diabetes.*Adjusted for age(continuous,from20–79years),race(5categories),hypertension(yes/no),

HbA1c(4categories)and study.

562D IABETES C ARE,VOLUME35,M https://www.wendangku.net/doc/0512504868.html, Global prevalence and risk factors of DR

different inclusion criteria,sample selec-tion,and study protocols.For example, population samples could have varied con-siderably between a cardiovascular disease study and an eye survey,or a study on diabetes complications.

There was also a range of methods used in ascertaining diabetes status.Stud-ies in which diagnosis of diabetes was based on self-report,without con?rma-tion from blood tests,could have resulted in an overestimate of DR prevalence rates because those with undiagnosed diabetes might have been erroneously excluded from the sample denominator.

Furthermore,there were differences in the methodologies used to detect and diagnose DR,such as the number of eyes photographed per subject,number of retinal?elds examined per eye,and the grading protocols and de?nitions used.In studies that did not collect data on di-abetes type,this information was de?ned on the basis of age of diagnosis,with a cutoff at age30years to use as many studies with detailed information other than types of diabetes.Misclassi?cation could have occurred as a result of this assumption.This,however,would not have affected the overall prevalence esti-mates but could have had a small effect of attenuating the comparative estimates between the type1and type2diabetes groups.A few studies with large numbers of participants could have in?uenced our results.Finally,the absence of studies from the Middle East,Africa,or South America could also affect the accuracy of our?ndings.

In conclusion,our current study pro-vides the?rst global estimate of DR and, more important,the two sight-threatening end points(PDR and DME),based on a pooled individual participant analysis of more than20,000participants from35 studies around the world.Our study shows that35%of people with diabetes had some form of DR,and that7%had PDR,7%had DME,and10%were affected by these vision-threatening stages.We estimate that in2010,approximately93million were affected by DR,and28million by VTDR. This suggests that DR has the potential to be the leading cause of visual impairment and blindness worldwide.We con?rmed the importance and impact of three major modi?able risk factors d hyperglycemia, hypertension,and dyslipidemia d on the risk of all DR end points,including for the?rst time,PDR and DME.These results highlight the substantial public health effect of diabetes,and thus,the need for effective screening and management of

DR risk factors.

Acknowledgments d Funding for the data

pooling analysis was provided by Global Health

Outcomes Research,Allergan,Inc.(Irvine,CA).

The National Institutes of Health grant EY-06594

(to B.E.K.K.,R.Kle.)and,in part,by the Research

to Prevent Blindness(to B.E.K.K.,R.Kle.,Senior

Scienti?c Investigator Awards),New York,New

York,provided funding for the entire study,in-

cluding collection and analyses and of data.

Andhra Pradesh Eye Disease Study:Sup-

ported by grants from the Hyderabad Eye

Research Foundation,Hyderabad,India and

Christoffel-Blindenmission,Bensheim,Ger-

many.Funagata Study:Supported by Grant-

in-Aid Global COE program of the Japanese

Society for the Promotion of Science,Japan.

Blue Mountains Eye Study:Supported by

grants from the Australian National Health&

Medical Research Council.New Jersey725

Study:Supported by grant R01-EY-09860

from the National Eye Institute.Samutsakon

Study:Supported by grants provided by the

Samutsakhon General Hospital.Rotterdam

Study Ophthalmology:Swart van Essen,Rot-

terdam;Blindenpenning,Amsterdam;Blind-

enhulp,The Hague;Algemene Nederlandse

Vereniging ter Voorkoming van Blindheid

(ANVVB),Doorn;Stichting Oogfonds Neder-

land,Utrecht;Stichting Lijf en Leven,Krimpen

aan de Lek;Rotterdamse Vereniging Blnden-

belangen,Rotterdam;MD Fonds,Utrecht;

Oogfonds Nederland,Utrecht;Laméris

Ootech BV,Nieuwegein;Medical Workshop,

de Meern;Topcon Europe BV,Capelle aan de

IJssel,all in the Netherlands.No other potential

con?icts of interest relevant to this article were

reported.

J.W.Y.Y.researched the data and wrote and

edited the manuscript.S.L.R.analyzed the

data and reviewed and edited the manuscript.

R.Kaw.,E.L.L.,J.W.K.,T.B.,S.-J.C.,J.M.D.,

A.F.,J.G.,S.H.,R.F.H.,M.K.I.,T.K.,

B.E.K.K.,

R.Kle.,S.K.,K.M.,J.P.O.,T.J.O.,M.P.,M.R.,

M.S.R.,T.S.,J.S.,H.T.,J.M.T.,R.V.,J.J.W.,

N.W.,S.W.,L.X.,M.Y.,X.Z.,P.M.,and T.Y.W.

contributed to discussion and reviewed and

edited the manuscript.The sponsors or fund-

ing organizations had no role in the design,

conduct,analysis,or publication of this re-

search.T.Y.W.is the guarantor of this work

and,as such,had full access to all the data in the

study and takes responsibility for the integrity

of the data and the accuracy of the data analysis.

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