we conducted a systematic review and meta - analysis on the clinical course of diabetic retinopathy focusing primarily on two outcomes : 1 ) progression to proliferative diabetic retinopathy ( pdr ) and 2 ) progression to severe visual loss ( svl ) , defined as log  minimum angle of resolution ( mar ) visual acuity ( va ) < 1.0 ( defined as va < 5/200 in some studies ) . all studies published in english , french , german , spanish , italian , and portuguese assessing the progression of diabetic retinopathy among patients with diabetes were included . eligible studies included patients without and with diabetic retinopathy who had not received any specific ocular treatment for diabetic retinopathy ( including photocoagulation , vitrectomy , and intravitreal injections ) . among included studies were the control arms of clinical trials for treatment - nave patients assessed for diabetic retinopathy progression . we allowed study samples with up to 15% of patients in control groups to receive laser or other diabetic retinopathy  specific treatment . we searched medline , current contents , and the cochrane library for published studies from january 1975 through 20 february 2008 . search terms used included :  diabetes mellitus or diabet * or diabetes or insulin * or diabetic retinopathy  and  diabetic maculopathy or macular edema , cystoid or edema or macul * or exudate or laser coagulation or photocoagulat * or vitrect * or intravitr * or triamcinolone . the use of medical subject headings ( mesh ) terms and text words ( or equivalent ) in the appropriate syntax of each database were applied . we also reviewed pubmed for the 6 months prior to the search date ( 20 august 2007 through 20 february 2008 ) with no limits and current contents for the year prior to the search date ( 20 february 2007 through 20 february 2008 ) . additionally , manual reference checks were performed of bibliographies of articles and reviews published within the last 5 years ( 20042008 ) . we selected prospective interventional or observational studies reporting the progression of diabetic retinopathy to pdr and/or progression to svl at 4- , 5- , and 10-year time periods . inclusion criteria ( online - only appendix table s1 , available at http://care.diabetesjournals.org/cgi/content/full/dc09-0615/dc1 ) were patients not yet treated for diabetic retinopathy ( i.e. , treatment nave ) followed for at least 1 year , diabetic retinopathy assessed using retinal photography and/or fluorescein angiography , and categorized using the modified etdrsdr severity grades : grade 1 ( no diabetic retinopathy ) , grades 2 and 3 ( nonproliferative diabetic retinopathy [ npdr ] ) , and grade 4 ( pdr ) . in the initial screening , abstracts were reviewed by a single reviewer for obvious exclusion criteria . the complete studies were then rescreened and reviewed by two investigators based on prospective protocol , with discrepancies resolved by consulting a third investigator . studies were assigned a level of evidence using criteria from the centre for evidence - based medicine in oxford , u.k . if necessary , contact and clarification was made with authors of accepted studies for specific data and analyses . va assessments for baseline characteristics were reported as best - corrected distance va . when reported , logmar va was preferentially extracted . conversions between logmar and snellen values were performed using previously reported methods ( the mnread acuity chart ) , with logmar 0.0 corresponding to 20/20 snellen and 1.0 corresponding to 20/200 snellen . logmar values were then categorized into 0.0 , > 0.000.48 , > 0.481.0 , and > 1.0 . studies were stratified into two time periods ( defined by start date of patient accrual)19751985 and 19862008with the 1985 cutoff selected to coincide with publication of etdrs ( 19 ) . pooled baseline characteristics and outcome measures were summarized using weighted averages of counts , proportions , and means . weighted average proportions were reported as percentages , whereas weighted means were reported with ranges . for some studies , the number of eyes was used as the denomination ; however , when only patient numbers were reported , it was assumed that only one eye per patient was studied . meta - analyses were performed to pool within - study outcome measures . for efficacy outcomes of interest ( pdr and svl ) , meta - analyses for proportions with 95% cis were performed across the studies using both fixed - effects ( 25,26 ) and restricted - maximum likelihood random - effects ( 27,28 ) models . heterogeneity between studies was measured using the cochran q statistic for heterogeneity . for continuous outcomes , meta - analyses for means with 95% cis were performed . to account for variations in baseline severity , analyses were stratified by baseline diabetic retinopathy status ( no diabetic retinopathy and any diabetic retinopathy ) . all studies published in english , french , german , spanish , italian , and portuguese assessing the progression of diabetic retinopathy among patients with diabetes were included . eligible studies included patients without and with diabetic retinopathy who had not received any specific ocular treatment for diabetic retinopathy ( including photocoagulation , vitrectomy , and intravitreal injections ) . among included studies were the control arms of clinical trials for treatment - nave patients assessed for diabetic retinopathy progression . we allowed study samples with up to 15% of patients in control groups to receive laser or other diabetic retinopathy  specific treatment . we searched medline , current contents , and the cochrane library for published studies from january 1975 through 20 february 2008 . search terms used included :  diabetes mellitus or diabet * or diabetes or insulin * or diabetic retinopathy  and  diabetic maculopathy or macular edema , cystoid or edema or macul * or exudate or laser coagulation or photocoagulat * or vitrect * or intravitr * or triamcinolone . the use of medical subject headings ( mesh ) terms and text words ( or equivalent ) in the appropriate syntax of each database were applied . we also reviewed pubmed for the 6 months prior to the search date ( 20 august 2007 through 20 february 2008 ) with no limits and current contents for the year prior to the search date ( 20 february 2007 through 20 february 2008 ) . additionally , manual reference checks were performed of bibliographies of articles and reviews published within the last 5 years ( 20042008 ) . we selected prospective interventional or observational studies reporting the progression of diabetic retinopathy to pdr and/or progression to svl at 4- , 5- , and 10-year time periods . inclusion criteria ( online - only appendix table s1 , available at http://care.diabetesjournals.org/cgi/content/full/dc09-0615/dc1 ) were patients not yet treated for diabetic retinopathy ( i.e. , treatment nave ) followed for at least 1 year , diabetic retinopathy assessed using retinal photography and/or fluorescein angiography , and categorized using the modified etdrsdr severity grades : grade 1 ( no diabetic retinopathy ) , grades 2 and 3 ( nonproliferative diabetic retinopathy [ npdr ] ) , and grade 4 ( pdr ) . in the initial screening , abstracts were reviewed by a single reviewer for obvious exclusion criteria . the complete studies were then rescreened and reviewed by two investigators based on prospective protocol , with discrepancies resolved by consulting a third investigator . studies were assigned a level of evidence using criteria from the centre for evidence - based medicine in oxford , u.k . if necessary , contact and clarification was made with authors of accepted studies for specific data and analyses . va assessments for baseline characteristics were reported as best - corrected distance va . when reported , logmar va was preferentially extracted . conversions between logmar and snellen values were performed using previously reported methods ( the mnread acuity chart ) , with logmar 0.0 corresponding to 20/20 snellen and 1.0 corresponding to 20/200 snellen . logmar values were then categorized into 0.0 , > 0.000.48 , > 0.481.0 , and > 1.0 . studies were stratified into two time periods ( defined by start date of patient accrual)19751985 and 19862008with the 1985 cutoff selected to coincide with publication of etdrs ( 19 ) . pooled baseline characteristics and outcome measures were summarized using weighted averages of counts , proportions , and means . weighted average proportions were reported as percentages , whereas weighted means were reported with ranges . for some studies , the number of eyes was used as the denomination ; however , when only patient numbers were reported , it was assumed that only one eye per patient was studied . meta - analyses were performed to pool within - study outcome measures . for efficacy outcomes of interest ( pdr and svl ) , meta - analyses for proportions with 95% cis were performed across the studies using both fixed - effects ( 25,26 ) and restricted - maximum likelihood random - effects ( 27,28 ) models . heterogeneity between studies was measured using the cochran q statistic for heterogeneity . for continuous outcomes , meta - analyses for means with 95% cis were performed . to account for variations in baseline severity , analyses were stratified by baseline diabetic retinopathy status ( no diabetic retinopathy and any diabetic retinopathy ) . figure 1 shows the search yielded 3,130 abstracts screened for eligibility , of which 2,807 citations were rejected based on obvious exclusion criteria . full articles of 323 citations were retrieved , and 76 met all eligibility criteria ; 28 were primary studies , and 48 were related publications ( same patient populations contributing additional data , e.g. , outcome data at different time points ) . selection of studies for systematic review . supplemental tables s2 and s3 list study - level characteristics of the 28 included studies . of these , 14 were conducted during 19751985 and the rest during 19852008 . among the accepted studies , different methods were used to ascertain and classify diabetic retinopathy , although many used the etdrs severity scale ( 2931 ) . definitions for vision loss also varied , with studies reporting va change as va 2 lines lost ( or 10 etdrs letters lost ) or va 3 lines lost ( or 15 etdrs letters lost and doubling of the visual angle ) . the 28 studies enrolled 27,120 diabetic patients assessed for diabetic retinopathy at the 4- , 5- , and 10-year time points . the mean patient age was 49 years , 46% were female , 48% had type 2 diabetes , and the mean diabetes duration was 11 years ; 55% had no diabetic retinopathy at baseline , whereas 59% had baseline logmar va 0.0 . participants in 19862008 had similar sex distribution , age range , and diabetes duration as participants in 19751985 ; however , studies in the first time period enrolled more patients with type 1 diabetes ( supplemental table s4 ) . nearly 60% of included studies reported progression to pdr , and 35% reported progression to svl . in contrast , only 11% reported two - step and 4% three - step progression of diabetic retinopathy , whereas the loss of two and three lines was reported in 16 and 9% of the included studies , respectively . table 1 shows the incidence of each end point at the 4- , 5- , and 10-year time points , both overall and within each study period . incidence rates of outcomes after 4 , 5 , and 10 years data are  ( number of studies ) , percent ( proportion of patients with event at each time point ) , or n ( total number of patients at risk at each time point ) . diabetic macular edema . after 4 years , the pooled incidence of pdr and svl was 11.0 and 7.2% , respectively . table 2 shows the 4- , 5- , and 10-year incidence of pdr and svl stratified for time period . for studies reporting outcomes after 4 years for svl , 9.7% of patients in 19751985 developed svl compared with 3.2% in 19862008 . for example , for studies reporting outcomes after 5 years , 18.0% of patients in 19751985 developed pdr versus 6.4% in 19862008 ; for svl , corresponding rates were 13.7 versus 3.6% , respectively . of studies reporting outcomes at 10 years , rates for pdr were 11.5% in 19751985 versus 6.6% in 19862008 ; for svl , corresponding rates were 6.0 versus 2.6% , respectively . baseline distributions and 4- , 5- , and 10-year rates for pdf and svl by time periods data are  ( number of studies ) , n ( total number of patients at risk at each time point ) , percent , or mean ( 95% ci ) . * heterogeneity by cochran q : p < 0.05 . table 3 shows that when stratified by baseline diabetic retinopathy status , for participants without diabetic retinopathy at baseline , pdr developed in 6.3% during 19751985 ( two studies ) compared with 2.6% during 19862008 ( five studies ) ; similarly , 2.0% developed svl in 19751985 compared with none in 19862008 . for participants with diabetic retinopathy at baseline , pdr developed in 39.7% of patients in 19751985 , whereas no studies reported progression to pdr during 19862008 ; 17.5% progressed to svl during 19751985 ( two studies ) , whereas 5.4% progressed to svl in 19862008 ( one study ) . baseline distributions and 4-year incidence of pdf and svl by time periods and baseline retinopathy status data are  ( number of studies ) , n ( total number of patients at risk at each time point ) , percent , or mean ( 95% ci ) . figure 1 shows the search yielded 3,130 abstracts screened for eligibility , of which 2,807 citations were rejected based on obvious exclusion criteria . full articles of 323 citations were retrieved , and 76 met all eligibility criteria ; 28 were primary studies , and 48 were related publications ( same patient populations contributing additional data , e.g. , outcome data at different time points ) . selection of studies for systematic review . supplemental tables s2 and s3 list study - level characteristics of the 28 included studies . of these , 14 were conducted during 19751985 and the rest during 19852008 . among the accepted studies , different methods were used to ascertain and classify diabetic retinopathy , although many used the etdrs severity scale ( 2931 ) . definitions for vision loss also varied , with studies reporting va change as va 2 lines lost ( or 10 etdrs letters lost ) or va 3 lines lost ( or 15 etdrs letters lost and doubling of the visual angle ) . the 28 studies enrolled 27,120 diabetic patients assessed for diabetic retinopathy at the 4- , 5- , and 10-year time points . the mean patient age was 49 years , 46% were female , 48% had type 2 diabetes , and the mean diabetes duration was 11 years ; 55% had no diabetic retinopathy at baseline , whereas 59% had baseline logmar va 0.0 . participants in 19862008 had similar sex distribution , age range , and diabetes duration as participants in 19751985 ; however , studies in the first time period enrolled more patients with type 1 diabetes ( supplemental table s4 ) . nearly 60% of included studies reported progression to pdr , and 35% reported progression to svl . in contrast , only 11% reported two - step and 4% three - step progression of diabetic retinopathy , whereas the loss of two and three lines was reported in 16 and 9% of the included studies , respectively . table 1 shows the incidence of each end point at the 4- , 5- , and 10-year time points , both overall and within each study period . incidence rates of outcomes after 4 , 5 , and 10 years data are  ( number of studies ) , percent ( proportion of patients with event at each time point ) , or n ( total number of patients at risk at each time point ) . after 4 years , the pooled incidence of pdr and svl was 11.0 and 7.2% , respectively . table 2 shows the 4- , 5- , and 10-year incidence of pdr and svl stratified for time period . for studies reporting outcomes after 4 years for svl , 9.7% of patients in 19751985 developed svl compared with 3.2% in 19862008 . for example , for studies reporting outcomes after 5 years , 18.0% of patients in 19751985 developed pdr versus 6.4% in 19862008 ; for svl , corresponding rates were 13.7 versus 3.6% , respectively . of studies reporting outcomes at 10 years , rates for pdr were 11.5% in 19751985 versus 6.6% in 19862008 ; for svl , corresponding rates were 6.0 versus 2.6% , respectively . baseline distributions and 4- , 5- , and 10-year rates for pdf and svl by time periods data are  ( number of studies ) , n ( total number of patients at risk at each time point ) , percent , or mean ( 95% ci ) . * heterogeneity by cochran q : p < 0.05 . table 3 shows that when stratified by baseline diabetic retinopathy status , for participants without diabetic retinopathy at baseline , pdr developed in 6.3% during 19751985 ( two studies ) compared with 2.6% during 19862008 ( five studies ) ; similarly , 2.0% developed svl in 19751985 compared with none in 19862008 . for participants with diabetic retinopathy at baseline , pdr developed in 39.7% of patients in 19751985 , whereas no studies reported progression to pdr during 19862008 ; 17.5% progressed to svl during 19751985 ( two studies ) , whereas 5.4% progressed to svl in 19862008 ( one study ) . baseline distributions and 4-year incidence of pdf and svl by time periods and baseline retinopathy status data are  ( number of studies ) , n ( total number of patients at risk at each time point ) , percent , or mean ( 95% ci ) . this systematic review and meta - analysis provides estimates of the incidence of pdr and development of svl in patients who were untreated for diabetic retinopathy at baseline . our analyses show that the overall incidence of pdr and svl observed in studies after 1985 ( e.g. , 2.6% for pdr and 3.2% for svl at 4 years ) were substantially lower than rates observed before 1985 ( 19.5% for pdr and 9.7% for svl at 4 years ) . these findings support our a priori hypothesis that contemporary rates of progression to pdr and svl are substantially lower and may reflect improvements in the overall care and management of diabetes and associated risk factors ( e.g. , hyperglycemia and hypertension ) over time , together with earlier identification of type 2 diabetes . in terms of the principal risk factors for diabetic retinopathy , studies in the two time periods had relatively similar baseline duration of diabetes : 11.1 years for 19751985 versus 11.7 years for 19862008 . however , in the later period , substantially greater proportion of participants had type 1 diabetes ( 71.1 versus 48.3% ) , which could partly explain lower rates of baseline npdr and pdr . studies of type 2 diabetic patients report only a nominal duration of diabetes because its onset is gradual . thus , an earlier diagnosis of type 2 diabetes during 19862008 could partly explain lower baseline diabetic retinopathy during this period . differences in baseline diabetic retinopathy severity between the two time periods ( less severe after 1985 ) could also explain lower rates of progression to pdr and/or svl after 1985 . first , the observed differences in progression rates between the two periods were not independent of the distribution of the severity of diabetic retinopathy at baseline . studies conducted earlier had larger proportions of more advanced diabetic retinopathy at baseline , and progression rates between the two time periods could not be formally compared without appropriate adjustments . however , there were insufficient studies to enable regression - based adjustments for baseline severity . thus , we chose to stratify by baseline diabetic retinopathy severity , but even after stratification , the distribution of baseline diabetic retinopathy severity was not sufficiently balanced . baseline va and progression of vision - loss measurements by the loss of two and three lines ( or equivalent ) or diabetic retinopathy progression by two- or three - step progression ( or equivalent ) were reported by only a few studies . the failure to report progression of visual loss limited the ability to explore the impact of diabetic retinopathy progression before the development of pdr or svl . this may be important because current recommendations for diabetic retinopathy clinical trials emphasize the universal use of three - step progression of diabetic retinopathy as a disease progression marker at the 3-year time point ( 32 ) . we included only studies of treatment - nave patients in which outcomes were reported separately by diabetic retinopathy severity at baseline and where diabetic retinopathy assessment involved retinal photography and/or fluorescein angiography . although this improved comparability of studies , it limited the pool of data for analysis . additionally , we included both interventional and prospective observational studies covering a wide range of study designs , sample sizes , treatment settings , and study inclusion criteria . although these variations could be of concern , the broader inclusion reflected the diversity of diabetic retinopathy studies in the literature . finally , there were insufficient data on ethnic composition or socioeconomic status to determine whether rates varied by these factors . because the availability of numerous treatment modalities would make a new prospective study of untreated patients impossible , our study provides the best available evidence from the literature , even with the limitation that exact underlying causes for the temporal differences can not be fully explained . first , based on baseline diabetic retinopathy severity , researchers should consider contemporary rates of progression to pdr and/or svl in estimating sample sizes for clinical trials . second , future studies should report common nomenclature for diabetic retinopathy ( i.e. , etdrs scales ) and va outcomes ( e.g. , logmar va categories or number of logmar lines ) so that progression rates can be estimated consistently . third , there is a need for the publication of data on treatment - nave patients with diabetic retinopathy from larger population - based studies . in conclusion , our systematic review and meta - analysis in treatment - nave patients with diabetes covering 19752008 show that contemporary rates of pdr and/or svl are substantially lower than rates observed before 1985 . differences are explained , in part , by baseline differences in diabetic retinopathy severity , a1c , and possibly blood pressure levels . limitations from the available literature data prevented in - depth exploration as to exact causes for these differences . our analysis supports some studies that suggest changing patterns of care for diabetes , including earlier identification and initiation of care along with attention to appropriate management of diabetic retinopathy , may have led to substantially lower rates of diabetic retinopathy progression and incident visual loss over time ( 33,34 ) .
objectivethis meta - analysis reviews rates of progression of diabetic retinopathy to proliferative diabetic retinopathy ( pdr ) and/or severe visual loss ( svl ) and temporal trends.research design and methodsthis systematic literature review and meta - analysis of prospective studies assesses progression of retinopathy among diabetic patients without treatment for retinopathy at baseline . 
 studies published between 1975 to february 2008 were identified . 
 outcomes of interest were rates of progression to pdr and/or svl . 
 pooled baseline characteristics and outcome measures were summarized using weighted averages of counts and means . 
 baseline characteristics and outcomes were compared between two periods : 19751985 and 19862008.resultsa total of 28 studies comprising 27,120 diabetic patients ( mean age 49.8 years ) were included . 
 after 4 years , pooled incidence rates for pdr and svl were 11.0 and 7.2% , respectively . 
 rates were lower among participants in 19862008 than in 19751985 . 
 after 10 years , similar patterns were observed . 
 participants in 19862008 studies had lower proportions of pdr and non - pdr at all time points than participants in 19751985 studies.conclusionssince 1985 , diabetic patients have lower rates of progression to pdr and svl . 
 these findings may reflect an increased awareness of retinopathy risk factors ; earlier identification and initiation of care for patients with retinopathy ; and improved medical management of glucose , blood pressure , and serum lipids . 
 differences in baseline characteristics , particularly in the prevalence and severity of retinopathy , could also have contributed to these temporal differences .