in 1916 , despite the absence of data or the means of effectively controlling glucose levels , elliott p. joslin recommended diet , exercise , and medical blood glucose control as the three avenues to live well and reduce the risk of complications from diabetes ( 1 ) . in the postinsulin era , controversy surrounded the recommendation to reduce the risk of diabetes complications by maintaining intensive control of blood glucose levels until 1993 when the diabetes control and complications trial ( dcct ) conclusively demonstrated that intensive control of blood glucose levels significantly reduced the risk of microvascular complication for persons with type 1 diabetes ( t1d ) ( 2 ) . the dcct was designed to evaluate whether intensive treatment ( int ) , with the goal of achieving blood glucose levels as close to the nondiabetic range as safely possible , reduced the risk of onset and progression of microvascular complications of t1d compared with conventional therapy ( con ) . at the conclusion of the dcct , participants were invited to participate in the epidemiology of diabetes interventions and complications ( edic ) study to assess long - term microvascular and macrovascular outcomes . this article details the key findings of dcct and edic with regard to diabetic eye disease outcomes as reported to date . , all subjects were aged 1339 years , had t1d for 115 years , and had no diabetic retinopathy ( dr ) ( primary prevention cohort ) or mild nonproliferative dr ( npdr ) with at least one microaneurysm in either eye , but no more than moderate npdr ( secondary intervention cohort ) . participants were randomly assigned to int , requiring three or more insulin injections per day or use of an insulin pump , with doses adjusted based on frequent self - monitoring of blood glucose ( smbg ) , meal size and content , and exercise levels , or to con , with one or two insulin injections per day ( 3 ) . int was goal - driven , aiming for preprandial smbg between 70 and 120 mg / dl , postprandial levels < 180 , and hba1c , measured monthly , < 6.05% . con did not have specific smbg targets and was aimed at being free of symptoms of hyperglycemia . at the conclusion of the dcct , 97% ( n = 1,394 ) of the original dcct cohort joined the edic study . a more detailed description of the methods for both the dcct and edic is presented in the article by nathan ( 4 ) . in the dcct , dr was monitored by 7-field stereoscopic fundus photographs taken by certified photographers every 6 months and graded according to the early treatment diabetic retinopathy study ( etdrs ) protocol ( 5 ) . graders at a centralized reading center , masked to treatment group assignment , assessed the photographs for severity level of dr according to etdrs scales , with a 25-step scale representing the range of dr in each eye ( 6 ) . in both the primary prevention group and the secondary intervention group , the development of dr was defined as a three - step or greater change of retinopathy from baseline , sustained for 6 or more months . additional outcomes included the development of severe or worse npdr and proliferative dr ( pdr ) ( 2,7 ) . in the edic study , dr was evaluated as in the dcct , albeit with a reduced frequency of examinations ( 8,9 ) . approximately 25% of the edic cohort was photographed each year and the entire edic cohort was photographed at years 4 and 10 , except for those participants who had previous scatter ( panretinal ) laser photocoagulation ( prp ) in both eyes . the primary outcome was initial occurrence of a three - step or more progression of dr from the termination of the dcct through the edic follow - up using the etdrs grading scale ( 5 ) and dcct methods ( 10 ) . secondary outcomes included the initial occurrence of pdr during edic ; a three - step or greater progression from dcct baseline ; development of severe npdr ( etdrs level 53 ) or worse ; development of clinically significant macular edema ( csme ) ; and either prp or focal laser photocoagulation . of the 1,441 subjects in the dcct , at baseline 726 had no dr ( primary prevention cohort ) and 715 had mild dr ( secondary intervention cohort ) . subjects were followed for a mean of 6.5 years . at the conclusion of the dcct , the int group had a median hba1c of 7.2% compared with con median hba1c of 9.1% . a more detailed description of the participant characteristics for both the dcct and edic has been presented by nathan ( 4 ) . over the first 3 years of dcct follow - up , there was little difference between the int and con groups in the primary prevention cohort ( fig . 1 ) . in subsequent years , the int group had delayed onset of dr , and at the conclusion of the dcct the int group had a 76% ( p < 0.001 ) risk reduction for the development of dr compared with the con group . in the secondary intervention group ( fig . 2 ) , although there was an initial worsening of dr , by study completion int reduced the risk of dr progression by 54% ( p cumulative incidence of dr progression ( three - step or greater by etdrs criteria ) in the dcct primary prevention cohort . there was little difference in percentage of patients with retinopathy progression between the int and con groups over the first 3 years ; however , there was a 76% risk reduction for dr progression evident at the conclusion of the dcct after mean follow - up of 6.5 years ( 14 ) . cumulative incidence of dr progression in the dcct secondary intervention cohort . by the conclusion of the dcct , there was a 54% reduction in the risk of retinopathy (  three - step ) progression in the secondary intervention cohort for those in the int group as compared with the con group ( 11,14 ) . the benefits of int extended beyond dr progression alone . there were also marked risk reductions in development of pdr ( 47% ) , onset of macular edema ( 26% ) , and application of laser therapy ( 56% ) ( 2 ) . there was a 61% risk reduction in the development of severe npdr in the secondary intervention cohort ( fig . this beneficial effect was evident by year 4 and continued to increase throughout the study . the development of neovascularization of the optic disk or elsewhere was also benefitted by int during dcct , with a 48% risk reduction compared with the group receiving con in the secondary intervention cohort . again , the benefit of int became evident by year 4 and continued through study end . int was also associated with a 23% reduction in risk of developing csme in the secondary intervention cohort , with observed benefit accruing after year 5 . there was a 61% risk reduction in the development of severe npdr in the int cohort compared with the con cohort . in the dcct , , there is approximately a 44% decreased risk of dr progression over the range of hba1c levels studied ( 11,12 ) . the rate of dr progression per 100 patient - years ( 100 pyr ) was similar and highly associated with hba1c in the dcct for both the int and the con groups ( 12 ) . while int resulted in long - term risk reduction in the progression of dr , increased progression of dr did occur in the first year of follow - up after initiation of int for some subjects ( 13 ) . this phenomenon , termed  early worsening ,  underlies the crossing of the cumulative retinopathy progression curves for int and con between 2 and 3 years in the secondary intervention group ( fig . 2 ) . early worsening occurred most frequently in subjects with more advanced baseline dr , and was predominantly driven by the development of cotton wool spots and intraretinal microvascular abnormalities . risk factors for early worsening included higher hba1c levels at entrance to the study , magnitude of hba1c reduction , duration of diabetes , and the baseline level of dr ( 13 ) . early worsening occurred within 12 months in 13.1% of 711 subjects assigned to int and in 7.6% of 728 subjects assigned to con . crossover occurred at 18 months , with 51% of the int group and 55% of the con group showing recovery ( 13 ) . the long - term benefit of int and the limited risk associated with early worsening in most subjects strongly support the initiation of int in most cases . careful retinal monitoring during the initiation of int , especially in individuals with significant retinopathy or high hba1c at baseline , may be indicated . during edic , all subjects were instructed to use int , and hba1c values for the original int and con groups converged as described in previous articles in this series ( 4 ) . despite the nearly identical mean hba1c levels between int and con during edic ( 8.0% ) , the edic demonstrated a continued durable effect of initial assigned therapy with significantly lower incidence of further progression of dr and pdr in the int group . this phenomenon , whereby a period of previous glycemic control continues to affect future development of diabetes complications despite subsequent equivalency of hba1c between groups , was termed  metabolic memory  ( 8,14 ) . in the first 4 years of the edic observational study , those subjects from the int group did progressively better than those from the con group . starting from the adjusted retinopathy severity present at dcct closeout , there was a 70% ( p < 0.0001 ) risk reduction in dr progression in the initial int group as compared with those subjects in the con group ( 14 ) . in addition , at edic year 4 , in those subjects free of complications at the end of dcct , there were also marked risk reductions in development of pdr ( 55% ) , onset of macular edema ( 73% ) , and application of laser therapy ( 62% ) in the original int group compared with con group . the percent of these effects explained by the difference in hba1c levels between the treatment groups during dcct was nearly complete , accounting for 99.9% of new - onset pdr , 98.8% of new - onset severe npdr , 98.0% of new - onset diabetic macular edema , 97.7% of dr severity progression , and 94.3% of new laser surgery ( 14 ) . int benefit continued during subsequent follow - up such that at edic year 8 the int group experienced a 63% ( p < 0.0001 ) risk reduction in retinopathy progression adjusted for dcct closeout level as compared with con . risk reductions associated with int exceeded those observed in dcct for onset of csme and application of laser . the longest dcct / edic retinopathy follow - up data released to date reflects one decade of study after the close of the dcct ( 8) . after 10 years of edic observation , the benefit of early int persisted with a 53% ( p < 0.0001 ) reduction in the risk of further retinopathy progression ( fig . 5 ) . even after this decade of edic follow - up , and as observed at the conclusion of the dcct and at edic year 4 , the hba1c difference between the intervention groups during dcct explained the majority of the retinopathy progression benefit ( 97.7% at edic year 4 , 89.3% at edic year 10 ) ( 8) . after adjustment for dr severity at dcct closeout , the cumulative incidence of further dr progression during the first 10 years of edic follow - up is shown ( 8) . while the primary outcome in edic was the initial occurrence of a 3-step or more progression of dr from the termination of the dcct , during edic follow - up other important secondary outcomes even after a decade of edic follow - up , these secondary outcomes reflect the benefit of int as compared with con during the earlier dcct period ( 8) . similar to the effect on retinopathy progression , at edic year 10 , there was a 56% ( p < 0.001 ) risk reduction in the development of pdr in the int group . as shown in table 1 , odds reduction at edic year 10 for other end points included onset of severe npdr or worse ( 58% , p < 0.001 ) , onset of pdr or worse ( 58% , p < 0.001 ) , onset of csme ( 38% , p = 0.009 ) , and application of prp ( 57% , p < 0.001 ) . although the magnitude of these reductions is not as great as observed at dcct closeout and edic year 4 , there is still substantial benefit for the original dcct int group for at least 10 years after the close of the dcct . finally , the benefit of int for the cumulative incidence of major eye disease end points ( pdr , csme , application of laser , or development of blindness ) is also clearly evident in relation to increasing diabetes duration . this is true when comparing int to con in the dcct / edic , but is also evident in relation to large observational studies such as the pittsburgh epidemiology of diabetes complications ( edc ) study of patients with t1d from allegheny county , pennsylvania ( fig . 6 ) ( 15 ) . effect of dcct int on odds ratios for prevalence of dr complications at dcct closeout and edic years 4 and 10 the cumulative incidence of any major eye disease end point ( pdr , csme , application of laser , or development of blindness ) is shown in relation to diabetes duration . dcct con ( open squares ) and int ( solid circles ) groups are presented . also presented is the cumulative incidence of these major eye disease end points observed in the observational pittsburgh epidemiology of diabetes complications ( edc ) study ( solid triangles ) ( 15 ) . of the 1,441 subjects in the dcct , at baseline 726 had no dr ( primary prevention cohort ) and 715 had mild dr ( secondary intervention cohort ) . subjects were followed for a mean of 6.5 years . at the conclusion of the dcct , the int group had a median hba1c of 7.2% compared with con median hba1c of 9.1% . a more detailed description of the participant characteristics for both the dcct and edic has been presented by nathan ( 4 ) . over the first 3 years of dcct follow - up , there was little difference between the int and con groups in the primary prevention cohort ( fig . 1 ) . in subsequent years , the int group had delayed onset of dr , and at the conclusion of the dcct the int group had a 76% ( p < 0.001 ) risk reduction for the development of dr compared with the con group . in the secondary intervention group ( fig . 2 ) , although there was an initial worsening of dr , by study completion int reduced the risk of dr progression by 54% ( p cumulative incidence of dr progression ( three - step or greater by etdrs criteria ) in the dcct primary prevention cohort . there was little difference in percentage of patients with retinopathy progression between the int and con groups over the first 3 years ; however , there was a 76% risk reduction for dr progression evident at the conclusion of the dcct after mean follow - up of 6.5 years ( 14 ) . cumulative incidence of dr progression in the dcct secondary intervention cohort . by the conclusion of the dcct , there was a 54% reduction in the risk of retinopathy (  three - step ) progression in the secondary intervention cohort for those in the int group as compared with the con group ( 11,14 ) . the benefits of int extended beyond dr progression alone . there were also marked risk reductions in development of pdr ( 47% ) , onset of macular edema ( 26% ) , and application of laser therapy ( 56% ) ( 2 ) . there was a 61% risk reduction in the development of severe npdr in the secondary intervention cohort ( fig . this beneficial effect was evident by year 4 and continued to increase throughout the study . the development of neovascularization of the optic disk or elsewhere was also benefitted by int during dcct , with a 48% risk reduction compared with the group receiving con in the secondary intervention cohort . again , the benefit of int became evident by year 4 and continued through study end . int was also associated with a 23% reduction in risk of developing csme in the secondary intervention cohort , with observed benefit accruing after year 5 . there was a 61% risk reduction in the development of severe npdr in the int cohort compared with the con cohort . in the dcct , , there is approximately a 44% decreased risk of dr progression over the range of hba1c levels studied ( 11,12 ) . the rate of dr progression per 100 patient - years ( 100 pyr ) was similar and highly associated with hba1c in the dcct for both the int and the con groups ( 12 ) . while int resulted in long - term risk reduction in the progression of dr , increased progression of dr did occur in the first year of follow - up after initiation of int for some subjects ( 13 ) . this phenomenon , termed  early worsening ,  underlies the crossing of the cumulative retinopathy progression curves for int and con between 2 and 3 years in the secondary intervention group ( fig . 2 ) . early worsening occurred most frequently in subjects with more advanced baseline dr , and was predominantly driven by the development of cotton wool spots and intraretinal microvascular abnormalities . risk factors for early worsening included higher hba1c levels at entrance to the study , magnitude of hba1c reduction , duration of diabetes , and the baseline level of dr ( 13 ) . early worsening occurred within 12 months in 13.1% of 711 subjects assigned to int and in 7.6% of 728 subjects assigned to con . crossover occurred at 18 months , with 51% of the int group and 55% of the con group showing recovery ( 13 ) . the long - term benefit of int and the limited risk associated with early worsening in most subjects strongly support the initiation of int in most cases . careful retinal monitoring during the initiation of int , especially in individuals with significant retinopathy or high hba1c at baseline , may be indicated . during edic , all subjects were instructed to use int , and hba1c values for the original int and con groups converged as described in previous articles in this series ( 4 ) . despite the nearly identical mean hba1c levels between int and con during edic ( 8.0% ) , the edic demonstrated a continued durable effect of initial assigned therapy with significantly lower incidence of further progression of dr and pdr in the int group . this phenomenon , whereby a period of previous glycemic control continues to affect future development of diabetes complications despite subsequent equivalency of hba1c between groups , was termed  metabolic memory  ( 8,14 ) . in the first 4 years of the edic observational study , those subjects from the int group did progressively better than those from the con group . ( p < 0.0001 ) risk reduction in dr progression in the initial int group as compared with those subjects in the con group ( 14 ) . in addition , at edic year 4 , in those subjects free of complications at the end of dcct , there were also marked risk reductions in development of pdr ( 55% ) , onset of macular edema ( 73% ) , and application of laser therapy ( 62% ) in the original int group compared with con group . the percent of these effects explained by the difference in hba1c levels between the treatment groups during dcct was nearly complete , accounting for 99.9% of new - onset pdr , 98.8% of new - onset severe npdr , 98.0% of new - onset diabetic macular edema , 97.7% of dr severity progression , and 94.3% of new laser surgery ( 14 ) . int benefit continued during subsequent follow - up such that at edic year 8 the int group experienced a 63% ( p < 0.0001 ) risk reduction in retinopathy progression adjusted for dcct closeout level as compared with con . risk reductions associated with int exceeded those observed in dcct for onset of csme and application of laser . the longest dcct / edic retinopathy follow - up data released to date reflects one decade of study after the close of the dcct ( 8) . after 10 years of edic observation , the benefit of early int persisted with a 53% ( p < 0.0001 ) reduction in the risk of further retinopathy progression ( fig . as observed at the conclusion of the dcct and at edic year 4 , the hba1c difference between the intervention groups during dcct explained the majority of the retinopathy progression benefit ( 97.7% at edic year 4 , 89.3% at edic year 10 ) ( 8) . after adjustment for dr severity at dcct closeout , the cumulative incidence of further dr progression during the first 10 years of edic follow - up is shown ( 8) . while the primary outcome in edic was the initial occurrence of a 3-step or more progression of dr from the termination of the dcct , during edic follow - up other important secondary outcomes even after a decade of edic follow - up , these secondary outcomes reflect the benefit of int as compared with con during the earlier dcct period ( 8) . similar to the effect on retinopathy progression , at edic year 10 , there was a 56% ( p < 0.001 ) risk reduction in the development of pdr in the int group . as shown in table 1 , odds reduction at edic year 10 for other end points included onset of severe npdr or worse ( 58% , p < 0.001 ) , onset of pdr or worse ( 58% , p < 0.001 ) , onset of csme ( 38% , p = 0.009 ) , and application of prp ( 57% , p < 0.001 ) . although the magnitude of these reductions is not as great as observed at dcct closeout and edic year 4 , there is still substantial benefit for the original dcct int group for at least 10 years after the close of the dcct . finally , the benefit of int for the cumulative incidence of major eye disease end points ( pdr , csme , application of laser , or development of blindness ) is also clearly evident in relation to increasing diabetes duration . this is true when comparing int to con in the dcct / edic , but is also evident in relation to large observational studies such as the pittsburgh epidemiology of diabetes complications ( edc ) study of patients with t1d from allegheny county , pennsylvania ( fig . effect of dcct int on odds ratios for prevalence of dr complications at dcct closeout and edic years 4 and 10 the cumulative incidence of any major eye disease end point ( pdr , csme , application of laser , or development of blindness ) is shown in relation to diabetes duration . dcct con ( open squares ) and int ( solid circles ) groups are presented . also presented is the cumulative incidence of these major eye disease end points observed in the observational pittsburgh epidemiology of diabetes complications ( edc ) study ( solid triangles ) ( 15 ) . results from the dcct clearly demonstrated that int markedly delayed the onset and slowed the progression of dr . the edic study demonstrated the unexpected phenomenon of  metabolic memory ,  whereby a period of previous glycemic control continues to affect future development of diabetes complications despite subsequent equivalency of hba1c between groups . in edic , metabolic memory accounted for a profound reduction in risk of further disease progression that continues to be evident after more than a decade of follow - up . the observed benefits include many different diabetes - related ocular outcomes . furthermore , the effects of metabolic memory observed in edic through year 10 appear to be almost entirely explained by the previous dcct group difference in hba1c . nearly two decades of edic follow - up will be available soon , as will evaluation of the effect of glycemic control on the need for long - term surgical ocular intervention . these data will further extend the contributions of the dcct/ edic study and its already lasting legacy that guides therapy of t1d patients and provides marked reduction of the long - term burdens of eye disease and visual loss .
objectiveto evaluate whether intensive treatment ( int ) with the goal of achieving blood glucose levels as close to the nondiabetic range as safely possible reduced the risk of onset and progression of diabetic retinopathy ( dr ) in subjects with type 1 diabetes ( t1d ) compared with conventional therapy ( con).research design and methodsthe diabetes control and complications trial ( dcct ) ( 19821993 ) was a multicenter , controlled clinical trial comparing int with con for onset and progression of dr . 
 the epidemiology of diabetes interventions and complications ( edic ) study ( 1994present ) is an observational follow - up of the dcct cohort.resultsof the 1,441 dcct subjects , 726 had no dr ( primary prevention cohort ) and 715 had mild dr ( secondary intervention cohort ) at baseline . 
 subjects were followed for a mean of 6.5 years . 
 int median hba1c was 7% compared with con median of 9% . 
 int reduced the adjusted mean risk for the development of dr by 76% and slowed progression of dr by 54% compared with con . 
 following dcct , the hba1c levels in the original int and con groups converged ( year 8 , int 7.98% ; con 8.07% ) ; nevertheless , the groups continued to have a durable effect of initial assigned therapy with significantly lower incidence of further dr progression in the int group ( hazard reduction 5356% ) . 
 severe retinal outcomes and procedures to treat them were reduced by 50% in the original int group.conclusionsint delays the onset and slows the progression of dr . 
 furthermore , the early effects of metabolic control continue to accrue over many years despite subsequent comparable glycemic control ( metabolic memory ) . 
 these results emphasize the need for optimizing glycemic control as early as possible in patients with diabetes .