Diabetic Retinopathy and Other Ocular Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

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.

The DCCT was conducted from 1983 to 1993 and enrolled 1,441 subjects. At baseline, all subjects were aged 13–39 years, had T1D for 1–15 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 HbA_1c, measured monthly, <6.05%. CON did not have specific SMBG targets and was aimed at being free of symptoms of hyperglycemia. Avoidance of frequent or severe hypoglycemia was a goal of both treatment arms. 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 HbA_1c of 7.2% compared with CON median HbA_1c 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 < 0.001) as compared with the CON group (2).

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. 3). 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.

In the DCCT, the rate of retinopathy progression was highly associated with HbA_1c as shown in Fig. 4. For each 10% decrease in HbA_1c (e.g., 9.0–8.1%), there is approximately a 44% decreased risk of DR progression over the range of HbA_1c levels studied (11,12).

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 HbA_1c levels at entrance to the study, magnitude of HbA_1c 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 HbA_1c at baseline, may be indicated.

During EDIC, all subjects were instructed to use INT, and HbA_1c values for the original INT and CON groups converged as described in previous articles in this series (4). Despite the nearly identical mean HbA_1c 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 HbA_1c 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). This finding represented the first conclusive demonstration of the metabolic memory phenomenon.

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 HbA_1c 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 HbA_1c 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).

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 were also assessed. 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).

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 HbA_1c 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 HbA_1c.

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.

Acknowledgments. The author thanks Jerry D. Cavallerano, OD, PhD (Beetham Eye Institute, Joslin Diabetes Center, Boston, MA) for his contributions to the writing and review of the manuscript.

Funding.The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1982–93, 2011–2016) and contracts (1982–2011) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grant numbers U01-DK-094176 and U01-DK-094157) and through support of the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the Genetic Clinical Research Centers Program (1993–2007), and Clinical and Translational Science Center Program (2006–present), Bethesda, MD.

Industry contributors have had no role in the DCCT/EDIC but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care (Alameda, CA); Animas (West Chester, PA); Bayer Diabetes Care (Tarrytown, NY); Becton, Dickinson and Company (Franklin Lakes, NJ); CanAm (Atlanta, GA); Eli Lilly (Indianapolis, IN); LifeScan (Milpitas, CA); Medtronic Diabetes (Minneapolis, MI); Nova Diabetes Care (Bedford, MA); Omron (Shelton, CT); OmniPod Insulin Management System (Bedford, MA); Roche Diabetes Care (Indianapolis, IN); and Sanofi (Bridgewater, NJ).

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. L.P.A. researched and wrote the manuscript. L.P.A. 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.