Table 2

Definition of Clinically Significant Macular Edema

Clinically significant macular edema

Thickening of the retina at or within 500 m of the center of the macula

Or

Hard exudates at or within 500 m of the center of the macula, if associated with thickening of the adjacent retina (not residual hard exudates remaining after the disappearance of retinal thickening)

Or

Zone of retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of the center of the macula

RISK FACTORS FOR PROGRESSION OF RETINOPATHY

Severity of Retinopathy

As NPDR progresses, the risk of developing PDR or visual loss also increases. In the ETDRS Study, eyes with very severe NPDR or mild-to-moderate PDR, or both, had a 60-fold increased risk of developing high-risk PDR after 1 year of follow-up, compared with eyes with mild NPDR (48.5% vs. 0.8%). After 5 years of follow-up, there was still a fivefold increased risk (74.4% vs. 14.3%) (43).

The importance of retinopathy severity in predicting progression of retinopathy also was evaluated in the population-based Wisconsin Epidemiological Study of Diabetic Retinopathy (44). In 708 insulin-dependent patients younger than 30 years at time of diagnosis of diabetes, the odds ratio for 4-year progression to PDR was 2.1 for each step increase in baseline retinopathy severity on an 11-step scale. For patients with bilateral moderate NPDR, the 4-year risk of progression to PDR increased by 40-fold when compared with patients who had microaneurysms in only one eye.

Glycemic Control

Hyperglycemia is the instigator of a cascade of events leading to microvascular complications in diabetes. The landmark studies investigating glycemic control and its effects on diabetic complications include the Diabetes Control and Complications Trial (DCCT), Epidemiology of Diabetes Interventions and Complications Trial (EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS). These studies all demonstrated that tight blood glucose control decreases, but does not eliminate, the risk of diabetic retinopathy development and progression (Table 3).

The Diabetes Control and Complications Trial

The DCCT was a randomized, multicenter, prospective trial designed to determine whether intensive insulin treatment, with the goal of near-normal glucose levels, would affect the development and progression of diabetic complications. The 1,441 participant patients with type 1 diabetes were randomly assigned to either conventional or intensive

•35–40% reduction of risk

of retinopathy progression for

every 10% decrease in HbA1C (e.g. 8% – 7.2%)

insulin treatment and followed up for a period of 4–9 years (45–49). Of the participants, 726 had no retinopathy at baseline (the primary-prevention cohort) and 715 had mild nonproliferative retinopathy (the secondary-intervention cohort). Intensive therapy consisted of an external insulin pump or three or more daily insulin injections guided by frequent blood glucose monitoring, while conventional therapy consisted of one or two daily insulin injections.

Intensive insulin treatment in the DCCT study was associated with a decreased risk of either the development or progression of diabetic retinopathy in patients with type 1 diabetes. In patients without any visible retinopathy when enrolled in the DCCT, the 3-year risk of developing retinopathy was reduced by 75% in the intensive insulin treatment group when compared with the standard treatment group. However, even in the intensively treated group, retinopathy could not be completely prevented over the 9-year course of the study.

The benefit of the strict control was also evident in patients with existing retinopathy. There was a 50% reduction in the rate of progression of retinopathy when compared with controls. At 6- and 12-month visits, a small adverse effect of intensive treatment on retinopathy progression was seen, similar to that described in other trials of glucose control. However, in eyes with little or no retinopathy at the time of initiating intensive glucose control, this early worsening of retinopathy is unlikely to threaten vision. When the DCCT results were stratified by glycosylated hemoglobin (HbA1C) levels, there was a 35–40% reduction in the risk of retinopathy progression for every 10% decrease in HbA1C (e.g., from 8% to 7.2%). This represented a fivefold increase in the risk for patients with HbA1C of about 10% vs. those with a HbA1C of 7%. Furthermore, there was a statistically significant reduction in both diabetic neuropathy and nephropathy with intensive blood glucose control in the DCCT. The current recommendation for glycemic control is to achieve a HbA1C level below 7% for patients in general and a level as close to normal (<6%) as possible without significant hypoglycemia for individual patients (50).

Epidemiology of Diabetes Interventions and Complications Trial

EDIC is the long-term follow-up to the DCCT (51). At the conclusion of the DCCT, intensive glucose control was recommended for all participants and the conventional group started intensive diabetic management. Care of all participants was transferred to personal physicians during the EDIC study. Four years after the end of DCCT, the difference in HbA1C levels between the DCCT conventional-therapy and intensive-therapy groups had narrowed and both groups had a HbA1C level of 8%. This likely occurred in EDIC because the original intensive group was not monitored as frequently and the conventional group started intensive therapy. Retinopathy during the fourth year after the conclusion of DCCT was evaluated on the basis of centrally graded fundus photographs. Interestingly, despite the same HbA1C level in EDIC, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular edema, and the need for laser therapy, was lower in the original intensive-therapy group than in the original conventional-therapy group (odds reduction, 72–87%; P < 0.001). These data suggest that the original intensive-therapy group had a prolonged benefit in delaying progression of retinopathy. This phenomenon of cells “remembering” tight control for extended periods is known as metabolic memory. Clinically, as per the concept of metabolic memory and EDIC results, early intervention with intensive glucose management is critical for preventing long-term complications of retinopathy.

The United Kingdom Prospective Diabetes Study

The effect of glycemic control on the incidence and progression of diabetic retinopathy is similar in patients with type 2 diabetes. UKPDS (52), the largest and longest study of patients with type 2 diabetes, evaluated the effect of conventional vs. intensive glucose management on diabetic complications in 3,867 newly diagnosed patients. Intensive management involved either sulphonylureas or insulin, while conventional treatment relied on diet alone, with drugs added only if there were hyperglycemic symptoms or fasting plasma glucose greater than 15 mmol L−1. The UKPDS showed a 25% reduction

in the risk of the “any diabetes-related microvascular end point,” including the need for retinal photocoagulation, in the intensive treatment group, compared with the conventional treatment group. After 6 years of follow-up, a smaller proportion of patients in the intensive treatment group, compared with the conventional group, had a two-step progression (worsening) in diabetic retinopathy. Epidemiologic analysis of the UKPDS data showed a continuous relationship between the risk of microvascular complications and glycemia; for every percentage point decrease in HbA1C (e.g., 9% to 8%), there was a 35% reduction in the risk of microvascular complications.

Hypertension

Hypertension is theorized to exacerbate diabetic retinopathy through mechanical stretching of endothelial cells, resulting in increased VEGF release (53). The findings of multiple studies assessing the importance of blood pressure in the progression of NPDR, however, are inconsistent (54). Large studies correlating tight blood pressure control with reduced risk of retinopathy progression include the UKPDS and Appropriate Blood Pressure Control in Diabetes (ABCD) trials.

The United Kingdom Prospective Diabetes Study

In UKPDS, a randomized comparison of more intensive blood pressure control and less intensive blood pressure control in persons with type 2 diabetes demonstrated that intensive blood pressure control was associated with a decreased risk of retinopathy progression. Of the 1,148 hypertensive patients in the UKPDS, 758 were allocated to tight blood pressure control arm and 390 to less tight control arm, with a median fol- low-up of 8.4 years (55). Tight blood pressure control resulted in a 37% reduction in microvascular diseases, predominantly reduced risk of retinal photocoagulation, when compared to less tight control. A previously published study of blood pressure medication in diabetic retinopathy suggested that there might be a specific benefit of angi- otensin-converting enzyme (ACE) inhibition and blood pressure reduction, even in “normotensive” persons, on the progression of diabetic retinopathy (56). The UKPDS included a randomized comparison of beta-blockers and ACE inhibitors in the tight blood pressure control arm of that study. Benefits from tight blood pressure control were present in both the beta-blocker and ACE inhibitor treatment groups, with no statistically significant difference between them. This suggests that the treatment effect is more likely to be secondary to blood pressure reduction than to a specific effect of ACE inhibitors.

Appropriate Blood Pressure Control in Diabetes Trials

The ABCD trials also showed a correlation between tight blood pressure control and decreased risk of retinopathy (54, 57). This prospective, controlled, randomized study evaluated the effect of intensive vs. moderate diastolic blood pressure control on diabetic vascular complications in 480 normotensive type 2 diabetic patients. Over a 5-year follow-up period, there was less progression of diabetic retinopathy 35% for the intensive therapy group vs. 46% for the moderate control group).