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Handbook of Diabetes, 4th Ed., Excerpt #14: Diabetic Eye Disease

Classification of retinopathy

The clinical categories of non-proliferative and proliferative, although useful, have proven too broad for research purposes. Moreover, the nomenclature ‘background’ implies a somewhat benign condition, which nonetheless represents pathological damage and can progress.

The Early Treatment Diabetic Retinopathy Study (ETDRS) devised a modified scale based upon the Airlie House classification and this has become the gold standard for all intervention trials such as the DCCT and UKPDS (Box 15.3). A two- or three-step change in combined eye score is positively associated with progression to proliferative retinopathy and visual loss. Moreover, in the UKPDS, 30% of patients with a level of ≥ 35 in both eyes required photocoagulation after 9 years.

However, this grading is complex and was based upon seven-field stereo fundus photographs, which are both time-consuming and expensive as well as being uncomfortable for the patient. Moreover, the classification is hard to apply without expert training and experience. The UK National Screening Committee has proposed a simpler classification that feeds into a treatment algorithm with referral targets and forms the basis of the Diabetic Retinopathy Screening Program (Box 15.4).

Treatment of retinopathy
Glycemic control

Both the DCCT in type 1 and the UKPDS in type 2 diabetes demonstrated the benefit of glycemic control for the primary prevention of new retinopathy, and secondary prevention of progression of existing retinopathy. Moreover, there are long-term benefits of glycemic control (see Chapter 14).

However, as previously mentioned, rapid improvement in glycemia can result in an early worsening of retinopathy. Most of the trials in which this was noticed (DCCT, KROC, Stockholm and Oslo Studies) found that in the long term, patients on intensive insulin regimens still had better retinal outcomes than their conventionally treated controls.

Blood pressure control

Embedded within the UKPDS was a trial of tight (target < 150/ < 85 mmHg) or less tight (target < 180/ < 105 mmHg) blood pressure control in 1148 hypertensive newly diagnosed type 2 diabetic patients. There was a 34% (99% CI 11–50%) risk reduction in progression (two-step ETDRS change), and 35% risk reduction in the need for laser photocoagulation. Post hoc analysis suggested a 13% decrease in the aggregate microvascular endpoint (combination of retinopathy requiring photocoagulation, vitreous hemorrhage and/or fatal or non-fatal renal failure) for every 10-mmHg reduction in blood pressure.

Similar results were found in the normotensive (but not hypertensive) patients in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial. The ADVANCE study also found no benefit of a mean reduction in blood pressure of 5.6/2.2 mmHg on retinopathy progression in 11,140 mainly hypertensive type 2 patients. The reasons for these disparities between normo- and hypertensive patients are not clear. The magnitude of the blood pressure reduction was greater in the two positive studies, and the ascertainment of effect was most precise in the UKPDS.

There are no data on the effect of blood pressure lowering on retinopathy in type 1 diabetes.

Renin angiotensin system (RAS) blockade

The EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID) found a benefit of lisinopril on retinopathy progression over 2 years but statistical significance was lost when results were corrected for HbA1c.

The much larger and longer DIRECT study (DIabetic REtinopathy Candesartan Trial) looked at the effect of a median 4.7 years of candesartan 32 mg per day on development and progression of retinopathy in 3326 normotensive type 1 and 1905 normotensive or well-controlled hypertensive patients with type 2 diabetes. There was a 35% relative risk reduction in a three-step ETDRS change in incidence of retinopathy in type 1 diabetes, and a 34% increase in the chance of regression (three steps for 1 year or two steps for 2 or more years) in type 2 diabetes. No significant effect was seen on three-step progression of existing retinopathy in patients with type 1 or type 2 diabetes, although candesartan use was uniformly and statistically significantly associated with less retinopathy progression (one-step change).

PKCβ inhibition

Ruboxistaurin has been shown to reduce visual loss in patients with moderately severe non-proliferative retinopathy and macular edema. Further trials are ongoing to better establish its place in retinopathy management.

Lipid-lowering agents

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found a significant reduction in the need for laser therapy (5.2% versus 3.6%: p=0.0003) in 9795 patients with type 2 diabetes treated for 5 years. This effect was independent of blood lipid levels and is unexplained. Absolute numbers of patients were small and the indications for laser therapy were not specified so interpretation of these data is difficult. No consistent effect of statin therapy on retinopathy has been reported.

Growth hormone inhibitors

The observation of a regression in proliferative retinopathy in a woman with Sheehan’s syndrome (postpartum hypopituitarism) and the subsequent clinical trials (in the days before photocoagulation) of hypophysectomy in patients with advanced eye disease established a potential link between growth hormone and neovascularisation. Octreotide (a somatostatin analog that blocks growth hormone release) has been shown to decrease progression of severe non-proliferative or early proliferative retinopathy but had serious GI side effects.