WESDR. Less information is available for African Americans with type 1 DM. From the New Jersey 725 study, baseline poor glycemic control and proteinuria were predictors for higher 6-year incidence rates of doubling of the visual angle.25

4.3 Effects of Systemic Drugs

4.3.1 Diuretics

In a univariate analysis, the use of diuretics by patients with diabetes was associated with more severe diabetic retinopathy.58 Furosemide has been associated with improvement in DME in a patient with the nephrotic syndrome.97 This clinical observation contradicts the implication of an experimental study in monkeys showing inhibition of the retinal pigment epithelial pump by furosemide and was explained by hypothesizing a normalization of vascular oncotic pressure in the patient with nephrotic syndrome.97,115 History of diuretic use at baseline was not associated with 10-year incidence of DME in WESDR.23

4.3.2 Renin–Angiotensin System Drugs

The renin–angiotensin system is a biochemical pathway active within the retina and suspected to be of clinical importance in the regulation of retino-

vascular tone and inflammatory pathways (see Chapter 1).116,117 Renin cleaves angiotensinogen to

yield angiotensin I, which is in turn cleaved by angiotensin-converting enzyme (ACE) or chymase into angiotensin II. Angiotensin II binds to the angiotensin II receptor (type I) to produce vasoconstriction and activation of nuclear factor-kB. ACE inhibitors and angiotensin receptor (type 1) blockers treat hypertension by inhibiting this pathway, leading to vasodilation.117 Angiotensin II also promotes angiogenesis and increased vascular permeability, providing a rationale for how ACE inhibi-

tors might beneficially affect DME and progression to PDR.116

The clinical effects of drugs designed to act at various points of the RAS pathway have been

inconsistent. In a controlled, open label study, the ACE inhibitor lisinopril was effective in reducing DME.118 An acute decrease in blood pressure associated with a dose of captopril in hypertensive diabetics with nonproliferative retinopathy was not associated with an acute change in the blood–retinal

barrier permeability, but over 6 months of captopril therapy the permeability declined.119,120 In normo-

tensive diabetics treated with captopril for 18 months, the blood–retinal barrier permeability also declined.121 The EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes examined normotensive patients randomized to lisinopril 10–20 mg/day or placebo over 2 years of follow-up. Retinopathy severity was graded from fundus photographs and retinopathy end points were secondary outcomes. The odds ratios for risk of progression by two levels of retinopathy severity was 0.27 (95% CI 0.07–1.99, P ¼ 0.05) and for progression to PDR was 0.18 (95% CI 0.04–0.82, P ¼ 0.03).122 A meta-analysis of four clinical studies of ACE inhibitors on progression of DR led to a conclusion of a suggested beneficial effect.117

On the other hand, the ACE inhibitor captopril was no more effective than atenolol in retarding progression of retinopathy in the UKPDS.61 In a univariate analysis from a separate epidemiologic study, the use of angiotensin-converting enzyme inhibitors by patients with diabetes was associated with more severe, rather than less severe, diabetic retinopathy.58

In a trial of candesartan, a blocker of the angiotensin receptor (type 1), in which retinopathy end points were the primary outcomes, results depended on the presence or absence of retinopathy at baseline. Treatment of type 1 diabetic patients without retinopathy at baseline showed a reduction in incidence of 3-step progression of retinopathy at 4.7 years of follow-up.123 In a parallel study involving patients with baseline diabetic retinopathy and similar follow-up, candesartan did not affect 3-step progression of retinopathy.123 A phase 2 randomized clinical trial is presently underway comparing the renin inhibitor aliskiren versus amlopidine in patients with hypertension and DME (Novartis protocol SPP100A2244). Further work will be needed to unravel the complicated effects of the RAS pathway on DR.

4.3.3 Aldose Reductase Inhibitors

Aldose reductase inhibitors are hypothesized to be useful in treating diabetic retinopathy based on two mechanisms. First, hyperglycemia can cause increases in intracellular sorbitol mediated by the enzyme aldose reductase. Increased intracellular sorbitol in turn causes cytoplasmic swelling via osmosis. Second, the conversion of glucose to sorbitol catalyzed by aldose reductase requires NADPH as a cofactor. By depleting cellular NADPH supplies, the aldose reductase reaction reduces intracellular defenses against reactive oxygen species. Aldose reductase inhibitors thus act in two ways to mitigate the adverse effects of hyperglycemia.

Two aldose reductase inhibitors have been used clinically in the context of diabetic retinopathy. Sorbinil slightly reduces the rate of new microaneurysm formation. Tolrestat decreases leakage from focal intraretinal lesions on fluorescein angiography. Both effects, however, can be achieved by glucose control itself, and in clinical practice, the minimal beneficial effects and significant side effects of these drugs have prevented their widespread adoption as a method of treating diabetic retinopathy.55

4.3.4 Drugs That Target Platelets

Forty-five years ago it was observed that patients with rheumatoid arthritis taking aspirin who also had diabetes seemed to have a lower prevalence of DR than would have been expected, prompting the hypothesis that aspirin might be a medical therapy for DR.124 The hypothesis is rational because of evidence that capillary microthrombi are important in the pathogenesis of diabetic retinopathy and that hyperglycemia impairs platelet function.125 Subsequently, anti-platelet aggregation drugs have been studied in clinical trials designed to investigate their effects on diabetic retinopathy.55

Aspirin decreases platelet aggregation by inhibiting platelet cyclooxygenase-1. This in turn reduces production of thromboxane A2, a mediator of platelet aggregation. In a clinical trial of aspirin 1 g orally per day compared to placebo, there was a statistically significant but clinically unimpressive decrease in microaneurysm counts associated with aspirin use.

The lack of a clinically important effect together with a high incidence of gastrointestinal side effects with this high-dose aspirin therapy has not led to widespread advocacy of aspirin therapy for early diabetic retinopathy, but many patients do take such therapy for cardiovascular indications.55,126 Worries that aspirin therapy might lead to worse vitreous hemorrhaging in more advanced diabetic retinopathy was one concern studied in the ETDRS. In that study, the risk of vitreous hemorrhage and visual loss in the aspirin group was no higher than in the placebo group. In addition, progression of retinopathy was no different between the aspirin and control groups.127 Other studies provide supportive evidence of lack of effect of aspirin on time to occurrence or recurrence rates of diabetic vitreous hemorrhage.128

There is no evidence that aspirin use influences prevalence of DR.13,23 The 10-year incidence of DME in

both younger onset and older onset diabetics was not associated with baseline use of aspirin.23

Dipyridamole inhibits platelet aggregation by inhibiting platelet reuptake of adenosine and inhibiting platelet adenosine deaminase, both actions that increase extracellular adenosine concentrations, an anti-platelet aggregation mechanism independent of that of aspirin. A clinical trial comparing combination therapy with aspirin 1 g orally per day and dipyridamole 25 mg orally per day reduced microaneurysm counts compared to placebo and compared to aspirin alone. The effect, although statistically significant, was clinically unimpressive, and such therapy has not been adopted for the treatment of diabetic retinopathy. As with aspirin monotherapy, there are many patients who take such combined therapy for independent car-

diovascular indications, and they may be accruing a small benefit with regard to their retinopathy.55,126

Ticlopidine is an adenosine diphosphate receptor inhibitor that reduces platelet aggregation. Oral therapy reduced microaneurysm counts but side effects such as thrombotic thrombocytopenic purpura and neutropenia outweighed the retinopathy benefits, and in general it is not used for the treatment of diabetic retinopathy.55

In summary, considerable basic science suggests that anti-platelet drugs might have beneficial effects on DR, but no clinical trials have yet proven their importance.129 It is possible that different dosing regimens or combinations of drugs may realize the promise of this therapeutic avenue.130