The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy

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1 (2002) 16, S42 S Nature Publishing Group All rights reserved /02 $ : implications for therapy in diabetic retinopathy AK Sjølie 1 and N Chaturvedi 2 1 Department of Ophthalmology, Odense University Hospital, Odense, Denmark; 2 Imperial College, London, UK Retinopathy is the most common complication of diabetes, and a leading cause of blindness in people of working age. Optimal blood pressure and metabolic control can reduce the risk of diabetic retinopathy, but are difficult to achieve in clinical practice. In the EUCLID Study, the angiotensin converting enzyme (ACE) inhibitor lisinopril reduced the risk of progression of retinopathy by approximately 50%, and also significantly reduced the risk of progression to proliferative retinopathy. These findings are consistent with extensive evidence that the renin-angiotensin system is expressed in the eye, and that adverse effects of angiotensin II on retinal angiogenesis and function can be inhibited by ACE inhibitors or angiotensin II-receptor blockers. However, in the EUCLID Study retinopathy was not a primary end-point and the study was not sufficiently powered for the eye-related outcomes. Hence, the Diabetic Retinopathy Candesartan Trials (DIRECT) programme has been established to determine whether AT 1 -receptor blockade with candesartan can prevent the incidence and progression of diabetic retinopathy. This programme comprises three studies, involving a total of 4500 patients recruited from about 300 centres worldwide. The patients are normotensive or treated hypertensive individuals, and so the DIRECT programme should assess the potential of an AT 1 -receptor blocker to protect against the pathological changes in the eye following diabetes. (2002) 16, S42 S46. doi: /sj.jhh Keywords: candesartan; AT 1 -receptor blockers; diabetic retinopathy; DIRECT programme; EUCLID Study; lisinopril; reninangiotensin system Introduction Retinopathy is the most common complication of diabetes. Twenty years after the onset of diabetes, sight-threatening retinopathy is present in approximately 40% of patients with type 1 diabetes, and 20% of those with type 2 diabetes, making diabetic retinopathy one of the leading causes of blindness in people of working age. 1 3 Diabetic retinopathy is characterised by capillary dilatation and leakage, capillary occlusion, and subsequent new vessel formation. The presentation varies, however, depending on the type of diabetes. In type 1 diabetes, the most common cause of visual loss is proliferative retinopathy, 1,2,4 which leads to severe haemorrhage into the vitreous; in type 2 diabetes, the most common cause is macular oedema 1,5 caused by breakdown of the blood-retinal barrier. Current treatment of diabetic retinopathy focuses on good metabolic control with laser treatment being reserved for patients with severe and irrevers- Correspondence: AK Sjølie, MD, Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark. a.k.sjoelie@ouh.dk ible ischaemic damage to the retina. The importance of good metabolic control was shown in the Diabetes Control and Complications Trial (DCCT), in which intensive glycaemic control achieved an average reduction in glycosylated haemoglobin (HbA 1C ) from 9.0% to 7.1%, followed by a 76% reduction in the risk of new retinopathy, and a 56% reduction in progression of retinopathy. 6 Similarly, in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that as a result of intensive glycaemic control, progression of diabetic retinopathy was reduced by 21%, and need for laser photocoagulation by 29% over a 12 year period. 7 The degree of impact on retinopathy end points did not appear to differ by choice of agent (sulfonylurea or insulin). Optimal metabolic control can thus reduce the risk of diabetic retinopathy, but is difficult to achieve in clinical practice. Blood pressure and diabetic retinopathy Both observational and clinical trials have shown that blood pressure is an important modifiable risk factor for diabetic retinopathy, and that lowering high blood pressure significantly reduces the development and progression of retinopathy. 8,9

2 Evidence for the relationship between blood pressure and risk of diabetic retinopathy comes from a population-based study in Wisconsin in type 1 diabetes. 8 Increasing levels of diastolic blood pressure was associated with a moderate increase in the risk of any progression of retinopathy; however, the risk of progression to proliferative retinopathy was increased almost seven-fold in patients of the highest blood pressure quartile, compared with those of the lowest quartile (Figure 1). The EUCLID Trial The EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) was undertaken in 18 European centres. 10,11 This was a randomised, double-blind study involving 530 normotensive patients (normotensive BP 140/90 mm Hg) with type 1 diabetes, who were treated with the angiotensin converting enzyme (ACE) inhibitor lisinopril, mg/day, or placebo for 2 years. The primary end point was the progression of renal disease, assessed by the rate of change in albumin excretion rate; secondary end points included the progression of retinopathy, progression to proliferative retinopathy, and the incidence of new retinopathy. Retinal photographs were taken of two fields of each eye the macula temporal and the disc nasal on entry to the study and after 2 years treatment; a total of 354 patients had photographs on both occasions. The diapositives were graded according to the EURODIAB protocol at a central laboratory on a five-level scale 12 according to the severity of lesions. Patients who had panretinal photocoagulation were assigned to the proliferative level. The odds ratios for the risk of progression by at least one level or by two levels were 0.50 (95% confidence interval , P = 0.02) and 0.27 ( , P = 0.05), respectively in patients treated with lisinopril. The odds ratio for the risk of progression to proliferative retinopathy compared to placebo was 0.18 ( , P = 0.03; Figure 2). Lisinopril treatment was also associated with a 31% decrease in the incidence of new retinopathy, although this effect did not reach statistical significance (Figure 2). The effect of lisinopril was present independent of the degree of retinopathy at baseline (Figure 3). Although not reaching statistical significance, previous, smaller studies also indicate that ACE inhibitor treatment reduces the risk of progression of retinopathy in both type 1 and type 2 diabetes A meta-analysis of the pooled data from these studies and from the EUCLID study is shown in Figure 4. Evidence that lowering elevated blood pressure reduces the risk of retinopathy in type 2 diabetes comes from a substudy of the United Kingdom Prospective Diabetes Study (UKPDS), in which 1148 hypertensive patients (mean blood pressure 160/94 mm Hg at baseline) were randomised to receive tight blood pressure control aimed at achieving a Figure 2 Effect of lisinopril on the progression of diabetic retinopathy in the EUCLID Study. 11 Results are presented as odds ratio and 95% confidence intervals. Reprinted with permission from Elsevier Science (Lancet 1998; 351: 28 31). S43 Figure 1 Progression of diabetic retinopathy over 4 years in patients with type 1 diabetes, according to diastolic blood pressure (DBP). 8 Reproduced with permission from Klein R et al. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Arch Intern Med 1989; 149: Copyrighted (1989), American Medical Association.

3 S44 Figure 3 Effect of lisinopril on progression of diabetic retinopathy in the EUCLID Study, according to degree of retinopathy at baseline. 11 Reprinted with permission from Elsevier Science (Lancet 1998; 351: 28 31). Figure 4 Meta-analysis of effects of ACE inhibitor therapy on progression of diabetic retinopathy in the EUCLID Study 10 and previous studies Results are presented as odds ratios and 95% confidence intervals. Adapted with permission from reference 10. blood pressure below 150/85 mm Hg, or less tight control with a target blood pressure of less than 180/105 mm Hg. 9 Tight blood pressure control was associated with a 34% reduction (P = 0.004) in the risk of progression of retinopathy by two or more steps over 7 years. This reduction was partly attributable to a 35% reduction (P = 0.023) in the risk of retinal photocoagulation, but the effect was still present when retinal photocoagulation was excluded. Optimal metabolic and blood pressure control can thus reduce the risk of diabetic retinopathy, but are difficult to achieve in clinical practice. As a result, sight-threatening diabetic retinopathy remains a major clinical problem. The renin-angiotensin system in the eye The finding that ACE inhibitor treatment can delay the progression of diabetic retinopathy is consistent with extensive evidence that the renin-angiotensin system is expressed in the eye. Studies have shown that ACE is produced locally by vascular endothelial cells 16 and retinal pigment epithelial cells. 17 Furthermore, ACE expression has been reported to have adverse effects on retinal blood flow and vascular structure that are independent of changes in systemic blood pressure. 18 Similarly, angiotensin II has been shown to stimulate the formation of new retinal blood vessels, possibly via potentiation of vascular endothelial growth factor (VEGF) activity. 19 The role of the renin-angiotensin system in the development of proliferative retinopathy has been studied in experiments using a model of retinopathy of prematurity. In this model, neonatal rats are exposed to a high-oxygen environment, leading to cessation of normal retinal angiogenesis; when these animals are returned to room air, the retina becomes hypoxic, resulting in the development of proliferative retinopathy similar to that seen in diabetes. Recent studies have shown that the development of new retinal vessels in rats with retinopathy of prematurity can be inhibited by treatment with the ACE inhibitor lisinopril or the angiotensin II type 1 (AT 1 )-receptor blocker losartan. 20 Furthermore, lisinopril reduced the expression of VEGF and its type 2 receptor in the retina and proliferating blood vessels, whereas losartan had no such effect. A recent study has investigated the effect of the AT 1 -receptor blocker candesartan on VEGF expression and retinal function in spontaneously hypertensive rats with streptozotocin-induced diabetes. 21 A significant increase in retinal VEGF expression was found in the diabetic animals compared with control animals; treatment with candesartan cilexetil, 3 mg/kg, restored VEGF mrna expression to levels similar to those in untreated animals, whereas in animals receiving 1 mg/kg, VEGF expression was not significantly different from that in animals receiving streptozotocin alone. Similarly, streptozotocin treatment increased the latencies of the retinal oscillatory potential peaks (O1, O2 and O3) compared with untreated animals; candesartan cilexetil, 1 mg/kg, had no effect on the latency of these peaks, whereas a 3 mg/kg dose reduced the latency to that seen in untreated animals (Figure 5). These changes were independent of changes in blood pressure. Such studies suggest that complete blockade of the renin-angiotensin system is necessary for an organ protective effect. The DIRECT programme Although previous studies have shown that blockade of the renin-angiotensin system can reduce the progression, and possibly the incidence, of diabetic nephropathy, these were not designed primarily to

in the secondary prevention studies. Retinopathy will be assessed according to the ETDRS protocol at the Retinopathy Grading Centre at Imperial College, London.

4 in the secondary prevention studies. Retinopathy will be assessed according to the ETDRS protocol at the Retinopathy Grading Centre at Imperial College, London. The primary end point is incidence of retinopathy in the primary prevention study and progression of retinopathy in the secondary prevention studies. Incidence is defined as a two-step progression on the ETDRS scale from 10/10; progression is defined as a three-step change. The secondary end point is the rate of change in urinary albumin excretion rate. A pooled analysis of the data from all three studies will compare the incidence of microalbuminuria between the candesartan and placebo groups. The sample size of approximately 4500 patients has been calculated to provide 90% power at a 5% significance level to detect a clinically meaningful effect, taking withdrawals and treatment with ACE inhibitors into account. S45 Figure 5 Effect of candesartan cilexetil, 1 mg/kg or 3 mg/kg on the latency of the O1 oscillatory peak in the retina of spontaneously hypertensive rats with streptozotocin-induced diabetes. 21 Data are presented as means ± s.d. Reprinted with permission from Nagisa Y et al. The angiotensin II receptor antagonist candesartan cilexetil (TCV-116) ameliorates retinal disorders in rats. Diabetologia 2001; 44: study retinopathy and were under-powered for the eye-related outcome measures used. The Diabetic Retinopathy Candesartan Trials (DIRECT) programme has therefore been designed to answer the question of whether blockade of the renin-angiotensin system with the AT 1 -receptor blocker candesartan can prevent the incidence and progression of retinopathy in type 1 and type 2 diabetes. 22 This programme consists of three randomised, doubleblind, placebo-controlled, parallel-group studies: a primary prevention study involving 1700 type 1 diabetic patients without diabetic retinopathy; a secondary prevention study involving 1200 type 1 diabetic patients with diabetic retinopathy; a secondary prevention study involving 1600 type 2 diabetic patients with diabetic retinopathy. In each trial, patients will be randomised to receive candesartan cilexetil, mg/day, or placebo, and followed for at least 3 years. Patients with type 1 diabetes are eligible for inclusion if they are normoalbuminuric and normotensive (blood pressure 130/85 mm Hg or below). For patients with type 2 diabetes, the inclusion criteria are normoalbuminuria and either normal blood pressure without antihypertensive treatment or a blood pressure of 160/90 mm Hg or less during treatment. In the secondary prevention studies, patients have mild to moderate non-proliferative retinopathy, equivalent to levels on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Patients will be recruited in about 300 centres worldwide. Seven-field retinal photographs will be taken annually, and additionally after 6 months treatment Conclusions Diabetic retinopathy remains a serious clinical problem. Although optimal blood pressure and glycaemic control can significantly reduce the risk of progression of retinopathy, these are difficult to achieve in clinical practice. Pharmaceutical treatment that may prevent the development of retinopathy before irreversible ischaemic damage has occurred would offer an important contribution to the management of the diabetic patient. The DIRECT programme will assess the potential of AT 1 -receptor blockade with candesartan to prevent sight-threatening retinopathy or nephropathy, independently of changes in blood pressure. References 1 Klein R, Klein BEK. Vision disturbances in diabetes. In: Harris MI (ed). Diabetes in America, 2nd Edition National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease. US Public Health Service 1995 (NIH Publ no ). 2 Klein R et al. The Wisconsin epidemiologic study of diabetic retinopathy II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984; 102 : Sjølie AK et al. The EURODIAB IDDM Complications Study Group. Retinopathy and vision loss in insulin dependent diabetics in Europe. Ophthalmology 1997; 104: Sjølie AK. Ocular complications in insulin-treated diabetes mellitus. An epidemiological study. Acta Ophthalmol 1985; Suppl 172: Klein R et al. The Wisconsin epidemiologic study of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984; 102: The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: UK Prospective Diabetes Study Group. Intensive

5 S46 blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. (UKPDS 33). Lancet 1998; 352: Klein R et al. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Arch Intern Med 1989; 149: UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317: The EUCLID Study Group. Randomised placebocontrolled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997; 349: Chaturvedi N et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 1998; 351: Aldington SJ et al. Methodology for retinal photography and assessment of diabetic retinopathy: the EURODIAB IDDM Complications Study. Diabetologia 1995; 38: Larsen M, Hommel E, Parving HH, Lund-Andersen H. Protective effect of captopril on the blood-retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy. Graefes Arch Clin Exp Ophthalmol 1990; 228: Chase HP et al. Angiotensin-converting enzyme inhibitor treatment for young normotensive diabetic subjects: a two-year trial. Ann Ophthalmol 1993; 25: Ravid M et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type 2 diabetic patients. Ann Intern Med 1993; 118: Danser AH et al. Angiotensin levels in the eye. Invest Ophthalmol Vis Sci 1994; 35: Wagner J et al. Demonstration of renin mrna, angiotensinogen mrna, and angiotensin converting enzyme mrna expression in the human eye: evidence for an intraocular renin-angiotensin system. Br J Ophthalmol 1996; 80: Engler CB et al. Blood-retina barrier permeability in diabetes during ACE inhibition. Acta Ophthalmol 1991; 69: Otani A, Takagi H, Suzuma K, Honda Y. Angiotensin II potentiates vascular endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells. Circ Res 1998; 82: Moravski CJ et al. Retinal neovascularization is prevented by blockade of the renin-angiotensin system. Hypertension 2000; 36: Nagisa Y, Shintani A, Nakagawa S. The angiotensin II receptor antagonist candesartan cilexetil (TCV-116) ameliorates retinal disorders in rats. Diabetologia 2001; 44 : Sjølie AK for the DIRECT Programme Steering Committee. The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme. JRAAS 2001; 2: 58.

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