Prevention and Treatment of Diabetic Retinopathy

Current Diabetes Reviews, 2011, 7, 000-000

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Prevention and Treatment of Diabetic Retinopathy: Evidence from Clinical Trials and Perspectives Manuela Abbate1, Paolo Cravedi1, Ilian Iliev1, Giuseppe Remuzzi1,2 and Piero Ruggenenti1,2 1 2

Clinical Research Center for Rare Diseases ‘Aldo & Cele Daccò’, Mario Negri Institute for Pharmacological Research Unit of Nephrology, Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy Abstract: Diabetic retinopathy is the most common microvascular complication of diabetes mellitus and is the leading cause of blindness amongst working-age adults in Western countries. Large observational and randomized studies have consistently shown that optimal blood glucose and blood pressure control is the key component of intervention strategies aimed to halt or regress the disease, and limit the risk of progression to the proliferative stage, with consequent visual loss up to blindness in most severe cases. Amelioration of dyslipidemia by statins, especially if combined with fenofibrate, may also ameliorate retinopathy in line with a potential pathogenic role of hyperlipidemia. Recently, evidence has also emerged that renin-angiotensin system (RAS) inhibitors may electively prevent or delay progression of retinopathy, possibly because of specific protective effect against the structural and functional retinal changes sustained by local RAS activation. Thus, metabolic and blood pressure control by RAS inhibition is to prevent or limit the onset of retinopathy and its progression towards visual-threatening stages. Topic treatment with anti-vascular endothelial growth factor (VEGF) agents is emerging as a treatment option for retinopathy in advanced stages to limit the need for laser photocoagulation. This option however should be considered with caution due to the risk of systemic adverse events.

Keywords: Diabetic Retinopathy, Fenofibrates, Glycemic control, Renin-Angiotensin system, Statins, anti-VEGF agents. Diabetic retinopathy is a specific microvascular complication of diabetes mellitus and is the most common cause of blindness in Western countries [1]. Prevalence of retinopathy increases with the duration of diabetes, to the point that, after 20 years from onset, almost all type 1 diabetic patients and 60% of those with type 2 diabetes will develop some degree of retinopathy [2]. Notably, during the last 30 years, the incidence of diabetes has reached epidemic proportions and continues to rise both in industrialized [3, 4] and in emerging countries [5], which is expected to further increase the burden of retinopathy and other chronic complications. Thus, optimization of available prevention and treatment strategies and development of new tools will be instrumental to face this health care emergency. HISTORICAL PERSPECTIVE Though diabetes was already known as a clinical entity since the 2nd century A.D., it was only in 1846 that the French ophthalmologist and Professor of Hygiene in Paris, Apollinaire Bouchardat, proposed a link between diabetes and eye disease. He reported that diabetic patients may develop visual loss, whose severity is reduced up to complete recovery with better glycemic control [6]. Thereafter, the introduction of the ophthalmoscope allowed Henry Noyes in 1869 and by Edward Nettleship in 1872 to describe more in detail the retinal changes associated with diabetes [7-9].

*Address correspondence to this author at the Unit of Nephrology, Azienda Ospedaliera Ospedali Riuniti di Bergamo, Largo Barozzi 1, 24128 Bergamo, Italy; Tel: +39 035-269692; Fax: +39 035-266692; E-mail: [email protected] 1573-3998/11 $58.00+.00

Nevertheless, at the beginning of the 20th century, there were still controversies on the relative impact of diabetes and hypertension on macular changes. This debate continued until 1943, when Arthur James Ballantyne showed that retinopathy is a unique form of vasculopathy characterized by capillary wall alterations and presence of deep waxy exudates in the external plexiform layer [10]. At the same time, the German ophthalmologist Gerard Meyer-Scwickerath began to investigate the potential use of light to coagulate retinal tissue and in 1950 he reported treatment of retinal disorders with photocoagulation [11], which in 1963 was introduced in the clinics as treatment for retinopathy. Since then, new surgical treatments were continuously developed until the establishment of pan-retinal laser photocoagulation as the standard of care for advanced stages of retinopathy. Between the 80s and the 90s, three landmark trials, the Diabetes Control and Complications Trial (DCCT) [12], the United Kingdom Prospective Diabetes Studies (UKPDS) [13, 14] and the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) [15] found that poor glycemic and blood pressure control were major risk factors for the development of retinopathy in both type 1 and 2 diabetes. Since then, we have watched a closely spaced succession of interventional trials trying to assess novel medical strategies to prevent the onset, retard progression and, more recently, promote regression of retinopathy. This process has been paralleled by the development of standardized criteria for the diagnosis and grading of retinopathy to guide prevention and intervention strategies. One of the most commonly used reference scale is the one devel© 2011 Bentham Science Publishers Ltd.

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oped in 2003 by the World Health Organization (WHO) [16] that classifies retinopathy into five stages [17, 18]. Such classification was created to uniform a series of different scales which originated from the one proposed by the Early Treatment Diabetic Retinopathy Study (ETDRS) in 1980, based on the modified Airlie House classification [19]. RISK FACTORS AND THERAPEUTIC TARGETS Hyperglycaemia Poor glycemic control is associated with retinal microvascular injury and dysfunction [20]. According to the 2010 guidelines of the American Diabetes Association (ADA), risk of retinopathy and other micro-vascular diabetes associated complications dramatically rise at fasting plasma glucose levels higher than 126 mg/dl or when glycated haemoglobin (HbA1c) percentage exceeds 7.0% [21]. However, recent meta-analyses and population studies showed that risk of retinopathy is not an all-or nothing phenomenon. Indeed, there are no cut-off HbA1c levels that segregate patients with or without risk, and in actual facts even diabetic patients with HbA1c levels less than 7% may develop retinal changes [22-25]. Consistently, the WESDR II [15] and III [2] studies found a continuous, direct relationship between HbA1c levels and risk of retinopathy onset and progression and of macular edema onset. TYPE 1 DIABETES - The DCCT Research Group [12] compared the effect of targeting insulin therapy to fasting blood glucose between 70 and 120 mg/dl vs. a hyperglycaemic symptom-driven approach on retinopathy onset and progression in 1,144 type 1 diabetics with no (n=726) or mild retinopathy (n=715) at baseline. Over a mean follow-up period of 6.5 years, lower glucose targets reduced risk of retinopathy onset and progression by 76% and 54% compared to the clinical-based control, respectively. Interestingly, followup analyses of the DCCT trial showed that, at 4 years after the end of the trial, 17.8% of patients maintained on lower glycemic levels had progressed to various levels of retinopathy compared to 48.9% of those on less tight glycemic control and, at 10 years, the percentages were of 35.8% vs. 60.6%, respectively [27]. Notably, the ETDRS study found that beneficial effects of glycemic control on retinopathy prevention and treatment extends across all ages and all stages of retinopathy [26]. Thus, the protective effect of intensified blood glucose control against retinopathy is clear-cut and is even sustained over time, which led to the concepts of ‘metabolic memory’ or ‘legacy effect’ [28]. Indeed, beneficial effects of a period of intensive glycemic control have been shown to persist after return to higher glucose levels. Though no clear mechanistic explanation for this intriguing phenomenon exists, it has been hypothesized that long-term effects of relatively short periods of metabolic control may result into influence on gene expression by epigenetic processes. On the other hand, evidence that the positive effects observed in the DCCT trial were achieved at the expense of a three-fold higher risk of hypoglycaemic episodes in the intensive-therapy group compared to the conventional-therapy group must be taken to emphasize that intensified glucose control should be considered with caution, in particular in older subjects with established macrovascular disease who

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are at increased risk of cardio or cerebrovascular events associated with hypoglicemic episodes. TYPE 2 DIABETES – Beneficial effect of blood glucose control on ocular complications has been consistently reported also in type 2 diabetes patients. The UKPDS trial [29] randomised 3,867 newly diagnosed type 2 diabetic patients to hypoglycaemic therapy targeting fasting blood glucose levels lower than 108 mg/dl (intensive treatment) or 270 mg/dl (standard treatment). After 10.5 years of follow-up, patients randomized to lower blood glucose levels had a 29% lower need for photocoagulation compared to those in the conventional treatment group and risk reduction was independent of the use of either insulin or sulphonylureas to control glycaemia. On the other hand, as previously observed by DCCT in type 1 diabetes, patients in the intensive treatment group tended to have a higher incidence of hypoglycaemic episodes (6.1%) compared to those on control therapy (4.4%). Similar outcomes were observed in the Kumamoto Study [30], which included 110 type 2 diabetes patients randomized to a multiple insulin injection therapy group (MIT) with three or more insulin injections a day, or a conventional insulin injection therapy (CIT) with one or two daily intermediate-acting insulin injections. In both groups target fasting blood glucose was lower than 140 mg/dl. After 8 years of follow-up, incidence of new-onset retinopathy amongst patients with no retinal changes at baseline was significantly lower in the MIT compared to the CIT group (15.4% vs. 47.8%, p=0.022). Consistently, the percentage of patients with retinopathy at inclusion who progressed to proliferative retinopathy was significantly lower in the MIT compared to the CIT group (24.0% vs. 56.0%, p=0.023). Episodes of mild hypoglycaemia in the MIT occurred 1.6 times more frequently than in the CIT group. Consistent data showing a beneficial effect of very intensified metabolic control on ocular complications in diabetes patients, formed the rationale for three recent trials, the Action in Diabetes and Vascular Disease (ADVANCE) [31], the substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [32] on progression of retinopathy (the ACCORD eye study) [33], and the Veterans Affairs Diabetes Trial (VADT) [34] testing whether a therapeutic strategy targeting normal HbA1c levels (i.e., below 6.5%, 6%, or 6% respectively) would reduce the rate of microvascular complications, as compared with a strategy targeting HbA1c levels between 7.0, 7.9% and 9%, respectively. Unexpectedly, however, targeting therapy to normal or near normal glycemic levels provided no additional benefit in terms of prevention of retinopathy onset or progression over less tight metabolic control in the ADVANCE as well as in the VADT trials. The ACCORD eye trial was in fact the only study showing a significant reduction in the risk of progression of retinopathy after 4 years of follow-up (P=0.003). This benefit, however, was offset and increased all-cause and cardiovascular mortality [32, 35]. Debate has successively risen around the safety of the glucose-lowering strategy used, which included the use of rosiglitazone, a hypoglycaemic agent associated with increased risk of myocardial infarction and death from cardiovascular causes [36-38]. The role of a metabolic control aimed at achieving “normoglycemia” in prevention or treatment of retinopathy was

Medical Therapy of Diabetic Retinopathy

also challenged by results of the Veterans Affairs Diabetes Trial (VADT) [34], a study that in 1,791 military diabetic veterans, failed to detect any significant difference in all considered retinopathy outcomes between those randomized to more or less intensive glycemic control (HbA1c of 6% or 9%, respectively. Thus, hyperglycaemia is one of the major risk factors for retinopathy onset and progression and strict glycemic control is one of the cornerstones for its prevention and treatment. It could be argued that targeting HbA1c to normality (6.0 – 6.5%) is of no further benefit compared to levels around 7.0% and that titrating therapy to ‘normal’ Hb1C levels may even increase the risk of hypoglycaemic episodes and death. Nevertheless it should be acknowledged that, as demonstrated by studies with much longer follow ups such as the UKPDS [29] and the DCCT [27], benefits of glucose lowering strategies on retinopathy endpoints can be observed only after more than five years, which may explain negative outcomes seen in the ADVANCE and VADT trials. Hypertension Hypertension per se is strongly associated with a form of retinopathy characterised by retinal haemorrhages, macroand micro-aneurysms, cotton-wool spots and hard exudates [39]. Among diabetic patients, the prevalence of hypertension is two-fold higher than in the average population [40], and its incidence increases with duration of diabetes [41]. In combination with hyperglycaemia, hypertension may contribute to the onset and progression of retinopathy by altering endothelial cell structure and function and stimulating the release of vascular endothelial growth factor (VEGF) [42, 43]. Many cross-sectional and prospective studies showed a relationship between retinopathy and either systolic [2, 14, 44-48] or diastolic blood pressure [15, 49, 50]. In type 1 diabetes diastolic blood pressure higher than 90 mmHg is a risk factor for retinopathy occurrence and may accelerate its progression [51, 52], whereas in type 2 diabetes systolic blood pressure seems to play a more important role [53, 54]. To the best of our knowledge, no study formally compared the relationships between retinopathy (as well as other chronic complications) and systolic/diastolic blood pressure in subjects with type 1 or type 2 diabetes. However, we can speculate that this relationship may differ in the two cohorts of patients because of the different age at onset of retinopathy. Retinopathy is probably the earliest complication of type 1 diabetes and may affect relatively young subjects. In these subjects, increased blood pressure (BP) predominantly reflects peripheral vascular resistances that are too high compared to the cardiac output. The increase in peripheral vascular resistances is closely associated with an increase in diastolic BP, but has a lower effect on systolic BP. Thus, in younger subjects with type 1 diabetes diastolic BP might reflect the overall pressure stress to the vascular tree more closely than systolic BP. This might explain the closer relationship between diastolic BP and retinopathy and other complications in this population. In type 2 diabetes retinopathy normally affects subjects older than 60 years with long lasting history of hypertension. These are subjects with increased ventricular-arterial stiffness and a propensity to diastolic dysfunction [55]. These age-related changes are accelerated in subjects with diabetes and contribute to a progres-

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sive increase in systolic BP and a concomitant reduction in diastolic BP. This “paradoxical” reduction may confound the predictive role of diastolic BP vs macro and microvascular complications. Conversely, age-related worsening in arterial hypertension and vascular stiffness both converge to increase the systolic BP. Thus, a relatively old subject with type 2 diabetes and severe vascular disease will eventually have severe systolic hypertension with normal or even discordantly low diastolic BP. This reasonably explains why systolic hypertension is a strong predictor of both cardiovascular and microvascular complications in this population. The above considerations suggest that antihypertensive treatment in older subjects with type 2 diabetes should primarily target systolic BP. At the same time, however, too large reductions in diastolic BP that might impair diastolic coronary perfusion should be avoided to limit the risk of coronary events [56]. Independent of the above, hypertension is a crucial modifiable risk factor for retinopathy [44, 57-59]. A reduction in blood pressure decreases the risk of onset and progression of retinopathy, independently from the type of antihypertensive used and from glycemic control [14, 57, 60, 61]. TYPE 1 D IABETES - The WESDR XVII [57] study found that, in type 1 diabetes patients, blood pressure higher than 160/95 mmHg or 140/90 mmHg according to the age older or younger than 25 years, respectively, was associated with a 91% increase in the risk of progression to proliferative retinopathy and a 40% increase in the risk of developing macular edema compared to lower levels over 14 years of followup. Diastolic blood pressure was also found to be a predictor in the progression of retinopathy. Each 10 mmHg diastolic blood pressure increase during the first 4 years was associated with a 35% increase in the rate of progression across the whole 14-year period. Further analyses at 25 years of followup, however, found a less clear relationship between blood pressure and retinopathy, which led to the idea that, in type 1 diabetes, the association between hypertension and risk of retinopathy onset and progression is probably weaker than in type 2 diabetes [62]. TYPE 2 D IABETES - Prospective observational, and population-based cohort studies like the UKPDS, found a significant association between systolic blood pressure and incidence of retinopathy in subjects with type 2 diabetes [14]. Consistently, systolic/diastolic blood pressure reduction to less than 150/85 mmHg reduced by 34% the risk of retinopathy progression, compared to blood pressure levels lower than 180/105 mmHg, independently of which medications were used [60, 63]. Long term benefit of blood pressure control is demonstrated by further analysis of the UKPDS trial [64], where early blood pressure reduction in patients with newly diagnosed type 2 diabetes and hypertension reduced risk of complications at 10 years. Notably, systolic more than diastolic blood pressure appears to be a significant predictor of onset and progression of retinopathy in type 2 diabetes patients. Consistently, the UKPDS found that for each 10 mmHg decrease in mean systolic blood pressure corresponded a 13% reduction in the risk of developing retinopathy [61]. Results from the Appropriate Blood Pressure Control in Diabetes (ABCD) trial [65], which randomized, according to a factorial design, 470 hypertensive type 2 diabetes patients


to target diastolic blood pressure lower than 75 mmHg or between 80 and 89 mmHg with an antihypertensive regimen including either the calcium channel blocker (CCB) nisoldipine or the angiotensin converting enzyme (ACE) inhibitor enalapril found no significant differences on the progression of retinopathy over a 5 year period. Progression of retinopathy was indeed similar in all groups (30% and 33% in the intensive and moderate therapy groups respectively; 31% and 33% in patients randomized to either nisoldipine or enalapril, respectively), suggesting that very intensified blood pressure control - independently from antihypertensive drugs used - does not offer any advantage on prevention or progression of retinopathy, and may even expose patients to an increased risk of adverse events. Consistently, in 4733 patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure to less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events [66]. According to ADA guidelines [21], antihypertensive therapy aimed at preventing or limit the onset and progression of retinopathy should target blood pressure levels less than 130/80 mmHg. This applies both to type 1 and type 2 diabetes mellitus and should always be associated with optimized metabolic control since prolonged hyperglycemia may vanish beneficial effect of strict blood pressure control. Dyslipidemia Population-based studies suggest an association between hyperlipidemia and the presence of hard retinal exudates, and increased risk of macular edema, but data in type 1 and 2 diabetes are not homogeneous [26, 41, 50, 67-69]. Longitudinal analysis did not show association between hypercholesterolemia and risk of developing retinopathy or macular edema [70]. In the ETDRS [71], however, elevated levels of serum triglycerides, low-density lipoprotein (LDL) cholesterol, and decreased high-density lipoprotein (HDL) cholesterol values were associated with increased risk of developing hard exudates in the macula and a decrease in visual acuity. Some randomized clinical trials testing the effect of lipid-lowering therapy on retinal changes in type 1 and 2 diabetic patients suggested some efficacy of statins and fibrates in the prevention of retinopathy, hard exudates, and clinically relevant macular edema [72-74]. The results of these studies, however, were flawed by small sample-sizes and short follow-ups [75, 76]. TYPE 1 DIABETES - A cross-sectional analysis from the WESDR study showed that higher total serum cholesterol levels were associated with higher prevalence of retinal hard exudates in type 1 diabetic patients, independently of age, but did not significantly predict severity of retinopathy [77]. Small studies suggest that strict lipid control by statin therapy may have a beneficial effect on background retinopathy [76, 78], but larger trials are needed to support the use of these drugs for this indication. TYPE 2 DIABETES - The largest study on statin therapy, the Collaborative Atorvastatin Diabetes Study (CARDS), showed that, over a median follow-up of 3.9 years, there were no significant benefits of atorvastatin over placebo on retinal changes in 2,838 type 2 diabetic patients with reti-

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nopathy [79]. Recently, attention has also focused on fibrates as a novel treatment for dyslipidemia and retinopathy [80]. Fenofibrate is a peroxisome proliferactor-activated receptor (PPAR)- agonist which lowers plasma triglyceride levels, lowers LDL-cholesterol and apolipoprotein B levels, and raises HDL-cholesterol due to an overexpression of apolipoprotein A-I and II, and to an inhibition of apoliporpotein CIII expression [81, 82]. Thus in addition to influencing lipid metabolism, fenofibrate also exerts effects mediated by PPAR- activity which are likely to have beneficial effects on diabetes-related retinopathy [83]. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) was the first large randomized trial looking at the effect of fenofibrate on progression of retinopathy and need for laser treatment in 9,795 type 2 diabetic patients. Results showed that, compared to placebo, fenofibrate reduced the need for laser treatment for proliferative retinopathy by 30%, and for macular edema by 31% over a 5-year follow-up period [84, 85]. The ACCORD-Eye study [86] found than in 3,537 type 2 diabetic patients, 4-year combined fenofibrate and simvastatin therapy reduced the risk of retinopathy progression by 40% compared to simvastatin therapy alone, independently of glycemic control [33]. Finding that the protective effect of fenofibrates against retinopathy onset and progression observed in the FIELD and the ACCORD-Eye studies were independent of achieved serum lipid levels, consistently suggests that fenofibrate may have a specific role in intervention strategies aimed to prevent the onset and limit the progression of retinopathy in subjects with type 2 diabetes. The Role of Renin-Angiotensin System Inhibition Tissutal renin-angiotensin system (RAS) in the eye is activated by chronic hyperglycaemia [87] and eye RAS activation is in turn associated with local micro-vascular remodelling and proliferation [88]. Chronic hyperglycaemia induces over-expression of angiotensin II (AngII), which, through AngII receptor type 1 (AT-1), increases microvascular permeability and local oxidative stress [89-91], influences vasoconstriction [92] and promotes migration of pericytes [93]. Moreover, AngII induces cell growth and remodelling of extracellular matrix through stimulation of different growth factors, including transforming growth factor-beta (TGF-) and VEGF [94-97]. These experimental data converge to indicate that RAS blockers, namely ACE inhibitors and AngII Receptor Blockers (ARBs), might have a role in the prevention of retinopathy onset and progression [98-100]. The assumption that pharmacological inhibition of local RAS is effective in ameliorating retinal injury by reducing the over-expression of its ocular components is based on a number of in vitro and in vivo experimental studies [94, 101]. Through retinal proteome analysis, Gao et al. [102] showed that ARB candesartan normalized 72% of proteins differently expressed in diabetic vs. aged-matched non diabetic mice. Moreover, in 39 samples of vitreous fluid from type 1 and 2 diabetic patients affected by proliferative retinopathy, the ACE inhibitor enalapril reduced VEGF concentrations in a dose-dependent manner and independently of levels of systemic blood pressure [94]. Clinical trials were therefore designed to test whether drugs targeting the RAS



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Fig. (1). Effect of RAS inhibitor therapy on diabetic retinopathy prevention and treatment in diabetes patients. Treatment effects of ACE inhibitor or ARB therapy in main randomized clinical trials of RAS inhibition in the regression of retinopathy and prevention of retinopathy onset and progression in type 1 and type 2 diabetes patients.

might be a better option than other blood pressure lowering agents to prevent and treat retinopathy (Fig. 1). TYPE 1 DIABETES - The EURODIAB (Europe and Diabetes) Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID) study [103] was a double-blind,

randomised, clinical trial which sought to investigate the effect of 2-year therapy with ACE inhibitor lisinopril on retinopathy onset and progression in 530 normotensive type 1 diabetic patients, 41.5% of whom had retinopathy at baseline. Compared to placebo, lisinopril therapy reduced the risk


of retinopathy progression by 50% and the risk of progression to proliferative retinopathy by 80%. After adjusting for HbA1c and systolic blood pressure, lisinopril-associated reduction of onset was still significant, whereas decreased progression from non proliferative to proliferative retinopathy was not significant any longer. Authors concluded that although appropriate glycemic and blood pressure control can already halve the risk of retinopathy, the concomitant treatment with lisinopril may reduce risk even further, possibly due to a specific effect of ACE inhibitors on retinal flow and vascular structure. The Diabetic Retinopathy Candesartan Trial (DIRECT) Prevent-1, and Protect-1 [104, 105] randomized respectively 1421 and 1905 normoalbuminuric, normotensive or treated hypertensive patients with type 1 diabetes to either candesartan or placebo, and followed them for 4 years. In the DIRECT-Prevent 1 [104], the relative risk reduction in the incidence of retinopathy was of marginal significance in those taking candesartan (18%; p=0.051). The significance of treatment effect was fully lost after adjusting for baseline values of HbA1c, systolic blood pressure, duration of diabetes, and after adjusting for changes in systolic blood pressure during the trial. A significant difference was found between treatment arms only when a three-step increase on the ETDRS scale was considered instead of a two-step increase and data were adjusted for baseline values and timedependent systolic blood pressure. In the DIRECT-Protect-1 trial, progression of retinopathy to the proliferative state was identical in both groups (13%). In the multicenter Renin-Angiotensin System Study (RASS) [106], which compared the effect of ACE inhibitor enalapril, ARB losartan, and placebo on retinopathy progression for 5 years, both enalapril and losartan were associated with a reduction in the progression of diabetic retinopathy of 65% and 70% compared to placebo, respectively. Such effect was independent of glycemia and changes of blood pressure [106]. Altogether the above data converge to indicate that in type 1 diabetes patients, RAS inhibitor therapy may have a specific protective effect against onset and progression of retinopathy. However, as already observed for other chronic complications of diabetes [107], the incremental benefit of RAS vs non-RAS inhibitor therapy might increase for increasing levels of arterial blood pressure. Thus, in normotensive subjects or in subjects with blood pressure control in recommended target, the specific effect of RAS inhibition may be small and difficult to appreciate, whereas in those with severe or poorly controlled hypertension the benefit of RAS inhibition may be large and clinically relevant. TYPE 2 D IABETES – The Advance trial [108] compared the effect of combined ACE inhibitor perindopril and diuretic indapamide vs. placebo on macro- and microvascular outcomes in 11,140 type 2 diabetes patients. After 4.3 years of follow-up, incidence of microvascular outcomes, including retinopathy, was lower in the combined therapy cohort compared to the placebo arm, but the observed difference between treatment arms did not reach the statistical significance. Consistently, The DIRECT-Protect 2 trial [109] showed a non significant 13% reduction of progression of retinopathy in type 2 diabetics on ARB candesartan compared to placebo over a 4.7-year follow-up period. However,

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in patients with established retinal changes at inclusion, regression of retinopathy was 34% higher in the candesartan group (p=0.009). By the end of the trial, an overall change towards less severe retinopathy was observed in the candesartan group. Consistent findings were observed with the use of ACE inhibitors in a recent, pre-specified analysis of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) [110]. BENEDICT [111] was a prospective, randomized, double blind, parallel group study which was originally designed to evaluate the effects of the ACE inhibitor trandolapril, the non-dihydropyridine CCB (nd-CCB) verapamil, their combination, and placebo, on new onset microalbumiuria in type 2 diabetic patients with normal urinary albumin excretion at inclusion. Target systolic/diastolic blood pressure and HbA1c were 120/80 mmHg and 7%, respectively. The study also included the evaluation of ophthalmoscopies and retinal images at baseline, at yearly follow-up visits for 3 years, and at final visit. The analysis comprised 550 type 2 diabetic hypertensive patients, 90 of which already presented with non-proliferative or proliferative retinopathy at inclusion. At inclusion, patients with retinopathy (non- and proliferative) reported longer duration of diabetes, higher blood pressure levels, higher HbA1c and blood glucose levels, and higher urinary albumin excretion as compared to patients without retinopathy. Serum creatinine and blood lipids profile were comparable between the two groups. In the group with established retinal changes at inclusion, regression of retinopathy during follow-up was significantly more frequent in patients on ACE inhibitor therapy with trandolapril alone or combined to verapamil (42.9%) compared to those on non-ACE inhibitor therapy with placebo or verapamil (18.8%) (p=0.0193). Finding that the difference was significant also after adjusting for potential confounders such as baseline and follow-up metabolic and blood pressure control, provided convincing evidence that the higher rate of regression with trandolapril or trandolapril plus verapamil was explained by a specific affect of RAS inhibition. On the other hand, in the BENEDICT trial trandolapril as well as verapamil had no specific protective effect against the development of retinopathy in patients with no evidence of retinal involvement at study entry. This finding confirmed and extended data from DIRECT-Protect 2 trial that the ARB candesartan had no appreciable effect on progression of retinopathy in type 2 diabetic patients without retinal involvement at inclusion [109]. A reasonable explanation is that all patients were on intensified BP and metabolic control, which substantially decreased the overall incidence of events, reducing the statistical power of comparative analyses between treatment groups. Indeed, while optimized BP and metabolic control increased the number of regressions in those with retinal involvement at baseline, which increased the power of comparative analyses between treatment groups, in those without retinal disease optimized treatment decreased the incidence of newly onset retinopathy, which decreased the statistical power of between-group comparisons. An alternative or complementary explanation would be that mechanisms sustaining progression of retinopathy may differ from those at the basis of disease regression, which might translate into different response to ACE inhibitor therapy of patients with or without retinal changes to start with.


PERSPECTIVES Increased intraocular VEGF is associated with proliferative retinopathy in humans and intraocular injections of VEGF may induce the complication in non-human primates [112]. Recent findings suggest that, in subjects with diabetes, VEGF up-regulation is the main mediator of ocular neovascularisation. On the other hand, it has been suggested that at least part of the protective effect of ACE inhibitors and ARBs against progression of retinopathy could be mediated by retinal VEGF down-regulation [113-115]. Thus, experimental and clinical data converge to indicate that VEGF plays a major role in the pathogenesis of retinopathy and macular edema [116, 117], and VEGF inhibition might be a valuable option for the treatment of both conditions. The potential benefits of VEGF inhibitors, however, must be weighted against the potential harm, in particular because systemic VEGF inhibition has been associated with hypertension, arterial thromboembolic events [118], proteinuria, and suppressed angiogenesis with impaired wound healing and collateral vessel development. Diabetic patients could suffer an even greater risk as diabetes is characterised by a decreased expression of cardiac VEGF and its receptors [119]. Although safety issues cannot be fully prevented by intravitreal injections of anti-VEGF agents recent observations have shown, in the case of ranibizumab and bevacizumab, improved tolerability. The VEGF family comprises various isoforms, with VEGF165 being the one electively involved in the pathology of diabetic retinopathy [120]. Since the expression of this isoform is largely confined within the retina, specific VEGF165 inhibition might achieve the same benefits of unselective treatment but with a reduced risk of systemic adverse events. The first randomized prospective double-blind multicenter dose-ranging controlled trial which reported the effects of anti-VEGF therapy in diabetic patients, included 172 patients with macular edema, who were randomized to repeated intravitreal injections of the anti-VEGF165 pegaptamib or sham injections [121]. Patients receiving pegaptamib had lower need for photocoagulation, reduced retinal thickness, and better visual outcomes after 36 weeks compared with those on sham injections. A retrospective analysis of data from patients with proliferative retinopathy also showed regression of neovascularisation in patients treated with pegaptamib, even if recurrence was high after its discontinuation [116]. Additional uncontrolled studies on intravitreal injections of ranibimizumab and bevacizumab were later carried out, showing regression of neovascularisation, decreased retinal thickness, and improved visual acuity [122, 123]. In spite of these positive results, the topic use of ranibimizumab and bevacizumab in clinical practice was also characterised by a trend towards increased frequency of cardiovascular events and bleeding [124, 125]. More recent evidence, on the other hand, supports the safety of such treatments [126, 127]. The Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE) study [126] was a 12-months, multicenter, sham-controlled, double-masked trial, which randomized 151 type 1 and 2 diabetes patients with macular edema to intravitreal ranibizumab or sham injections. Ranibizumab therapy significantly improved visual acuity and was well


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tolerated. The Efficacy and Safety of Ranibizumab (Intravitreal Injections) in Patients With Visual Impairment Due to Diabetic Macular Edema (RESTORE) trial involved 345 DME patients with an average age of 63 years randomized into three treatment arms: ranibizumab plus sham laser treatment, ranibizumab plus active laser treatment, and sham injection plus active laser treatment. Preliminary data at 1 year showed that patients treated with ranibizumab plus laser were able to read an additional 5.9 letters on a standard eye chart, while those treated with ranibizumab alone could read 6.1 letters more than at the start of the study. The safety profile of ranibizumab was excellent, with no cases of endophthalmitis reported and a low incidence (less than one per cent) of increased intra-ocular pressure [128]. On the basis of the above data, although pan retinal photocoagulation remains the gold standard for the treatment of retinal involvement in diabetes, anti-VEGF agents are being proposed as pre-operative therapy [129], et least until long term efficacy is warranted. The observation by Powell and co-workers in 1964 that diabetic patients with arthritis on aspirin therapy had a lower-than-expected severity of retinopathy [130], led to support the hypothesis that aspirin might have a protective effect against retinal changes of diabetes [131]. Five year aspirin therapy limited degeneration of retinal capillaries in diabetic dogs [132], and subsequent studies showed that salicylate may inhibit retinal capillary and neuron degeneration in experimental animals via inhibition of NF-B dependent inflammatory response [133]. The above experimental findings fueled trials to assess the effect of aspirin in humans, but results waved conflicting and inconsistent [132, 134]. Thus, the role of aspirin for prevention or treatment of diabetic retinopathy remains unproven, and preventing retinopathy cannot be considered an indication to aspirin therapy in this population. CONCLUSIONS Diabetic retinopathy is the most frequent complication of diabetes and a major cause of visual impairment in both type 1 and type 2 diabetic patients. Evidence from experimental and clinical studies show that optimized metabolic and blood pressure control targeting HbA1c