2.3.1Primary Interventions

2.3.1.1 Glycemic Control

The level of glucose in the blood is probably the most important predictive factor for development of diabetic retinopathy. Different randomized clinical trials have confirmed this hypothesis, showing that tight glycemic control can reduce the incidence and progression of diabetic complications, such as retinopathy [56–62]. The relationship between the control of glycemic level and the onset of microscopic complications of diabetes was studied in two multicenter clinical trials, the DCCT (Diabetes Control and Complications Trial) [57–60] and the UKPDS [61, 62].

In the DCCT, 1,441 patients with type 1 diabetes were randomized to receive conventional or intensive insulin therapy. After a follow-up of 6 years, patients treated with intensive therapy (median HbA1c 7.2 %) showed a reduction in the incidence and progression of diabetic retinopathy (by 76 and 54 %, respectively), as compared with patients treated with conventional therapy (median HbA1c 9.1 %) [60].

Some other studies analyzed the importance of glycemic control in type 2 diabetes, showing similar results. In the UKPDS (UK Prospective Diabetes Study), 3,867 newly diagnosed patients were randomized once more to receive conventional or intensive therapy. The second group showed a reduction in microvascular endpoints by 25 % and the need for laser photocoagulation by 29 % [61, 62].

In the EDIC study (Epidemiology of Diabetes Intervention and Complications), the authors followed up participants of the DCCT study after its end and analyzed their long-term observational data. The results showed that despite the progressive equalization of HbA1c values, in the group of patients that had been treated with intensive approach, the rate of diabetic retinopathy progression was lower than in the group previously treated with conventional therapy [63, 64]. This data stressed the importance of keeping tight glycemic control from the beginning of the disease.

Even if the advantages of tight glycemic control emerged from these studies, this approach could produce severe side effects, such as an early worsening of diabetic retinopathy. In the DCCT, this risk is reported in 13.1 % of patients with intensive treatment instead of 7.6 % of patients with conventional insulin therapy [65]. However, within 18 months the effect disappeared without causing an important visual loss. Patients with greater risk of developing this complication had higher HbA1c levels at baseline and a faster reduction of HbA1c levels within 6 months (Fig. 2.24). Thus, it is important to choose a therapeutic strategy focused on a slow reduction of glycemic levels.

The results of a meta-analysis of the DCCT and other clinical trials showed that two other dangerous risks related to intensive insulin therapy are hypoglycemia and diabetic ketoacidosis [66].

Nowadays the aim of diabetic treatment can be summarized in the “target glycemic control.”

The therapy of diabetes includes lifestyle modification, physical activity, and medical or nutritional therapy; all these approaches can be used together to achieve personal glycemic goals.

f

Fig. 2.24 Progression from NPDR to PDR. Biomicroscopic picture, FA frame, and OCT scan of a young female with a history of uncontrolled IDDM at baseline (a–c) and 4 months later (d–f) after a too fast improvement of glycemic control (HbA1c from 11.2 % at baseline to 7.5 %). The arrow in FA image (e) indicates a hyperfluorescence due to the presence of a neovascularization

Current management of type 1 DM (T1DM) is based on the replication of normal insulin secretion. An optimal control of the disease is achieved by continuous subcutaneous insulin infusion with an insulin pump or by multiple daily insulin injections. Patients should also frequently control their own blood glucose level and calculate the correct insulin dose in accord to food intake and physical activities. In patients with type 2 DM (T2DM), pharmacologic therapy is needed when a normalization of blood glucose level is impossible to obtain with lifestyle modifications alone. The therapy consists in progressive stepwise additions of different classes of agents in order to achieve optimal glycemic goals.

Today there are many classes of pharmacologic agents available for the treatment of diabetes. For insulin therapy, diabetic patients may use rapid-acting insulin analogs, needed to replace physiological postprandial insulin secretion, and long-acting insulin, designed to regulate the basal glycemic control. For patients with type 2 diabetes, generally, the first antidiabetic drug utilized is metformin, a biguanide, which acts in reducing hepatic glucose production; the other classes of insulin

sensitizers are glitazones, which effect results in increased glucose utilization. Other important agents are sulfonylureas and glinides, which act as insulin secretagogues. There are also the α-glucosidase inhibitors and the bile acid sequestrant that retard glucose absorption from the gastrointestinal tract. At last, there are two new classes of agents, the incretin mimetics and the incretin enhancers, which promote the actions of incretins GLP-1 and GIP, two key glucoregulatory hormones [67].

The advantage of having multiple agents with different mechanisms of action is that they should be used in various combinations in order to obtain the optimal solution for each patient.

2.3.1.2 Blood Pressure Control

Hypertension is a frequent comorbid condition in patients with diabetes, and it has been hypothesized for a long time to be a risk factor for developing diabetic retinopathy with different mechanisms. Elevated blood pressure should be considered as the main cause of impairment of the retinal vascular autoregulation, which could lead to endothelial damage. Hypertension should also induce an increase in the expression of vascular endothelial growth factor (VEGF) and its receptors in diabetic patients.

Many randomized clinical trials showed that blood pressure control is a changeable factor implicated in the incidence and progression of diabetic retinopathy. In the UKPDS [62], 1,048 hypertensive patients were randomized to tight blood pressure control (<150/<85 mmHg) or conventional control (<180/<105 mmHg). After a follow-up of 9 years, the group of patients with tight control showed a reduction of 34 % in DR progression, 47 % in deterioration of visual acuity, and 35 % in needing of laser photocoagulation therapies, compared to the group with conventional control. In this study, the benefits obtained with tighter blood pressure control exceed the benefits seen with tight glycemic control.

Within new approaches to retinopathy prevention, there is evidence that the renin-angiotensin system (RAS) might play a decisive role in the pathogenesis of DR. Scientific studies confirmed that there is a local RAS that operate in the eye and that it is upregulated in active retinopathy. In particular, recent trials have demonstrated that angiotensin II causes an increasing in retinal vessels exudation [68] and that this is a promoting factor for neovascularization, via upregulation of VEGF and other growth factors. Moreover, studies in animal models suggested that the blockage of RAS should be associated with protective effects on the retina [69, 70].

For these reasons there is a crescent interest in looking for agents that could block the RAS system, in order to obtain a preventive effect on the retina that is independent from their antihypertensive action.

In the EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID) [71], normotensive and normoalbuminuric patients with T1DM were treated for 2 years with lisinopril in order to evaluate the effect of ACE inhibitors on the progression of DR. This treatment did not modify the rate of incidence of DR but produced a reduction of progression of DR by 50 % and a reduction of progression from NPDR to PDR by 80 %. Because the patients were normotensive at baseline, this study suggested that the effectiveness of ACE inhibitor was due to other pathogenetic mechanisms independent from blood pressure lowering. The

limits of EUCLID study were a too short follow-up (only 2 years) and a difference in the glycemic levels between the two studied groups, with a lower HbA1c in the treated group.

The Diabetic Retinopathy Candesartan Trial (DIRECT) [72, 73] involved 5,231 patients and included three placebo-controlled trials. This huge study was focused on the determination of the impact of the angiotensin receptor blocker (ARB) candesartan on the incidence and progression of DR in patients with type 1 or type 2 diabetes. During a 4-year follow-up, in patients with T1DM, a decrease in DR incidence and progression was reported; instead, in patients with T2DM only, a reduction of DR progression was noticed.

The three components of DIRECT trial included DIRECT-Prevent 1, with 1,421 T1DM normotensive patients without diabetic retinopathy at baseline; DIRECTProtect 1, with 1,905 T1DM normotensive patients with only mild to moderate NPDR at baseline; and DIRECT-Protect 2, with 1,905 T2DM normotensive or mildly hypertensive-treated patients and with mild to moderate NPDR at baseline.

This trial had two important endpoints:

•A two-step increase, on the ETDRS scale, in incidence and a three-step increase in progression

•The regression of baseline retinopathy that means a reduction of three steps at any follow-up visit, or two or more steps measured in two different visits within the space of a year

The Prevent-1 data showed a positive effect of candesartan, with a reduction of

incidence of retinopathy from 31 to 25 %; a post hoc analysis demonstrated also a reduction in DR aggravation (three steps on the ETDRS scale) from 16 to 10.5 %.

In Protect 1 subgroup, the use of candesartan did not modify anyway the rate of progression of the diabetic retinopathy present at baseline; Protect 2 also failed to show any significant change in the progression of established DR but demonstrated an important regression (34 %) of previous DR.

The regression of retinopathy was seen only in those patient that had a mild disease at the beginning, supporting the hypothesis of the existence of a “point of no return” for diabetic retinopathy.

Even if the DIRECT did not achieve its primary endpoint, in all three trials, the patients treated with candesartan showed, at the end of the study, an improvement of ETDRS level compared to the placebo group. This advantage was showed both in type 1 and type 2 DM and suggested a biological effect of the treatment on the disease process. The DIRECT Program did not investigate the exact mechanism for apparent positive effect of candesartan; probably it might be partially related to a reduction of blood pressure with another important effect in blockage of RAS eyespecific system.

The Renin-Angiotensin System Study (RASS) analyzed patients with type 1 diabetes mellitus, looking for evidence of a slowdown in progression of retinopathy after blockade of the RAS system [74]. This study represents a further support of the idea that blocking RAS system represents an advantage for diabetic retinopathy.

In RASS, 223 normotensive patients were assigned in three different groups, receiving the ACE inhibitor enalapril 20 mg daily, the ARB losartan 100 mg daily,