or placebo. At baseline, 34 % of the patients had no signs of retinopathy, 58 % of them had minimal/early NPDR, and only 9 % had moderate/severe NPDR. The study focused on retinopathy progression of two to three steps or more on the ETDRS severity scale. After a follow-up of 5 years, progression was seen only in 25 % of patients treated with enalapril and 21 % of patients on losartan, compared with 38 % of patients receiving placebo.

In summary, these studies suggest that RAS inhibitors, such as candesartan, should be considered for T1DM patients at risk with more than 6 years’ duration of diabetes, especially if there is an indication for RAS blockade, such as the presence of hypertension or signs of diabetic nephropathy such as albuminuria. In T2DM patients, RAS inhibitors should be considered for patients with early stages of diabetic retinopathy, particularly if the RAS blockade is indicated.

The aim of the therapy for diabetic adults is to reduce blood pressure to <130 mmHg systolic and <80 mmHg diastolic and its maintenance. In children, the primary goal is a reduction of blood pressure to the corresponding age-adjusted 90th percentile values.

Some debates exist over the correct selection of antihypertensive agents in diabetic patients. From the evidence of results of clinical trials discussed before, many authors support the beneficial effect of ACE inhibitors and ARBs, especially in terms of DR progression, renal function, and cardiovascular complications.

2.3.1.3 Lipid-Lowering Therapy

There are many evidences that dyslipidemia plays an important role in the development of retinopathy and macular edema in patients affected by diabetes mellitus.

The ETDRS analyzed the serum lipid level of 2,709 patients and showed a clear association between high level of triglyceride, LDL, and VLDL and an increased risk of hard exudates and vision loss [75].

In the Collaborative Atorvastatin Diabetes Study (CARDS) [76], 2,830 T2DM patients were enrolled, receiving atorvastatin 10 mg daily or placebo. This trial failed to show a significant reduction in DR progression; nevertheless, the study proved a reduction of laser therapy in the group treated with statins. The CARDS had some important limitations: first of all, only 65 % of patients had a description of the retinopathy status at baseline; secondly, there was a missing photographic grading of DR. Therefore, the role of statins on diabetic retinopathy is still now debated. Probably, if statins have an effect, this may be small [77] and other proofs on the effect of larger doses of statins are needed.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has recently proved that a lipid-lowering therapy might prevent or reduce visual loss related to DR.

In this clinical trial, 9,795 T2DM dyslipidemic patients, who were not treated with statin at baseline, were investigated for the effect of fenofibrate 200 mg daily on retinal vascular alterations [78].

The primary endpoint of the trial was a strictly cardiovascular outcome, with reduction in myocardial infarction or death from coronary heart disease.

An ophthalmological substudy, in a subset of 1,012 patients, showed a reduction from 5.2 to 3.6 % in the rate of laser-requiring retinopathy, in the fenofibrate group compared to placebo, in a follow-up of 5 years [79]. This result pointed out how fenofibrate can reduce the need of laser therapy and prevent disease progression in patients with established retinopathy.

Another evidence of the important role of the lipid control has been brought to the fore from the ACCORD Eye Study [80]. The authors explored a subgroup of 2,856 T2DM patients selected for increased cardiovascular risk in the main ACCORD Study [81, 82]. In this trial the effects of intensive glycemic and blood pressure control have been analyzed, compared to standard control; the project also considered lipid management in the context of good glycemic control using simvastatin in all patients with the addition of fenofibrate 160 mg daily or placebo.

In the eye subgroup [80], the effects of different treatments were analyzed after a 4-year follow-up.

In summary, the results at the end of the study showed that in the group of patients treated with intensive glycemic control therapy and in the fenofibrate group, there has been a reduction in the rate of DR progression; on the other hand, no significant differences were reported in the intensive blood pressure control group.

Both FIELD and ACCORD Eye studies confirmed the efficacy of the new lipidlowering therapeutic approach based on the combination of fenofibrate and statin therapy in the control of diabetic retinopathy. The 40 % reduction of progression of DR and laser treatment over 4 years achieved with fenofibrate, compared with simvastatin alone, is a notable discovery. The direct effect of treatment with fenofibrate, in the ACCORD Eye study, was an increase in HDL cholesterol and a decrease in the serum triglyceride levels; this effect appeared in the first year of treatment and lasted to the end of the study. In contrast, the FIELD study suggested that the efficacy of fenofibrate might be independent from lipid-lowering therapy because there was no difference in the lipid levels between patients requiring laser or not. Anyway, it is important to notice that in both studies, the advantage obtained with fenofibrate treatment was independent from glycemic control.

The precise mechanism of action of fenofibrate in reducing the progression of DR is still unclear, even if many scientific studies showed its primary role as inhibitor of peroxisome proliferator-activated receptor (PPAR). PPARs have become a new therapeutic target in diabetic vascular damage [83].

Fenofibrate probably has also anti-inflammatory effects and may prevent apoptotic cell death that typically occurs in diabetic retinopathy, through the adenosine monophosphate-activated protein kinase (AMPK) signal transduction pathway [84, 85].

Dyslipidemia is an important risk factor for cardiovascular disease. Diabetic patients should maintain their LDL-C serum levels <100 mg/dl, HDL-C levels >40 mg/dl (>50 mg/dl if woman), and triglyceride levels <150 mg/dl [86]. For that purpose, it is important to consider a possible combination therapy with a fibrate and an LDL-lowering drug in high-risk diabetic patients with dyslipidemia.