The American Diabetes Association recommendations suggested that a statin therapy should be started in all dyslipidemic diabetic patients with a diagnosed cardiovascular disease (CVD) or in patients without cardiovascular disease but more than 40 years old and with one or more CVD risk factors. With lipid-lowering therapy, it is important to reach an LDL-C level <100 mg/dl; in high-risk patients, with an overt CVD, it is necessary to obtain an LDL-C level <70 mg/dl using a high dose of statin [86].

2.3.2Secondary Interventions

2.3.2.1 Protein Kinase C Inhibitors

The presence of high blood glucose level in diabetic patients causes the activation of many metabolic pathways, resulting in an increase of oxidative stress and polyol pathway flux, with a production of AGEs (advanced glycation end products) and diacylglycerol. One of the biological effects of these alterations is the direct activation of protein kinase C (PKC), an enzyme present with different isoforms in many tissues [87, 88]. In particular, studies have revealed that there is a higher PKC activation in tissues involved in diabetic disease, such as the retina, peripheral nervous system, kidneys, and heart. As reported by several investigations, the increased synthesis of diacylglycerol induced by hyperglycemia in the early stage of diabetic disease causes the activation of the β-isoform of PKC (PKC-β), particularly present in the eye tissues [89]. Studies suggested that the chronic activation of this enzyme has an important role in determining the progression of diabetic retinopathy. For these reasons, nowadays there is a crescent interest in the analysis of the possible therapeutic use of PKC inhibitors in diabetic retinopathy. Two recent phase III clinical trials have studied the efficacy of ruboxistaurin (RBX), a selective PKC-β inhibitor.

In the PKC-Diabetic Retinopathy Study [90], 252 diabetic patients with moderate to severe NPDR at baseline were randomized to receive oral ruboxistaurin (8, 16, or 32 mg) or placebo.

After a 3-year follow-up, this clinical trial failed to demonstrate an effect of this treatment in modifying DR progression, but it clearly showed a reduction in the risk of moderate visual loss (MVL) in the group of patients treated with 32 mg of ruboxistaurin.

The PKC-DRS2 trial [91] enrolled 685 diabetic patients with moderate to severe NPDR at baseline and no prior panretinal photocoagulation (PRP) treatment in at last one eye. These patients were treated with 32 mg/day of ruboxistaurin, and after a 3-year follow-up, the study showed a 40 % risk reduction of developing sustained moderate visual loss: data showed that severe and moderate visual loss occurred only in 5.5 % of the patients treated with ruboxistaurin, rather than in 9.1 % of the placebo control.

This large study pointed out many advantages related to the use of ruboxistaurin: first of all, the rate of visual improvement in patients treated with RBX was 4.9 %, compared with 2.4 % of placebo group; this was also associated with a reduction in the frequency of visual loss (6.7 % in treated group versus 9.9 % of placebo). Moreover, ruboxistaurin showed also a positive effect in reducing the progression of macular edema (68 % vs 50 %) and the need of laser treatment (26 % less frequent