**Abstract**

Diabetes mellitus is a global epidemic that leads to multiple macrovascular and microvascular complications. The complex interrelated pathophysiological mechanisms triggered by hyperglycemia underlie the development of diabetic retinopathy (DR). Proliferative diabetic retinopathy (PDR) is a microvascular complication, considered the main cause of irreversible blindness in patients of productive age in the world. On the other hand, diabetic macular edema (DME) remains the clinical feature most closely associated with vision loss. In general, both manifestations are due to an increase in inflammatory factors, such as specific pro-inflammatory prostaglandins, interleukins and angiogenic substances including vascular endothelial growth factor (VEGF). Laser photocoagulation and VEGF inhibitors have been shown to be effective in the treatment of PDR and DME. Currently, randomized protocols suggest that VEGF inhibitors therapy could displace laser photocoagulation in the treatment of PDR with and without the presence of DME. The ongoing discussion still prevails about the different treatment modalities for both retinal manifestations in real-world settings.

**Keywords:** proliferative diabetic retinopathy, diabetic macular edema, treatment algorithm, treatment guidelines, panretinal photocoagulation, antiangiogenic therapy

#### **1. Introduction**

Diabetic retinopathy (DR) is characterized by progressive damage to retinal capillaries causing retinal ischemia. In severe cases, it leads to DR, which threatens vision induced by angiogenesis [1]. Vascular endothelial growth factor (VEGF) is an important agent in the development and progression of DR and diabetic macular edema (DME) [2, 3].

The Early Treatment of DR (ETDRS) study showed that focal photocoagulation of "clinically significant" DME reduces the risk of visual loss and increases the chances of visual improvement, decreases the frequency of persistent DME, and

causes minor visual field losses [4]. Panretinal photocoagulation (PFC) has been the standard treatment for proliferative diabetic retinopathy (PDR) since the DR study (DRS) demonstrated its benefit more than 40 years ago [5]. PFC has demonstrated permanent peripheral visual field loss and decreased night vision. On the other hand, it can exacerbate existing DME or increase its incidence. Different treatment alternatives in PDR should be considered [6].

DME can affect the macular center considering it as "with center-involving" (CI-DME) or it can respect the same, considering it as "non-center-involving" (NCI-DME). Anti-angiogenic (anti-VEGF) therapy in DME, has shown superior visual acuity results and acceptable risks compared to focal, grid, or untreated laser, and has also led to the observation that DR lesions can be reversed during treatment [7–14]. Anti-VEGF therapy is currently considered the first-line treatment for DME.

The objective of this chapter is to describe an algorithm in the treatment of PDR based on current publications that could be used in real-world scenarios and different practice settings.

## **2. Current treatments in DME and PDR**

According to the results of the DRCR.net Protocol S, at two years of follow-up, intravitreal ranibizumab (RBZ) achieved the result of non-inferiority in the change of best-corrected visual acuity (BCVA), which was no worse than in the PFC group treatment for PDR [15]. There were no statistically significant differences in BCVA between the RBZ and PFC groups, with the recognition that 53% of the PFC group received additional RBZ injections to treat DME and only 6% of the RBZ group required PFC. There was greater peripheral visual field loss (95% CI for difference, 213–531 dB) and more vitrectomies (PPV) were performed (95% CI for one difference, 4% -15%) in the PFC group compared to the RBZ group. In addition, RBZ-treated eyes were less likely to develop CI-DME causing visual impairment of 20/32 or worse, similar to the 1-year results with aflibercept (AFB) in the CLARITY randomized clinical trial [16]. In the DRCR.net Protocol S, a greater number of patients in the PFC group developed DME (28 vs. 9). At 5-year results, the mean number of injections in the PFC group was 7.9 and 19.2 in the RBZ group. The mean final BCVA in both groups was 20/25. Despite the fact that at 2 years the PFC group presented a greater visual field loss, the decrease in the peripheral visual field progressed in both groups during the following 5 years of follow-up [17].

In a post hoc analysis of the DRCR.net Protocol T [18], after 2 years of follow-up, an improvement in DR severity was demonstrated by approximately 25% for AFB, 22% for bevacizumab (BVZ) and 31% for RBZ in patients without proliferative-DR (NPDR) at baseline. This analysis also suggests a secondary benefit of DME after intravitreal AFB with respect to improvement in DR severity among patients who had PDR from baseline. Anti-VEGF therapy for DME improves the score of the DR severity scale (DRSS), evaluated in color fundus photos and can reduce the deterioration of the edema. Other randomized trials comparing anti-VEGF therapy and PFC in PDR, have demonstrated the non-inferiority of anti-VEGF over PFC in preventing PDR complications, at least during the first 2 years [19, 20]. Similar studies using ultra-wide-field (UWF) photographs and comparing them with ultra-wide-field fluorescein angiography (UWF-FAG) or wide field swept source optical coherent tomography (WF-SS-OCTA) in eyes with DR and DME [21, 22], conclude that after injections with anti-VEGF, improvement in the DRSS score can occur without vessel reperfusion or retinal capillary in UWF-FAG or WF-SS-OCTA. Therefore, the strong correlation between the number of lesions in DR and the areas of non-perfusion, established before any treatment, could no longer be relevant after anti-VEGF therapy. *Treatment Algorithm in Proliferative Diabetic Retinopathy - From Protocols to the Real World DOI: http://dx.doi.org/10.5772/intechopen.99843*

These results should be taken into account in future studies, in order to demonstrate an improvement in peripheral retinal perfusion in DR after anti-VEGF therapy.
