Vascular endothelial growth factor inhibition for proliferative diabetic retinopathy: Et tu, Brute?

P roliferative diabetic retinopathy (PDR) is a leading cause of blindness which in 25 years will affect 3– 10% of patients in type 1 diabetes (Grauslund et al. 2009; Klein et al. 2010). If left untreated, almost half of the patients with high-risk PDR will have severe visual loss within 5 years (The Diabetic Retinopathy Study Research Group 1981). For more than 40 years, such patients have benefited from panretinal photocoagulation (PRP) that effectively reduces the risk of blindness but also introduces deleterious side-effects such as night blindness and constriction of peripheral visual field (1978). Intravitreal vascular endothelial growth factor (VEGF) inhibition has successfully been implemented in centred-involving diabetic macular oedema (DMO) (Wells et al. 2016). In PDR, VEGF triggers the growth of retinal neovascularization (Aiello et al. 1994). Panretinal photocoagulation improves the retinal oxygenation (Stefansson 2006), which then lowers the level of VEGF. With this in mind, pharmacological treatment of PDR could also be an appealing option if it could demonstrate the same efficacy as well as a lower number of side-effects as compared to PRP. To address this, we have now solid evidence from two major clinical trials. The Diabetic Retinopathy Clinical Research Network (DRCR.net) has published 2-year data from Protocol S, which aimed to compare ranibizumab 0.5 mg with PRP in 394 eyes in a randomized, non-inferiority trial (Writing Committee for the Diabetic Retinopathy Clinical Research Network et al. 2015). Patients with competing DMO were allowed in the trial and composed 22–23% of patients at baseline. In the ranibizumab group, all patients received four mandatory, monthly injections and then injections as needed. The median number of injections through 2 years for patients with and without DMO was 14 and 10, respectively. In the PRP group, laser was given at baseline and supplemented if needed during follow-up (45%). As a main finding, the study demonstrated that ranibizumab was non-inferior to PRP in terms of mean visual acuity letter improvement (+2.8 versus +0.2, p < 0.001). In addition, patients in the ranibizumab group had less peripheral visual field sensitivity loss ( 23 dB versus 422 dB, p < 0.001), less vitrectomy (4% versus 15%, p < 0.001) and a lower risk of DMO development (9% vs 28%, p < 0.001). Recently, the CLARITY study presented a randomized 1-year study comparing aflibercept with PRP in 232 patients with no central DMO at baseline (Sivaprasad et al. 2017). Patients in the aflibercept group were given three mandatory, monthly injections and then treated as needed. In median, patients only needed one additional injection after the loading phase. The CLARITY study met its primary endpoint demonstrating that aflibercept was non-inferior and even superior to PRP with a best corrected visual acuity difference of 3.9-4.0 letters. Like in DRCR.net Protocol S, no safety concerns were raised in the injection group. Even though many physicians are excited about VEGF inhibitions as an additional option in the box of tools, points of concern have also been raised. Firstly, so far the efficacy of treatment has only been demonstrated for up to 2 years of treatment. This needs to be balanced against the wellknown, long-lasting effect of PRP. Secondly, a good compliance would be essential for successful treatment with intravitreal VEGF inhibition. Close monitoring is needed on a continuous basis given that patients in DRCN.net Protocol S still needed a substantial number of treatments within the second year. Thirdly, costeffectiveness should be considered. Based on the data from DRCR.net Protocol S, Lin et al. (2016) extrapolated the cost of lifetime therapy under the assumption that an annual number of two ranibizumab injections would be needed. Based on this, the expected cost per quality-adjusted life year (QUALY) would be $24 005 for PRP and $164 360 for ranibizumab. This would, in particular, be important in younger patients with type 1 diabetes with a long life-expectancy. Fourthly, it has been a concern that intravitreal VEGF inhibition might cause tractional retinal detachment in PDR (Torres-Soriano et al. 2009). However, this was not an issue in DRCR.net Protocol S, which in fact had fewer cases of tractional detachment in the ranibizumab group (5% versus 8%) (Writing Committee for the Diabetic Retinopathy Clinical Research Network et al. 2015). In CLARITY, there were no cases of retinal detachment in either group (Sivaprasad et al. 2017). Intravitreal VEGF inhibition has revolutionized the treatment of various retinal diseases such as neovascular age-related macular degeneration, retinal vein occlusion and DMO. In