Clinical outcomes of ranibizumab treatment in diabetic eye disease

Background: The vascular endothelial growth factor (VEGF) inhibitor ranibizumab is emerging as an efficacious treatment for diabetic macular oedema. Large clinical trials have shown improvements in visual acuity and reduced central retinal thickness. Details of its effect on other retinal functional parameters are lacking. There is a concern that repeated ranibizumab treatment could exacerbate macular ischaemia or lead to global retinal dysfunction by inhibiting physiological isoforms of VEGF. Outcomes of surgery for advanced proliferative retinopathy remain variable and post-operative complications including recurrent haemorrhage can limit visual recovery. VEGF is strongly implicated in the pathogenesis of advanced retinopathy, so VEGF inhibition prior to surgery may improve outcomes. Trials have failed to demonstrate a clear benefit for bevacizumab, so investigation of the licensed intraocular agent ranibizumab represents a logical next step. Aims: To investigate the effects of ranibizumab and laser treatment in diabetic macular oedema on the following parameters: visual acuity, protan and tritan colour contrast sensitivity, 4° and 12° macular sensitivity by microperimetry, electrophysiological indices from pattern and full field electroretinograms. To report structural retinal changes following ranibizumab and laser treatment in terms of qualitative and quantitative optical coherence tomography outcomes, and to quantify macular ischaemia by fluorescein angiography. To investigate the effect on visual acuity at three months post-surgery of ranibizumab pre-treatment in patients undergoing vitrectomy for advanced proliferative diabetic retinopathy. Methods: Randomised clinical trial of intravitreal ranibizumab vs. laser in 36 subjects with centre-involving diabetic macular oedema (The LUCIDATE study). Randomised clinical trial of pre-operative intravitreal ranibizumab vs. subconjunctival saline injection in 30 subjects undergoing vitrectomy-delamination for advanced proliferative diabetic retinopathy (The RaDiVit study). Results: Thirty six subjects with diabetic macular oedema were recruited and 33 completed the trial. Ranibizumab treated subjects gained a mean of 6 letters compared with 0.9 letter loss for laser at 48 weeks. Retinal sensitivity improved in the central macular 4° and 12° in both groups but to a greater extent with ranibizumab. There was no evidence of worsening global retinal dysfunction by electroretinograms in either group. Retinal thickness decreased in both groups: there was a 132 µm reduction in central macular thickness with ranibizumab compared with 103 µm for laser. Fluorescein angiography showed no evidence of significantly increased macular ischaemia in either group. Thirty subjects with advanced proliferative diabetic retinopathy were recruited, underwent surgery, and completed the study. At three months post-surgery, visual acuity in the ranibizumab group was 53 letters compared with 47 letters in the control group. Conclusion: In diabetic macular oedema, there is evidence that ranibizumab leads to greater improvements in visual acuity and retinal sensitivity than laser, with a corresponding greater reduction in retinal thickness. There is no evidence that it worsens macular ischaemia or indices of global retinal electrophysiological function, but larger trials designed to address each of the outcomes investigated here would be required to confirm these findings. In proliferative diabetic retinopathy, there is evidence from this small pilot study that ranibizumab treatment leads to better visual acuity at 3 months post-surgery. An appropriately powered trial would be required to confirm this.