Long-term Effects of Therapy with Ranibizumab on Diabetic Retinopathy Severity and Baseline Risk Factors for Worsening Retinopathy

Purpose To assess the effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity when administered for up to 3 years, evaluate the effect of delayed initiation of ranibizumab therapy on DR severity, and identify baseline patient characteristics associated with the development of proliferative DR (PDR). Design Exploratory analyses of phase III, randomized, double-masked, sham-controlled multicenter clinical trials. Participants Adults with diabetic macular edema (DME) (N = 759), baseline best-corrected visual acuity 20/40 to 20/320 Snellen equivalent, and central foveal thickness ≥275 μm. Methods Patients were randomized to monthly 0.3 or 0.5 mg ranibizumab or sham injections. Sham participants could switch to 0.5 mg ranibizumab during the third year (sham/0.5 mg crossover). Baseline risk factors were evaluated to explore potential associations with development of PDR. Time to first development of PDR was analyzed by Kaplan–Meier methods to calculate cumulative probabilities by group. Main Outcome Measures Study eye change on the Early Treatment Diabetic Retinopathy Study severity scale and a composite clinical outcome evaluating progression to PDR based on photographic changes plus clinically important events defining PDR. Results At month 36, a greater proportion of ranibizumab-treated eyes had ≥2- or ≥3-step DR improvement compared with sham/0.5 mg crossover. A ≥3-step improvement was achieved at 36 months by 3.3%, 15.0%, and 13.2% of sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab-treated eyes, respectively ( P < 0.0001). Through 36 months, 39.1% of eyes in the sham/0.5 mg group developed PDR, as measured by composite outcome, compared with 18.3% and 17.1% of eyes treated with 0.3 or 0.5 mg ranibizumab, respectively. The presence of macular capillary nonperfusion at baseline seems to be associated with progression to PDR in ranibizumab-treated eyes but did not meaningfully influence visual acuity improvement in eyes with DME after ranibizumab therapy. Conclusions Ranibizumab, as administered to patients with DME for 12 to 36 months in these studies, can both improve DR severity and prevent worsening. Prolonged delays in initiation of ranibizumab therapy may limit this therapeutic effect. Although uncommon, the development of PDR still occurs in a small percentage of eyes undergoing anti–vascular endothelial growth factor therapy and may be related to the presence of macular nonperfusion.