title: Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  Exploratory analyses of phase III, randomized, double-masked, sham-controlled multicenter clinical trials.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin. Electronic address: msip@wisc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ip
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Amitha
authors.initials: A
authors.lastname: Domalpally
authors.affiliation: Joslin Diabetes Center, Harvard Department of Ophthalmology, Boston, Massachusetts.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Sun
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Ehrlich
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003930:Diabetic Retinopathy / Q000175:diagnosis / Q000188:drug therapy*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000175:diagnosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab; D015861:Retinal Neovascularization / Q000175:diagnosis; D012307:Risk Factors; D012720:Severity of Illness Index; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014792:Visual Acuity
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab