Effect of ruboxistaurin on blood-retinal barrier permeability in relation to severity of leakage in diabetic macular edema.
OBJECTIVE
The purpose of the study was to investigate the effect of orally administered ruboxistaurin (RBX, LY333531), a selective protein kinase C beta inhibitor, on the permeability of the blood-retinal barrier in patients with diabetic macular edema.


METHODS
Forty-one patients with diabetic macular edema were randomly assigned to an 18-month randomized, placebo-controlled, double-masked trial including four study arms (4, 16, or 32 mg/d RBX, or placebo). The RBX group comprised 30 patients (42 eyes) and the placebo group 11 patients (13 eyes). Retinal vascular leakage was assessed using vitreous fluorometry at baseline and after 3, 12, and 18 months. Statistical analysis of the effect of treatment accounted for repeated measurements and tested potential interaction with baseline permeability, HbA(1c), and arterial blood pressure.


RESULTS
Statistical analysis and modeling demonstrated a significant interaction between RBX treatment at any dosage and baseline permeability (P = 0.032, mixed models). A threefold or higher increase in retinal vascular leakage at baseline was associated with a significant reduction (30%) in retinal vascular leakage after RBX treatment compared with placebo. Visual acuity was normal at baseline and remained unchanged throughout the study.


CONCLUSIONS
RBX treatment was associated with a reduction of retinal vascular leakage in eyes that had diabetic macular edema and markedly elevated leakage at baseline. These data suggest that clinical benefit from RBX treatment may be most prominent in patients with severe macular edema at baseline, and trials investigating this therapy may benefit from stratification according to baseline leakage.
Strøm
Charlotte
C
Department of Ophthalmology, Herlev Hospital, University of Copenhagen, Denmark.
Sander
Birgit
B
Klemp
Kristian
K
Aiello
Lloyd Paul
LP
Lund-Andersen
Henrik
H
Larsen
Michael
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001794:Blood Pressure; D001813:Blood-Retinal Barrier; D002199:Capillary Permeability / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008269:Macular Edema / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000627:therapeutic use*; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012160:Retina / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D007211:Indoles; D008301:Maleimides; D011493:Protein Kinase C; C099154:ruboxistaurin