Elsevier

Ophthalmology

Volume 113, Issue 12, December 2006, Pages 2221-2230
Ophthalmology

Original Article
Effect of Ruboxistaurin on Visual Loss in Patients with Diabetic Retinopathy

Data presented in part at: American Academy of Ophthalmology scientific sessions, October 2005, Chicago, Illinois.
https://doi.org/10.1016/j.ophtha.2006.07.032Get rights and content

Objective

To evaluate the effect of ruboxistaurin, an orally administered protein kinase C β (PKC β) isozyme-selective inhibitor, on vision loss in patients with diabetes.

Design

Thirty-six-month, randomized, double-masked, placebo-controlled, parallel, multicenter trial.

Participants

Six hundred eighty-five patients randomized at 70 clinical sites.

Methods

Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30° color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of ≥45 letters, retinopathy level ≥ 47A and ≤ 53E, and no prior panretinal photocoagulation in at least one eye.

Main Outcome Measure

Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (≥15-letter decrease in ETDRS VA score maintained ≥ 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy.

Results

Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline–to–end point visual improvement of ≥15 letters was more frequent (4.9% vs. 2.4%) and ≥15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 μm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 μm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008).

Conclusion

Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.

Section snippets

Study Design and Subjects

The PKC-DRS2 was a 36-month, multicenter, double-masked, parallel, placebo-controlled study in which patients were randomized to either a placebo or ruboxistaurin (LY333531, Eli Lilly and Co., Indianapolis, IN) (32 mg) administered orally once daily. A total of 1197 patients were screened to obtain the 685 patients randomized at 70 clinical sites (“Appendix”). Randomized patients had type 1 or type 2 diabetes mellitus and hemoglobin A1c values ≤ 13% (Table 1). A centralized randomization system

Baseline Characteristics

Baseline characteristics by treatment group are summarized in Table 1. Patients were predominantly male and Caucasian with type 2 diabetes, a mean age of 59±11 years (range, 23–87), a mean hemoglobin A1c level of 8.1±1.4% (range, 4.9%–13%), and a mean duration of diabetes of 16±8 years (range, <1–51). Nearly 75% of patients had two study eyes. Over half of the study eyes had clinically significant macular edema (CSME), and over a third had center-involved macular edema, at baseline. The mean

Discussion

Substantial data support the role of diabetes-induced PKC β activation as a key mediator of diabetic microvascular complications and the potential for inhibitors of PKC β to ameliorate these conditions,7, 8, 9, 17, 26 especially in the eye.10, 11, 12, 13, 27 Indeed, analyses of the secondary end point of moderate visual loss in a previous dose-ranging study (PKC-DRS) suggested a beneficial effect of ruboxistaurin.21

To date, only intensive glycemic, BP, and serum lipid control, as well as laser

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    Manuscript no. 2006-498.

    Study funded by Eli Lilly and Company, Indianapolis, Indiana.

    E-mail: [email protected].

    See “Appendix” for group membership.

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