Original ArticleEffect of Ruboxistaurin on Visual Loss in Patients with Diabetic 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
References (43)
- et al.
The Wisconsin Epidemiologic Study of Diabetic RetinopathyIV. Diabetic macular edema
Ophthalmology
(1984) - et al.
Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema
Ophthalmology
(2003) - et al.
The incidence of vision loss in a diabetic population
Ophthalmology
(1988) - et al.
Protein kinase C signaling regulates ZO-1 translocation and increased paracellular flux of T84 colonocytes exposed to Clostridium difficile toxin A
J Biol Chem
(2002) - et al.
Progression of renal insufficiency in type 2 diabetes with and without microalbuminuria: results of the Heart Outcomes and Prevention Evaluation (HOPE) randomized study
Am J Kidney Dis
(2003) Blindness caused by diabetes—Massachusetts, 1987–1994
MMWR Morb Mortal Wkly Rep
(1996)The prevalence of diabetic retinopathy among adults in the United States
Arch Ophthalmol
(2004)- et al.
Epidemiology of diabetic retinopathy and macular oedema: a systematic review
Eye
(2004) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus
N Engl J Med
(1993)Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
Lancet
(1998)
Molecular understanding of hyperglycemia’s adverse effects for diabetic complications
JAMA
The microvasculature in type 1 diabetes
Semin Vasc Med
Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation
Proc Natl Acad Sci U S A
Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor
Diabetes
Blood-retinal barrier breakdown induced by activation of protein kinase C via vascular endothelial growth factor in streptozotocin-induced diabetic rats
Curr Eye Res
Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531
Invest Ophthalmol Vis Sci
Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients
Invest Ophthalmol Vis Sci
Characterization of protein kinase C beta isoform’s action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization
Proc Natl Acad Sci U S A
Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor
Science
Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes
FASEB J
Effects of the protein kinase C beta inhibitor LY333531 on neural and vascular function in rats with streptozotocin-induced diabetes
Clin Sci (Lond)
Cited by (0)
Manuscript no. 2006-498.
Study funded by Eli Lilly and Company, Indianapolis, Indiana.
E-mail: [email protected].