European Association for the Study of Diabetic Eye Complications

Annual Meeting Munich 21-23rd May 2004

Paper Abstracts

STUDIES ON DIABETIC RETINOPATHY

STUDIES ON DIABETIC RETINOPATHY INITIAL RESULTS OF THE PROTEIN KINASE C b INHIBITOR DIABETIC RETINOPATHY STUDY (PKC-DRS).

Roy C. Milton3, Lloyd P. Aiello1, Matthew D. Davis2, Matthew J. Sheetz4, Vipin Arora4, Louis Vignati4, Aniz Girach5, and the PKC-DMES Study Group

1 Joslin Diabetes Center, Boston, MA, US
2University of Wisconsin, Madison, WI, USA
3 EMMES Corp., Rockville, MD, US
4Eli Lilly and Co., Indianapolis, IN, USA
5 Eli Lilly and Co., Erl Wood, U

Background & Methods: The PKC-DRS was a multi-center, double-masked, placebo-controlled, parallel study that evaluated 252 patients with moderately severe to very severe nonproliferative diabetic retinopathy (NPDR; ETDRS retinopathy severity grades 47B-53E in at least one eye) who were randomly assigned to placebo or one of three doses of ruboxistaurin (RBX, LY333531) mesylate, a selective PKC b inhibitor. Eligibility and outcome were assessed at a reading center using stereoscopic fundus photographs taken at six-month intervals. The primary outcome was >3-step retinopathy progression on the ETDRS scale or application of scatter photocoagulation.

Results: Patients were 56±12 years, 68% male, 19% Type 1, 16±7 years diabetes duration, & HbA1c 8.8±1.4% (range 5.7-13.0%). Treatment duration was 36-48 months. At baseline, ETDRS visual acuity was 80+11 letters (~20/25 Snellen), 78% had diabetic macular edema (33% center involved), and retinopathy severity of the more severe eye was level 47 in 45% and level 53 in 55%. The primary analysis was based on time to occurrence of the primary outcome using the intent-to-treat population. At 42 months, Kaplan-Meier event rate estimates were 55%, 57%, 72% & 52% in the placebo, 8, 16 & 32mg groups, respectively (p=0.54 32mg vs. placebo). For progression of >2-steps on the ETDRS scale in patients with NPDR in both eyes, 42 month rates were 72% & 49% for placebo and 32mg, respectively (p=0.048), a 32% risk reduction. Sustained moderate visual loss (SMVL; 15 letters for at least six months) occurrence at each visit is outlined in the table.

SMVL at Each Visit (Percent of Patients)

    Visit (Months)  
  12 18 24 30 36
Placebo 15 19 20 22 30
32 mg RBX 5 4 4 11 19
p-value 0.113 0.028 0.027 0.171 0.246
Treatment effects adjusted for important covariates are consistent with results of unadjusted analyses and will be presented. Initial analyses suggest RBX treatment for 36-48 months in patients with diabetic retinopathy was well tolerated and was not associated with significant adverse events.

Conclusions: Unadjusted analyses did not demonstrate a RBX treatment effect on diabetic retinopathy progression; however, a potential beneficial effect of RBX in reducing MVL warrants further investigation.

INITIAL RESULTS OF THE PROTEIN KINASE C β INHIBITOR DIABETIC MACULAR EDEMA STUDY (PKC-DMES).

Lloyd P. Aiello1, Matthew D. Davis2, Roy C. Milton3, Matthew J. Sheetz4, Vipin Arora4, Louis Vignati4, Aniz Girach5, and the PKC-DMES Study Group

1Joslin Diabetes Center, Boston, MA, US
2University of Wisconsin, Madison, WI, US
3EMMES Corp., Rockville, MD, US
4Eli Lilly and Co., Indianapolis, IN, US
5Eli Lilly and Co., Erl Wood, UK

Background & Methods: The multi-center, multi-national, double-masked, placebo-controlled, parallel PKC-DMES study evaluated 686 patients with DME that was not imminently sight threatening who were randomly assigned to placebo or one of three doses of ruboxistaurin (RBX, LY333531) mesylate, a selective PKC β inhibitor. Eligibility and outcome were assessed at a reading center using stereoscopic fundus photographs taken at 3-6 month intervals. The primary outcome was progression of DME to involve or imminently threaten the macula center or application of focal/grid photocoagulation.

Results: Patients were 55±10.6 years, diabetes duration 16±8.5 years, 18% Type I, and HbA1c 8.9+1.5% (range 5.1- 13.1%). Treatment duration was >30 months with 45% receiving therapy for 36 months or more. The primary analysis was based on time to occurrence of primary outcome using the intent-to-treat population. At 36 months, Kaplan-Meier event rate estimates were 55%, 51%, 53% and 47% in the placebo, 4, 16 & 32mg groups, respectively (p=0.23 overall, p=0.15 for pair wise comparison of 32mg vs. placebo). When the 18% (55/305) of outcomes based on photocoagulation were excluded, event rates in placebo and RBX groups were 48% & 37%, respectively, a risk reduction of 23% (p=0.046). When subgroup analysis of these patients was conducted based on baseline HbA1c (HbA1c at baseline <10%, <75th percentile), placebo and RBX (32mg) event rates were 45% and 31%, respectively, a risk reduction of 31% (p=0.019). Treatment effect adjusted for important covariates will be presented. Initial analyses suggest RBX treatment for over 30 months in patients with DME was well tolerated and was not associated with significant adverse events.

Conclusions: Unadjusted analyses did not demonstrate a significant effect of RBX treatment on the primary outcome of DME progression or need for focal laser, although in subgroup analysis excluding patients with very poor glycemic control at baseline, RBX was associated with a risk reduction of 31% in progression of DME.

DIABETIC MACULAR EDEMA: THE EFFECT OF TREATMENT WITH RUBOXISTAURIN ON BLOOD-RETINAL BARRIER PERMEABILITY

Sander B, Larsen M, Lund-Andersen H. Dept. of Ophthalmology, Herlev Hospital, University of Copenhagen, Denmark

Purpose: To investigate the effect of orally administered ruboxistaurin (LY333531), a selective protein kinase C bII inhibitor with the capacity to attenuate elevated retinal VEGF, on the blood- retinal barrier permeability in diabetic macular edema.

Methods: 55 eyes of 41 patients were randomly assigned to 18 months treatment with ruboxistaurin (3 treatment arms of 4 mg/day, 16mg/day and 32 mg/day) or placebo. Ocular eligibility was defined as non-clinically significant macular edema (ETDRS criteria). Blood-retinal barrier permeability was measured with vitreous fluorometry at baseline, 3 months, 12 months and 18 months. The statistical analysis of the treatment effect accounted for repeated measurements, baseline permeability and cofactors.

Results: A significant interaction was found between the treatment assigned and baseline permeability (mixed model, p= 0.029) indicating that high baseline permeability (the quantitative equivalent to marked leakage on fluorescein angiography) is associated with a benificial treatment effect of ruboxistaurin in contrast to eyes with low permeability. Visual acuity was normal at baseline and unchanged throughout the study.

Conclusions: The statistical analysis showed that the level of baseline permeability was a significant factor for the effect of ruboxistaurin. Thus diabetic patients with a high blood-retinal barrier permeability are more likely to demonstrate a stabilization or reduction of leakage and hence a decrease in macular edema than patients with low permeability.

PHENOTYPES IN DIABETES TYPE 2. PATTERNS OF RETINOPATHY PROGRESSION IN A TWO YEAR FOLLOW-UP.

José G. Cunha-Vaz1,2, Lilianne G. Duarte1, Rui C. Bernardes1, Mário A. Soares1, Conceição L. Lobo1,2, José F. Abreu2,3.

1 AIBILI
2Department of Ophthalmology, University Hospital
3Centre of Ophthalmology, IBILI, Coimbra, Portugal.

Purpose: To characterize retinopathy progression in the initial stages of retinal disease in diabetes type 2.

Methods: We classified 59 eyes of 59 patients with type 2 diabetes mellitus and mild nonproliferative retinopathy by 7 field stereoscopic fundus photography (levels 10, 20 and 35 of Wisconsing grading). They were examined 5 times at six-month intervals by fundus photography (FP), fluorescein angiography (FA), vitreous fluorometry (VF), retinal leakage analyzer (RLA) and retinal thickness analyzer (RTA).

Results: Red dots (microaneurysms and hemorrhages), increased fluorescein leakage and increased retinal thickness were present at some time during the follow-up in every eye. Capillary closure in the foveal avascular zone (FAZ) developed in only 11 eyes (18%). Three different patterns of progression of retinopathy were identified. Pattern A, involving 60% of the eyes, is characterized by slow increases in the rate of red dot accumulation (<3/year) and low fluorescein leakage (< 4mg/ml, VF). Pattern B, involving 22% of the eyes, is characterized by marked increases in the rate of red dot accumulation and in fluorescein leakage, defining a “wet” type of retinopathy. Pattern C, involving 18% of the eyes, is characterized by increased red dot accumulation associated with capillary closure in the FAZ, identifying an “ischemic” type of retinopathy

Conclusions: Three major evolutive patterns of retinopathy progression in diabetes type 2 were identified in a two year follow-up study, by combining different imaging techniques. They may characterise three different retinopathy phenotypes: one, more frequent, showing slow progression, and the other two, less frequent, which may be called “wet” and “ischemic” phenotypes.

 




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