HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Search for Related Content PubMed PubMed Citation Social Bookmarking                What's this?

The Effect of Ruboxistaurin on Visual Loss in Patients With Moderately Severe to Very Severe Nonproliferative Diabetic Retinopathy

Initial Results of the Protein Kinase C ß Inhibitor Diabetic Retinopathy Study (PKC-DRS) Multicenter Randomized Clinical Trial

	ABSTRACT

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The purpose of this study was to evaluate the Safety and efficacy of the orally administered protein kinase C (PKC) ß isoform-selective inhibitor ruboxistaurin (RBX) in subjects with moderately severe to very severe nonproliferative diabetic retinopathy (NPDR). In this multicenter, double-masked, randomized, placebo-controlled study, 252 subjects received placebo or RBX (8, 16, or 32 mg/day) for 36–46 months. Patients had an Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy severity level between 47B and 53E inclusive, an ETDRS visual acuity of 20/125 or better, and no history of scatter (panretinal) photocoagulation. Efficacy measures included progression of DR, moderate visual loss (MVL) (doubling of the visual angle), and sustained MVL (SMVL). RBX was well tolerated without significant adverse effects but had no significant effect on the progression of DR. Compared with placebo, 32 mg/day RBX was associated with a delayed occurrence of MVL (log rank, P = 0.038) and of SMVL (P = 0.226). RBX reduction of SMVL was evident only in eyes with definite diabetic macular edema at baseline (10% 32 mg/day RBX vs. 25% placebo, P = 0.017). In multivariable Cox proportional hazard analysis, 32 mg/day RBX significantly reduced the risk of MVL compared with placebo (hazard ratio 0.37 [95% CI 0.17–0.80], P = 0.012). In this clinical trial, RBX was well tolerated and reduced the risk of visual loss but did not prevent DR progression.

Abbreviations: ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; AREDS, Age-Related Eye Disease Study; DME, diabetic macular edema; DR, diabetic retinopathy; ECG, electrocardiogram; ETDRS, Early Treatment Diabetic Retinopathy Study; MVL, moderate visual loss; NPDR, nonproliferative DR; PRP, panretinal photocoagulation; PDR, proliferative DR; PKC, protein kinase C; PKC-DRS, Protein Kinase C ß Inhibitor Diabetic Retinopathy Study; PKC-DMES, Protein Kinase C ß Inhibitor Diabetic Macular Edema Study; RBX, ruboxistaurin; SMVL, sustained MLV; VEGF, vascular endothelial growth factor; VFQ, Visual Function Questionnaire

Diabetes is estimated to affect over 18 million Americans and is increasing rapidly in the U.S. and other developed countries (1). Diabetic retinopathy (DR) is the most prevalent diabetic microvascular complication, being present in nearly 50% of the diabetic population at any time and eventually occurring in nearly all patients with diabetes (2,3). Despite the availability of laser photocoagulation and improved control of hyperglycemia and other risk factors, diabetes remains a leading cause of visual loss in working-age adults (4). Visual loss from diabetes results primarily from two ocular complications. DR can progress to a stage called proliferative diabetic retinopathy (PDR), where new vessels proliferate on the retina. PDR accounts for the majority of severe visual loss and is generally treated with laser panretinal photocoagulation (PRP). In addition, retinal vessels can become permeable and cause swelling of the retina, called diabetic macular edema (DME). DME is a leading cause of moderate visual loss (MVL) in diabetes (5) and is often also treated with laser. The development and progression of DR is related to blood glucose concentration and is slowed by intensive glycemic control (6,7).

The mechanisms by which elevated blood glucose concentrations cause DR and DME remain incompletely understood. Substantial evidence suggests that hyperglycemia-induced synthesis of diacylglycerol results in the activation of protein kinase C (PKC), which plays a central role in mediating diabetes complications in the eye and elsewhere in the body (8). PKC is a family of 13 enzymes (9), of which the ß-isoform has been most closely linked to the development of diabetic microvascular complications (10). Diabetes-induced activation of PKC ß appears to mediate increases in retinal vascular permeability and neovascularization in animal models (11–13) and changes in retinal blood flow in diabetic patients (14). PKC activation is important in the intracellular signaling of vascular endothelial growth factor (VEGF), which is hypothesized to be a principal mediator of retinal neovascularization and permeability in diabetes (11,15,16).

Ruboxistaurin (RBX) is a PKC ß isozyme-selective inhibitor that is orally bioavailable and has been shown to ameliorate the adverse effects of high glucose in a number of animal models of diabetic microvascular complications, including DR, DME, diabetic peripheral neuropathy, and diabetic nephropathy (11,13,17–20). Early safety studies (14) indicated that RBX was well tolerated in individuals with diabetes and reached the retina in bioeffective concentrations as evidenced by an amelioration of diabetes-induced retinal blood flow abnormalities. The Protein Kinase C ß Inhibitor Diabetic Retinopathy Study (PKC-DRS) reported here was a randomized clinical trial that evaluated the effect of three orally administered doses of RBX on DR progression.

	RESEARCH DESIGN AND METHODS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The trial enrolled 252 participants (170 men and 82 women) between the ages of 20 and 84 years with type 1 or type 2 diabetes and HbA_1c (A1C) values from 5.1 to 13% inclusive (Table 1). Participants were excluded if they had 1) a history of significant heart disease (including unstable angina, acute coronary syndrome, myocardial infarction, or history of coronary revascularization procedure) within 6 months before visit 1; 2) significant hepatic disease (defined as aspartate transaminase, alkaline phosphatase, or total bilirubin more than twice the upper limit of normal), renal disease (defined as serum creatinine >2.5 mg/dl, history of renal transplant, or undergoing dialysis at screening), or anemia (defined as hemoglobin <10 g/dl); 3) a systolic blood pressure 180 mmHg or a diastolic blood pressure 105 mmHg; or 4) undergone a major surgery within the previous 3 months.

The PKC-DRS was a multicenter, double-masked, placebo-controlled study in which subjects were randomized to one of four treatment groups: 1) placebo (n = 61), 2) RBX (LY333531; Eli Lilly and Co., Indianapolis, IN) mesylate 8 mg/day (n = 60), 3) RBX 16 mg/day (n = 64), or 4) RBX 32 mg/day (n = 67). A total of 617 patients were screened to obtain the 252 patients randomized (Fig. 1). Randomization was performed at the site level and stratified based upon diabetes type with a block size of 8. The sample size of the study was estimated based on an anticipated 2-year primary outcome event rate in the placebo group of 0.64 obtained by interpretation of the ETDRS results (21) and was estimated to have 80% power to detect a clinically significant 50% reduction in event rate. Failure to meet ocular criteria accounted for 317 (87%) of the 365 patients not entered into the study.

View larger version (45K): [in this window] [in a new window]   FIG. 1. PKC-DRS patient disposition. NOS, not otherwise specified.

Decisions regarding application of photocoagulation resided with individual study investigators and patients, but study policy discouraged initiation of scatter (panretinal) photocoagulation in study eyes before the development of ETDRS level 65 proliferative retinopathy. Focal/grid photocoagulation for DME was initiated at the investigators’ discretion.

Safety assessments.
All serious and nonserious adverse events were analyzed regardless of the investigators’ assessments of causality. Adverse events that resulted in death, hospitalization, cancer, permanent disability, or threat to life were classified as serious. The Medical Dictionary for Regulatory Activities (MedDRA) was used to categorize reported adverse events. Laboratory evaluations were performed at each visit. Physical examinations and electrocardiograms (ECGs) were performed at screening and every 6 months thereafter. ECGs were also performed 1 month postrandomization. To better assess safety data and account for less-common adverse events, safety data from the PKC-DRS trial were pooled with data from the PKC-Diabetic Macular Edema Study (PKC-DMES), a trial of similar duration with a similar patient population. Both studies were conducted in parallel at the same investigative sites. With the exception of the ophthalmologic entry criteria (PKC-DMES study eyes had macular edema >300 µm from the center, ETDRS retinopathy severity level between 20 and 47A inclusive, best-corrected ETDRS visual acuity of >74 letters, and no history of scatter or focal/grid photocoagulation for DR), the inclusion and exclusion criteria were similar for each study. At baseline, no significant differences in the patient characteristics were evident between the two study groups, and there was no clearly evident disparity in reported adverse events. Therefore, in this report, pooled safety data from these 937 patients followed for periods ranging from 30 to 52 months are presented. Subjects from both studies were questioned regarding adverse effects of treatment at each visit. All categories of adverse events for which the frequency was at least 1% and was significantly different (P < 0.05) across treatment groups are reported.

Assessment of DR, DME, and visual acuity.
Ophthalmologic examination was performed at screening and every visit during the treatment period. Ophthalmologic examinations included a best-corrected visual acuity assessment at each visit using the ETDRS protocol (22), intraocular pressure, and Age-Related Eye Disease Study (AREDS) (AREDS Manual of Operations; EMMES, Rockville, MD; available from http://spitfire.EMMES.com/study/AREDS/mop.htm) clinical lens grading every 3 months. DR and DME were assessed by masked grading of ETDRS seven-field stereoscopic color fundus photographs (23,24) performed at the University of Wisconsin Fundus Photograph Reading Center. Photograph sets were obtained at screening, 3 months, 6 months, every 3 months through 24 months, and every 6 months thereafter and were graded using the ETDRS protocol, modified to include estimates of area of retinal thickening in each subfield of the ETDRS grid and of proximity of retinal thickening to the center of the macula. Gradings of right and left eyes from various visits were performed independently of each other.

Study outcomes.
The primary end point for this study was progression of DR defined as a greater than or equal to three-step worsening in the ETDRS retinopathy person severity scale (patients with two study eyes), a greater than or equal to two-step worsening in the ETDRS retinopathy eye severity scale (patients with only one study eye), or a scatter (panretinal) photocoagulation for DR in a study eye. The person scale is an adaptation of the eye scale for individuals who have two simultaneously eligible eyes (23,25). Both scales were used to allow assessment of patients with either one or two eligible eyes. Patients with both eyes of less than proliferative retinopathy without previous PRP had both eyes classified as study eyes, whereas patients with only one such eye were deemed to have only one study eye. In nearly all cases, retinopathy progression meeting the study end point would have resulted in patients developing PDR from their baseline NPDR state.

The secondary study outcome of MVL was defined as a decrease from baseline in ETDRS visual acuity score of 15 or more letters, corresponding to a decrease of three or more lines on the ETDRS chart (doubling or more of the visual angle). Sustained MVL (SMVL) was defined as a decrease from baseline of 15 or more letters observed at each of two consecutive visits 6 or more months apart. For patients with two study eyes, MVL occurring in either eye counted as an event for the patient. Additional subgroup analyses were performed to determine the effect of DME or DR severity on SMVL. Analyses of change in visual acuity included all study eyes, and no adjustments were made for correlation between eyes.

Statistical analyses.
Baseline patient characteristics were compared among treatment groups by categorical tests or ANOVA. All analyses were done using the intent to treat principle. P values from pairwise comparisons between RBX (Eli Lilly) doses and placebo were not adjusted for multiple comparisons. The unadjusted effect of treatment on the occurrence of events (progression of DR, MVL, and SMVL) was analyzed by Kaplan-Meier time-to-event curves, Cox proportional hazard models adjusted for diabetes type, and observed proportions of patients or eyes with events. The impact of treatment effect by baseline DR and DME severity levels was examined by performing stratified analysis of proportions of patients with SMVL. Treatment effect (32 mg RBX vs. placebo) on MVL was assessed using a Cox proportional hazard model adjusting for important baseline covariates identified among potential effect modifiers including ACE inhibitor (ACEI)/angiotensin receptor blocker (ARB) use, age, alcohol use, antibiotic use, antihypertensive use, BMI, urine protein level, DME level, DR level, duration of diabetes, elevated LDL cholesterol or triglycerides, A1C level, insulin use, mean arterial blood pressure, nitrate use, race, sex, tobacco use, type of diabetes, and visual acuity score. Covariates that were either clinically relevant or statistically significant were included in the final Cox proportional hazard (adjusted) model.

Adverse event data were analyzed using categorical (² or Fishers exact) tests. Continuous safety parameters (e.g., laboratory data, intraocular pressure) were analyzed using ANOVA.

	RESULTS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Baseline demographic characteristics.
Baseline demographic characteristics by treatment group are summarized in Table 1. Presence of sites enrolling fewer than eight patients led to some numerical imbalances among treatment groups due to the randomization block size. Participants were predominantly Caucasian with type 2 diabetes, mean age 56 ± 12 years (range 20–84), mean A1C 8.8 ± 1.4% (5.1–13%), and mean duration of diabetes 16 ± 8 years (1–38). BMI was significantly different among the treatment groups (P = 0.046 overall). However, placebo and 32 mg/day RBX groups had similar BMI. There were no other statistically or clinically significant differences observed at baseline among treatment groups for demographic characteristics, laboratory values, or concomitant medications. Notably, A1C was comparable across all groups at baseline, and the change from baseline to end point was not statistically significantly different among treatment groups (range –0.2 to –0.4%).

Baseline ophthalmic characteristics.
There were no statistically or clinically significant differences in baseline ophthalmic characteristics among treatment groups, although severe nonproliferative retinopathy (level 53) tended to be less frequent and DME within 500 µm of the center of the macula or involving it tended to be more frequent in the 32 mg/day group than in the placebo group (Table 2). Mean best-corrected visual acuity score was 80 letters in both placebo and 32 mg/day groups.

View larger version (33K): [in this window] [in a new window]   FIG. 2. Effect of RBX on time to progression of DR or to application of PRP (A) and on the cumulative percentage of patients reaching this end point (B).

View larger version (38K): [in this window] [in a new window]   FIG. 3. Effect of RBX on time to MVL (A) and on the percentage of patients with MVL at each visit (B).

View larger version (32K): [in this window] [in a new window]   FIG. 4. Effect of RBX on time to SMVL (A) and on the percentage of patients with SMVL at each visit (B).

View larger version (17K): [in this window] [in a new window]   FIG. 5. SMVL by baseline retinopathy severity level and by presence at baseline of definite DME, defined as retinal thickening 1/6 disc area in extent located >500 µm from the center of the macula or any retinal thickening within 500 µm of the center.

Cox proportional hazard analyses.
The final Cox proportional hazard model (adjusted) included these significant or clinically relevant baseline covariates: ACEI/ARB use, age, antibiotic use, urine protein level, DME level, DR level, elevated LDL cholesterol or triglycerides, nitrate use, race, sex, tobacco use, type of diabetes, and visual acuity score. The strongest predictors are shown in Fig. 6. Treatment with 32 mg/day RBX reduced the risk of MVL compared with placebo (hazard ratio 0.37 [95% CI 0.17–0.80], P = 0.012). Male sex and ACEI/ARB use at baseline were also associated with a reduced risk of MVL, while tobacco use, age, and severe DME at baseline were associated with increased risk of MVL

View larger version (24K): [in this window] [in a new window]   FIG. 6. Cox proportional hazard model for MVL. Severe DME is defined as retinal thickening (or adjacent hard exudates) located at or within 100 µm of the center of the macula. Horizontal bars indicate 95% CIs, and P values are indicated to the right.

	DISCUSSION

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

There are cellular and animal data suggesting that the ß-isoform of PKC may be involved in mediating diabetes-induced retinopathy (18), retinal vascular permeability (11,27), and retinal neovascularization (13,28). The apparent lack of efficacy of RBX in preventing progression of retinopathy to the proliferative stage could occur for several reasons. Study patients had moderately severe to very severe NPDR at baseline. It has been well established that PKC ß is activated very early in diabetes, well before clinically apparent retinopathy (29,30). Thus, in our study participants, significant biochemical and pathologic retinal changes that are no longer amenable to PKC ß inhibition may have already occurred before enrollment. Alternatively, RBX may not be potent enough to overcome these effects. It is also known that the majority of the neovascular response in the retina is mediated by VEGF (31–33). Although activation of PKC ß is involved in mediating VEGF-induced intracellular signaling (11,28,34,35), RBX is not primarily a VEGF inhibitor, and in cellular and animal models, its antiproliferative effect is weaker than its antipermeability activity (11,13,28). Over time, different growth factors or other molecules, including different isoforms of PKC, could be compensating any potential beneficial effects of PKC ß inhibition. In addition, it is possible that PKC ß activation is not critical for the progression of DR to the proliferative stage in humans.

However, there did appear to be a beneficial effect of RBX on the secondary study outcomes of MVL and SMVL (Figs. 3–5). MVL, defined as a loss of 15 letters or more of best-corrected visual acuity on the ETDRS visual acuity chart, and SMVL, defined as MVL at each of two consecutive visits 6 or more months apart, are clinically meaningful end points (36,37) equivalent to a doubling of the visual angle (e.g., deterioration from 20/20 to 20/40). Although reduction in SMVL by RBX treatment did not reach statistical significance, the relative risk reductions for SMVL and MVL were in the same direction and generally of similar magnitude (0.62 vs. 0.37, respectively). Since SMVL occurs less frequently than MVL, there is less chance of observing a statistical difference in SMVL in this study. However, reduction of SMVL by RBX in eyes with DME at baseline did achieve statistical significance (P = 0.017, Fig. 5). Thus, these findings are consistent with a beneficial effect of RBX on the occurrence of SMVL.

The trends for better visual acuity outcome in the RBX 32-mg/day group were not apparent in the VFQ scores. This is not surprising since VFQ results reflect visual acuity in the patient’s better-seeing eye, and while 22% of placebo-treated patients experienced SMVL, this occurred in the better-seeing eye in only 7% (four patients).

SMVL and MVL are often caused by DME involving the center of the macula. In the PKC-DRS, 79% of patients had DME in at least one study eye at baseline and 34% had DME involving the center of the macula in at least one study eye at baseline. The rate of SMVL was higher in eyes with definite DME at baseline, and it was among these eyes that there was a trend for a beneficial effect of 32 mg/day RBX (Fig. 5). This study was not designed to demonstrate an effect of RBX on DME or visual function, and patients were enrolled regardless of their DME status at baseline. The broad range of baseline DME severity in study eyes (Table 2) makes it difficult to detect an effect of RBX on change in distance of edema from the center of the macula.

DME results from increased leakage of plasma components from the retinal vasculature and has been postulated to occur via two different PKC ß–mediated mechanisms. Diabetes-induced de novo synthesis of diacylglycerol activates PKC ß in the retina (30), which increases vascular permeability through various mechanisms (38,39) including phosphorylation of junctional proteins and dissolution of tight junctions (40,41). In addition, VEGF is a potent vasopermeability factor that may be involved in DME, the intracellular signaling pathway of which involves activation of PKC ß (11). RBX prevents diabetes- and VEGF-induced retinal vascular leakage in animals (11). RBX is more effective at preventing diabetes-induced retinal vascular leakage in these models than in preventing retinal neovascularization (13,28). Treatment of DME patients for 3 months with a multitargeted kinase inhibitor, which also acts as a nonspecific PKC inhibitor, led to reductions in some measures of retinal thickening as evaluated by optical coherence tomography (42). Systemic applicability of this nonselective compound was limited by gastrointestinal side effects and dose-related problems with tolerability, glycemic control, and liver toxicity.

A beneficial effect of RBX on MVL might also be the result of improved retinal cell viability resulting from PKC ß inhibition. PKC ß activation occurs very early in diabetes, before the onset of clinically relevant retinopathy (29,30). Considerable evidence suggests that the activation of the PKC ß isoform is responsible for subsequent diabetes-induced ocular and nonocular microvascular complications (8). Reduction of PKC ß activity might therefore result in greater resistance of retinal vascular and neural cells to the pathologic stresses of hyperglycemia. This may result in greater resistance to cellular damage, reduced cellular dysfunction and/or loss, and prevention of subsequent visual decline. Such a mechanism would be consistent with the prevention of visual decline noted in those patients with DME at baseline (Fig. 5B) even though resolution of DME was not observed. Even if the mechanism by which RBX reduces vision loss involves decreasing edema, the degree of vision loss from involvement of the center of the macula by edema depends on the degree and duration of such involvement, as well as other factors that are not well understood (43). Not all DME progression to the center of the macula results in vision loss, and numerous patients with substantial central retinal thickening from DME may retain excellent visual acuity (L.P.A., personal communication, http://www.drcr.net/ preliminary data) (44,45).

When considering systemic therapy, the safety profile of a compound is of substantial importance. This is particularly true when inhibiting a key signaling enzyme such as PKC, where substantial toxicity might be expected. As indicated above, treatment of DME patients with an inhibitor of multiple kinases and PKC isoforms resulted in significant liver enzyme elevations, nausea, vomiting, and diarrhea (42). In contrast, RBX is selective for the ß-isoform of PKC and highly selective for PKC as compared with other kinases (46). This selectivity for a single PKC isoform involved in mediating diabetes-induced ocular complications would be expected to result in limited side effects. Indeed, the safety profile in 937 patients derived from two studies of ocular complications in individuals with diabetes demonstrates that RBX is well tolerated without significant adverse effects over 30 to 52 months of treatment.

Only nine adverse events occurred, with an incidence exceeding 1%, that were statistically different among groups (Table 3). No serious adverse events were reported more frequently in RBX treatment groups. Although the nonserious adverse event occurrence frequency of diarrhea, flatulence, nephropathy, proteinuria, and coronary artery disease was highest among patients in the 16-mg/day RBX treatment group (Table 3), there did not appear to be RBX dose-response effects. In addition, the small number of events makes it likely that any disparity in the 16-mg group was due to chance. However, safety has been carefully monitored in numerous completed and ongoing trials assessing DME as well as other diabetes complications.

Patients taking the highest RBX dose (32 mg/day) did not experience these same events more frequently than placebo patients. First-degree atrioventricular block, asthma, and dysuria were statistically different among treatment groups, with the highest rate of occurrence in the 32-mg/day RBX group. These events represent spontaneous reports from investigative sites where test abnormalities were not uniformly acquired. When ECGs of all 937 patients in both the PKC-DRS and PKC-DMES were examined, there was no evidence of cardiac conduction interval prolongation in any RBX treatment group. For the events of asthma and dysuria, there were no concomitant increases in the occurrence of related conditions such as bronchospasm, wheezing, or urinary tract infection, and there were no observed differences among treatment groups in serious adverse events in the system organ classes related to these events. Furthermore, the same adverse events were not seen with greater frequency in RBX-treated patients in analyses of five nonocular trials of 6–12 months’ duration. To date, over 1,400 patients have been exposed to RBX, and no clinically significant increase in adverse effects has been identified. Careful monitoring of adverse effects is continuing.

The PKC-DRS is the first clinical trial evaluating the effect of a PKC isoform-selective inhibitor on ocular complications in patients with diabetes. These data demonstrate that, unlike less selective compounds, oral administration of RBX at doses up to 32 mg/day was well tolerated without significant adverse effects over 30 to 52 months of treatment. In patients with moderately severe to very severe NPDR at baseline, RBX did not prevent retinopathy progression to proliferative disease. However, compared with placebo, treatment with 32 mg/day RBX was associated with less visual loss, especially in patients with DME at baseline and when accounting for important retinopathy covariates. These data support further evaluation of RBX to prevent MVL in diabetes.

	APPENDIX

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Members of the PKC-DRS Study Group.
Canada: Philip Hooper, London, Ontario; S.A. Ross, Calgary, Alberta. Denmark: Henrik Lund-Andersen, Herlev. Netherlands: Bettine Polak, Amsterdam. U.K.: John V. Forrester, Aberdeen; Eva M. Kohner, London; J. Vora, Liverpool. U.S.: Everett Ai, San Francisco, CA; Lloyd M. Aiello, Boston, MA; Raijv Anand, Dallas, TX; Mark Blumenkranz, Menlo Park, CA; Alexander J. Brucker, Philadelphia, PA; Thomas Chandler, Austin, TX; Lawrence Chong, Los Angeles, CA; Doug Dehning, Independence, MO; Dan Finkelstein, Baltimore, MD; Robert Frank, Detroit, MI; Charles Garcia, Houston, TX; Thomas W. Gardner, Hershey, PA; Karen M. Gehrs, Iowa City, IA; Roy A. Goodart and David Faber, Salt Lake City, UT; Justin Gottlieb, Madison, WI; Craig M. Greven, Winston-Salem, NC; William E. Jackson, Denver, CO; James L. Kinyoun, Seattle, WA; Michael L. Klein, Portland, OR; Hilel Lewis, Cleveland, OH; Helen K. Li, Galveston, TX; Colin Ma and Richard Dreyer, Portland, OR; Raymond Margherio, Royal Oak, MI; Daniel F. Martin, Atlanta, GA; Philip Y. Paden, Medford, OR; George Sharuk, Boston, MA; Lawrence J. Singerman, Beachwood, OH; William E. Smiddy, Miami, FL; Michael Trese, Royal Oak, MI; James P. Tweeten, Boise, ID; Andrew Vine, Ann Arbor, MI.

Members of the Manuscript Writing and Study Executive Committee.
Lloyd P. Aiello, Boston, MA (Chair); Matthew D. Davis, Madison, WI; Roy C. Milton, Rockville, MD; Matthew J. Sheetz, Indianapolis, IN; Vipin Arora, Indianapolis, IN; Louis Vignati, Indianapolis, IN.

	ACKNOWLEDGMENTS

 
This study was funded by Eli Lilly.

The authors thank all the subjects who participated in the study and Rocky Johnson, Keri Kles, Tim Mason, and Kuolung Hu for their valuable assistance with the preparation of the manuscript.

	FOOTNOTES

 
^* A complete list of the members of the PKC-DRS Study Group can be found in the APPENDIX.

Received for publication November 16, 2005 and accepted in revised form April 14, 2005

	REFERENCES

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 

1. Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053, 2004[Abstract/Free Full Text]
2. Kempen JH, O’Colmain BJ, Leske MC, Haffner SM, Klein R, Moss SE, Taylor HR, Hamman RF: The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol 122:552–563, 2004[Medline]
3. Klein R, Klein BE, Moss SE: The Wisconsin Epidemiological Study of Diabetic Retinopathy: a review. Diabetes Metab Rev 5:559–570, 1989[Medline]
4. Blindness caused by diabetes: Massachusetts, 1987–1994. MMWR Morb Mortal Wkly Rep 45:937–941, 1996[Medline]
5. Early photocoagulation for diabetic retinopathy: ETDRS report number 9: Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98:766–785, 1991[Medline]
6. The Diabetes Control and Complications Trial Research Group: 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 329:977–986, 1993[Abstract/Free Full Text]
7. UK Prospective Diabetes Study (UKPDS) Group: 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 352:837–853, 1998[Medline]
8. Sheetz MJ, King GL: Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA 288:2579–2588, 2002[Abstract/Free Full Text]
9. Mellor H, Parker PJ: The extended protein kinase C superfamily. Biochem J 332:281–292, 1998
10. Bullock WH, Magnuson SR, Choi S, Gunn DE, Rudolph J: Prospects for kinase activity modulators in the treatment of diabetes and diabetic complications. Curr Top Med Chem 2:915–938, 2002[Medline]
11. Aiello LP, Bursell S-E, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, Jirousek M, Smith LEH, King GL: Vascular endothelial growth factor–induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective ß-isoform–selective inhibitor. Diabetes 46:1473–1480, 1997[Abstract]
12. Xu X, Zhu Q, Xia X, Zhang S, Gu Q, Luo D: Blood-retinal barrier breakdown induced by activation of protein kinase C via vascular endothelial growth factor in streptozotocin-induced diabetic rats. Curr Eye Res 28:251–256, 2004[Medline]
13. Danis RP, Bingaman DP, Jirousek M, Yang Y: Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKC ß inhibition with LY333531. Invest Ophthalmol Vis Sci 39:171–179, 1998[Abstract/Free Full Text]
14. Aiello LP, Bursell SE, Devries T, Alatorre C, King GL, Ways DK: Amelioration of abnormal retinal hemodynamics by a protein kinase C ß selective inhibitor (LY333531) in patients with diabetes: results of a phase 1 safety & pharmacodynamic clinical trial. Invest Ophthalmol Vis Sci 40:S192, 1999
15. Funatsu H, Yamashita H, Ikeda T, Nakanishi Y, Kitano S, Hori S: Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular edema and other retinal disorders. Am J Ophthalmol 133:537–543, 2002[Medline]
16. Suzuma K, Takahara N, Suzuma I, Isshiki K, Ueki K, Leitges M, Aiello LP, King GL: Characterization of protein kinase C ß 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 99:721–726, 2002[Abstract/Free Full Text]
17. Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S, Sugimoto T, Yasuda H, Kashiwagi A, Ways DK, King GL, Kikkawa R: Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC ß inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 14:439–447, 2000[Abstract/Free Full Text]
18. Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL: Amelioration of vascular dysfunctions in diabetic rats by an oral PKC ß inhibitor. Science 272:728–731, 1996[Abstract]
19. Cotter MA, Jack AM, Cameron NE: Effects of the protein kinase C ß inhibitor LY333531 on neural and vascular function in rats with streptozotocin-induced diabetes. Clin Sci (Lond) 103:311–321, 2002[Medline]
20. Kelly DJ, Zhang Y, Hepper C, Gow RM, Jaworski K, Kemp BE, Wilkinson-Berka JL, Gilbert RE: Protein kinase Cß inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes 52:512–518, 2003[Abstract/Free Full Text]
21. Early Treatment Diabetic Retinopathy Study Research Group: Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics: ETDRS report number 7. Ophthalmology 98:741–756, 1991[Medline]
22. Early Treatment Diabetic Retinopathy Study Group: Early Treatment Diabetic Retinopathy Study (ETDRS) Manual of Operations. Springfield, Virginia, U.S. Department of Commerce, National Technical Information Service, 1993
23. Early Treatment Diabetic Retinopathy Study Research Group: Grading diabetic retinopathy from stereoscopic color fundus photographs: an extension of the modified Airlie House classification: ETDRS report number 10. Ophthalmology 98:786–806, 1991[Medline]
24. Early Treatment Diabetic Retinopathy Study Research Group: Fundus photographic risk factors for progression of diabetic retinopathy: ETDRS report number 12. Ophthalmology 98:823–833, 1991[Medline]
25. The Diabetes Control and Complications Trial Research Group: Clustering of long-term complications in families with diabetes in the Diabetes Control and Complications Trial. Diabetes 46:1829–1839, 1997[Abstract]
26. Clemons TE, Chew EY, Bressler SB, McBee W: National Eye Institute Visual Function Questionnaire in the Age-Related Eye Disease Study (AREDS): AREDS report no. 10. Arch Ophthalmol 121:211–217, 2003[Abstract/Free Full Text]
27. Idris I, Gray S, Donnelly R: Protein kinase C ß inhibition and diabetic microangiopathy: effects on endothelial permeability responses in vitro. Eur J Pharmacol 485:141–144, 2004[Medline]
28. Xia P, Aiello LP, Ishii H, Jiang ZY, Park DJ, Robinson GS, Takagi H, Newsome WP, Jirousek MR, King GL: Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98:2018–2026, 1996[Medline]
29. Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL: Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes 43:1122–1129, 1994[Abstract]
30. Shiba T, Inoguchi T, Sportsman JR, Heath WF, Bursell S, King GL: Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Physiol 265:E783–E793, 1993
31. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487, 1994[Abstract/Free Full Text]
32. Ozaki H, Seo MS, Ozaki K, Yamada H, Yamada E, Okamoto N, Hofmann F, Wood JM, Campochiaro PA: Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol 156:697–707, 2000[Abstract/Free Full Text]
33. Aiello LP, Wong JS: Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int Suppl 77:S113–S119, 2000[Medline]
34. Yoshiji H, Kuriyama S, Ways DK, Yoshii J, Miyamoto Y, Kawata M, Ikenaka Y, Tsujinoue H, Nakatani T, Shibuya M, Fukui H: Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis. Cancer Res 59:4413–4418, 1999[Abstract/Free Full Text]
35. Takahashi T, Ueno H, Shibuya M: VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18:2221–2230, 1999[Medline]
36. Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema: ETDRS report no. 1. Arch Ophthalmol 103:1796–1806, 1985[Abstract]
37. Brown MM, Brown GC, Sharma S, Busbee B: Quality of life associated with visual loss: a time tradeoff utility analysis comparison with medical health states. Ophthalmology 110:1076–1081, 2003[Medline]
38. Yuan SY, Ustinova EE, Wu MH, Tinsley JH, Xu W, Korompai FL, Taulman AC: Protein kinase C activation contributes to microvascular barrier dysfunction in the heart at early stages of diabetes. Circ Res 87:412–417, 2000[Abstract/Free Full Text]
39. Saishin Y, Saishin Y, Takahashi K, Melia M, Vinores SA, Campochiaro PA: Inhibition of protein kinase C decreases prostaglandin-induced breakdown of the blood-retinal barrier. J Cell Physiol 195:210–219, 2003[Medline]
40. Chen ML, Pothoulakis C, LaMont JT: Protein kinase C signaling regulates ZO-1 translocation and increased paracellular flux of T84 colonocytes exposed to Clostridium difficile toxin A. J Biol Chem 277:4247–4254, 2002[Abstract/Free Full Text]
41. Lacaz-Vieira F, Jaeger MM: Protein kinase inhibitors and the dynamics of tight junction opening and closing in A6 cell monolayers. J Membr Biol 184:185–196, 2001[Medline]
42. Campochiaro PA: Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest Ophthalmol Vis Sci 45:922–931, 2004[Abstract/Free Full Text]
43. Yang CS, Cheng CY, Lee FL, Hsu WM, Liu JH: Quantitative assessment of retinal thickness in diabetic patients with and without clinically significant macular edema using optical coherence tomography. Acta Ophthalmol Scand 79:266–270, 2001[Medline]
44. Early Treatment Diabetic Retinopathy Study Research Group: Focal photocoagulation treatment of diabetic macular edema: relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Arch Ophthalmol 113:1144–1155, 1995[Abstract]
45. Hee MR, Puliafito CA, Duker JS, Reichel E, Coker JG, Wilkins JR, Schuman JS, Swanson EA, Fujimoto JG: Topography of diabetic macular edema with optical coherence tomography. Ophthalmology 105:360–370, 1998[Medline]
46. Jirousek MR, Gillig JR, Gonzalez CM, Heath WF, McDonald JH 3rd, Neel DA, Rito CJ, Singh U, Stramm LE, Melikian-Badalian A, Baevsky M, Ballas LM, Hall SE, Winneroski LL, Faul MM: (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C ß. J Med Chem 39:2664–2671, 1996[Medline]

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				M. Meier, J. Menne, J.-K. Park, and H. Haller Nailing down PKC isoform specificity in diabetic nephropathy two's company, three's a crowd Nephrol. Dial. Transplant., September 1, 2007; 22(9): 2421 - 2425. [Full Text] [PDF]

				B. Sander, D. N. Thornit, L. Colmorn, C. Strom, A. Girach, L. D. Hubbard, H. Lund-Andersen, and M. Larsen Progression of Diabetic Macular Edema: Correlation with Blood Retinal Barrier Permeability, Retinal Thickness, and Retinal Vessel Diameter Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 3983 - 3987. [Abstract] [Full Text] [PDF]

				G. J. Ryan New pharmacologic approachesto treating diabetic retinopathy Am. J. Health Syst. Pharm., September 1, 2007; 64(17_Supplement_12): S15 - S21. [Abstract] [Full Text] [PDF]

				Q. Mohamed, M. C. Gillies, and T. Y. Wong Management of Diabetic Retinopathy: A Systematic Review JAMA, August 22, 2007; 298(8): 902 - 916. [Abstract] [Full Text] [PDF]

				D. J. Kelly, D. Buck, A. J. Cox, Y. Zhang, and R. E. Gilbert Effects on protein kinase C-beta inhibition on glomerular vascular endothelial growth factor expression and endothelial cells in advanced experimental diabetic nephropathy Am J Physiol Renal Physiol, August 1, 2007; 293(2): F565 - F574. [Abstract] [Full Text] [PDF]

				K. R. Tuttle, J. B. McGill, D. J. Haney, T. E. Lin, P. W. Anderson, and for the PKC-DRS, PKC-DMES, and PKC-DRS 2 Study Gro Kidney Outcomes in Long-Term Studies of Ruboxistaurin for Diabetic Eye Disease Clin. J. Am. Soc. Nephrol., July 1, 2007; 2(4): 631 - 636. [Abstract] [Full Text] [PDF]

				R. K. Campbell Etiology and effect on outcomes of hyperglycemia in hospitalized patients Am. J. Health Syst. Pharm., May 15, 2007; 64(10_Supplement_6): S4 - S8. [Abstract] [Full Text] [PDF]

				C. M. Casellini, P. M. Barlow, A. L. Rice, M. Casey, K. Simmons, G. Pittenger, E. J. Bastyr III, A. M. Wolka, and A. I. Vinik A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-{beta} Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy Diabetes Care, April 1, 2007; 30(4): 896 - 902. [Abstract] [Full Text] [PDF]

				Z. T. Bloomgarden Diabetic Retinopathy and Diabetic Neuropathy Diabetes Care, March 1, 2007; 30(3): 760 - 765. [Full Text] [PDF]

				The PKC-DMES Study Group Effect of Ruboxistaurin in Patients With Diabetic Macular Edema: Thirty-Month Results of the Randomized PKC-DMES Clinical Trial Arch Ophthalmol, March 1, 2007; 125(3): 318 - 324. [Abstract] [Full Text] [PDF]

				K. Ullman Is Ruboxistaurin the Next Major Treatment for Microvascular Complications? DOC News, February 1, 2007; 4(2): 1 - 13. [Full Text]

				J. L. Burkey, K. M. Campanale, R. Barbuch, D. O'Bannon, J. Rash, C. Benson, and D. Small Disposition of [14C]Ruboxistaurin in Humans Drug Metab. Dispos., November 1, 2006; 34(11): 1909 - 1917. [Abstract] [Full Text] [PDF]

				D. A. Antonetti, A. J. Barber, S. K. Bronson, W. M. Freeman, T. W. Gardner, L. S. Jefferson, M. Kester, S. R. Kimball, J. K. Krady, K. F. LaNoue, et al. Diabetic Retinopathy: Seeing Beyond Glucose-Induced Microvascular Disease Diabetes, September 1, 2006; 55(9): 2401 - 2411. [Abstract] [Full Text] [PDF]