Blood pressure control for diabetic retinopathy.

BACKGROUND: Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Simultaneous blood pressure control has been advocated for the same purpose, but findings reported from individual studies have supported varying conclusions regarding the ocular benefit of interventions on blood pressure. OBJECTIVES: The primary aim of this review was to summarize the existing evidence regarding the effect of interventions to control or reduce blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs. A secondary aim was to compare classes of anti-hypertensive medications with respect to the same outcomes. SEARCH METHODS: We searched a number of electronic databases including CENTRAL as well as ongoing trial registries. We last searched the electronic databases on 25 April 2014. We also reviewed reference lists of review articles and trial reports selected for inclusion. In addition, we contacted investigators of trials with potentially pertinent data. SELECTION CRITERIA: We included in this review randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to intense versus less intense blood pressure control, to blood pressure control versus usual care or no intervention on blood pressure, or to different classes of anti-hypertensive agents versus placebo. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently reviewed titles and abstracts from electronic and manual searches and the full text of any document that appeared to be relevant. We assessed included trials independently for risk of bias with respect to outcomes reported in this review. We extracted data regarding trial characteristics, incidence and progression of retinopathy, visual acuity, quality of life, and cost-effectiveness at annual intervals after study entry whenever provided in published reports and other documents available from included trials. MAIN RESULTS: We included 15 RCTs, conducted primarily in North America and Europe, that had enrolled 4157 type 1 and 9512 type 2 diabetic participants, ranging from 16 to 2130 participants in individual trials. In 10 of the 15 RCTs, one group of participants was assigned to one or more anti-hypertensive agents and the control group received placebo. In three trials, intense blood pressure control was compared to less intense blood pressure control. In the remaining two trials, blood pressure control was compared with usual care. Five of the 15 trials enrolled type 1 diabetics, and 10 trials enrolled type 2 diabetics. Six trials were sponsored entirely by pharmaceutical companies, seven trials received partial support from pharmaceutical companies, and two studies received support from government-sponsored grants and institutional support.Study designs, populations, interventions, and lengths of follow-up (range one to nine years) varied among the included trials. Overall, the quality of the evidence for individual outcomes was low to moderate. For the primary outcomes, incidence and progression of retinopathy, the quality of evidence was downgraded due to inconsistency and imprecision of estimates from individual studies and differing characteristics of participants.For primary outcomes among type 1 diabetics, one of the five trials reported incidence of retinopathy and one trial reported progression of retinopathy after 4 to 5 years of treatment and follow-up; four of the five trials reported a combined outcome of incidence and progression over the same time interval. Among type 2 diabetics, 5 of the 10 trials reported incidence of diabetic retinopathy and 3 trials reported progression of retinopathy; one of the 10 trials reported a combined outcome of incidence and progression during a 4- to 5-year follow-up period. One trial in which type 2 diabetics participated had reported no primary (or secondary) outcome targeted for this review.The evidence from these trials supported a benefit of more intensive blood pressure control intervention with respect to 4- to 5-year incidence of diabetic retinopathy (estimated risk ratio (RR) 0.80; 95% confidence interval (CI) 0.71 to 0.92) and the combined outcome of incidence and progression (estimated RR 0.78; 95% CI 0.63 to 0.97). The available evidence provided less support for a benefit with respect to 4- to 5-year progression of diabetic retinopathy (point estimate was closer to 1 than point estimates for incidence and combined incidence and progression, and the CI overlapped 1; estimated RR 0.88; 95% CI 0.73 to 1.05). The available evidence regarding progression to proliferative diabetic retinopathy or clinically significant macular edema or moderate to severe loss of best-corrected visual acuity did not support a benefit of intervention on blood pressure: estimated RRs and 95% CIs 0.95 (0.83 to 1.09) and 1.06 (0.85 to 1.33), respectively, after 4 to 5 years of follow-up. Findings within subgroups of trial participants (type 1 and type 2 diabetics; participants with normal blood pressure levels at baseline and those with elevated levels) were similar to overall findings.The adverse event reported most often (7 of 15 trials) was death, yielding an estimated RR 0.86 (95% CI 0.64 to 1.14). Hypotension was reported from three trials; the estimated RR was 2.08 (95% CI 1.68 to 2.57). Other adverse ocular events were reported from single trials. AUTHORS' CONCLUSIONS: Hypertension is a well-known risk factor for several chronic conditions in which lowering blood pressure has proven to be beneficial. The available evidence supports a beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to 4 to 5 years. However, the lack of evidence to support such intervention to slow progression of diabetic retinopathy or to prevent other outcomes considered in this review, along with the relatively modest support for the beneficial effect on incidence, weakens the conclusion regarding an overall benefit of intervening on blood pressure solely to prevent diabetic retinopathy.

Cardiovascular disease, its risk factors and treatment, and age-related macular degeneration: Women's Health Initiative Sight Exam ancillary study.

PURPOSE: To examine the association of cardiovascular disease (CVD), CVD risk factors, and CVD treatment with age-related macular degeneration (AMD). DESIGN: Observational analysis of a randomized clinical trial. SETTINGS: The Women's Health Initiative Sight Examination (WHISE), an ancillary study to the Women's Health Initiative's clinical trial of hormone replacement therapy. STUDY POPULATION: A total of 4,288 women age 63 years and older. OBSERVATION PROCEDURES: Information on CVD and its risk factors were obtained from a standardized questionnaire and examination. MAIN OUTCOME MEASURE: AMD as determined by standardized grading of fundus photographs. RESULTS: Prevalence of any AMD was 21.4% (n = 919). Of those with AMD, 5.8% (n = 53) had signs of exudative AMD (n = 39) or pure geographic atrophy (n = 14), limiting the power to examine associations. Significant associations between late AMD and CVD risk factors were (odds ratio [OR], 95% confidence interval [CI]) older age (1.19, 1.13 to 1.27, P < .0001), more pack years smoked (1.02 per pack-year smoked, 1.003 to 1.03, P = .01), systolic blood pressure (0.84 per 10 mm Hg, 0.71 to 0.995, P = .04), report of taking calcium channel blockers (2.49, 1.21 to 5.12, P = .04), self-reported history of diabetes (2.00, 1.01 to 3.96, P = .05), and greater body mass index (1.05 per 1 kg/m, 1.001 to 1.10, P = .05). History of myocardial infarction, stroke, use of statins, or white blood cell count was not associated with AMD. CONCLUSIONS: Results suggest that smoking, use of calcium channel blockers, diabetes, and obesity are risk factors for late AMD in women. However, the association of late AMD with systolic blood pressure and the effects of other CVD risk factors on early AMD need to be further explored.

Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial.

Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 10(6) to 10(9.5) particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were negative. At 3 and 6 months after injection, 55 and 50%, respectively, of patients treated with 10(6)-10(7.5) PU and 94 and 71% of patients treated with 10(8)-10(9.5) PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 months was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 10(8) PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.

Localization of multifocal electroretinogram abnormalities to the lesion site: findings in a family with Best disease.

OBJECTIVE: To determine the association between multifocal electroretinogram (mfERG) abnormalities and macular lesions, as shown by retinal photography and optical coherence tomography (OCT), in a 3-generation family with vitelliform macular dystrophy. METHODS: Five family members were examined using OCT, mfERG, and retinal photography. To localize mfERG abnormalities in relation to retinal findings, we overlaid the mfERG trace arrays on the retinal images and aligned the mfERGs and OCT images in the 180 degrees meridian. RESULTS: Family members had typical macular lesions, normal full-field ERGs, and reduced electro-oculogram light-dark ratios. The OCT images demonstrated variable lesion severity. Some individuals with good vision and normal-appearing fundi showed OCT abnormalities of the choroid and retinal pigment epithelium. The overlay technique revealed that the depressed mfERGs corresponded with the lesions detected by OCT and retinal photography. The latencies of mfERG components in the 2 central stimulus rings in our patients were often prolonged. CONCLUSIONS: The mfERG abnormalities matched the localization of the macular lesions in our patients. The latencies of the mfERG N1 and P1 components in the first 2 concentric stimulus rings were often significantly (>2 SDs) delayed, an observation that has not been previously reported, to our knowledge.

Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats.

The study addressed the role for aldose reductase (AR) in 1) retinal oxidative stress and vascular endothelial growth factor (VEGF) overexpression in early diabetes, and 2) high glucose-induced oxidative stress in retinal endothelial cells. In vivo experiments were performed on control rats and diabetic rats treated with or without low or high dose of the AR inhibitor (ARI) fidarestat (2 or 16 mg. kg(-1). day(-1)). In vitro studies were performed on bovine retinal endothelial cells (BREC) cultured in either 5 or 30 mmol/l glucose with or without 1 micro mol/l fidarestat. Intracellular reactive oxygen species were assessed using the 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFDA) probe and flow cytometry. Both low and high doses of fidarestat (i.e., the doses that partially and completely inhibited sorbitol pathway hyperactivity) arrested diabetes-induced retinal lipid peroxidation. This was achieved due to upregulation of the key antioxidative defense enzyme activities rather than changes in reduced glutathione, oxidized glutathione, ascorbate and dehydroascorbate concentrations, and the glutathione and ascorbate redox states. Diabetes-associated 2.1-fold VEGF protein overexpression (enzyme-linked immunosorbent assay; ELISA) was dose-dependently prevented by fidarestat, whereas total VEGF mRNA and VEGF-164 mRNA (RT-PCR) abundance were not affected by either diabetes or the ARI. In BREC, fidarestat corrected hyperglycemia-induced increase in H(2)DCFDA fluorescence but not oxidative stress caused by three different pro-oxidants in normoglycemic conditions. In conclusion, increased AR activity contributes to retinal oxidative stress and VEGF protein overexpression in early diabetes. The findings justify the rationale for evaluation of fidarestat on diabetic retinopathy.

Diabetic retinopathy and systemic factors.

Diabetic retinopathy, an oculardisease, is governed by systemic as well as local ocular factors. These include primarily chronic levels of blood glucose. Individuals with chronically elevated blood glucose levels have substantially more, and more severe, retinopathy than those with lower blood glucose levels. The relationship of blood glucose to retinopathy is continuous, with no threshold although individuals with hemoglobin A1c levels (a measure of chronic glycemia) <6.5%, generally develop little or no retinopathy. Blood pressure levels have been claimed to influence retinopathy development and progression, but multiple controlled clinical trials of antihypertensive agents in diabetic subjects have produced only weak evidence of benefit from blood pressure lowering on the incidence and progression of diabetic retinopathy. Elevated blood lipids seem to play a role in the progression of retinopathy, and two trials of fenofibrate, a lipid-lowering agent that has not proved effective in preventing cardiovascular disease, have shown benefit in preventing retinopathy progression. The mechanism of this effect may not, however, be directly related to the reduction in blood lipids. Finally, there is strong, but only circumstantial, evidence for a genetic or epigenetic influence on the pathogenesis of diabetic retinopathy. Despite the power of large-scale epidemiologic studies and modern molecular biological and computational techniques, the gene or genes, which predispose or protect against the development and progression of diabetic retinopathy remain elusive.

Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors.

PURPOSE: To review the evidence supporting a role for the beta (beta) isoform of protein kinase C (PKC) in the pathogenesis of diabetic retinopathy and the possible therapeutic benefit of inhibiting this enzyme. DESIGN: Brief literature review of research suggesting the potential use for systemic inhibitors of the beta isoform of PKC as a medical therapy to prevent the progression of diabetic retinopathy. Brief consideration is given to previous, primarily clinical, studies dealing with other therapies for this disease. RESULTS: Kinases transfer the terminal, "high energy," phosphate group of ATP to a site on a target protein, thereby activating the protein, which may be an enzyme, cell membrane receptor, or ion transport channel. The PKC family is a group of such enzymes that require specific activator molecules, including diacylglycerol, whose intracellular concentration is substantially increased during the hyperglycemia of diabetes. Protein kinase Cbeta is present at high levels in the retina. Increased activation of this enzyme, perhaps by producing tissue hypoxia, leads to increased expression of vascular endothelial growth factor, a mitogen that increases proliferation of vascular endothelial cells leading to neovascularization and enhances breakdown of the blood-retinal barrier, perhaps resulting in macular edema. CONCLUSIONS: By interfering with the above biochemical pathways, PKC inhibitors may retard or prevent the development and progression of diabetic retinopathy. Because members of the PKC family are found throughout the body, a generalized inhibitor is likely to be toxic. However, an inhibitor specific for PKCbeta may act effectively within the retina and have a favorable toxicity profile. Two phase III randomized controlled clinical trials of such an inhibitor are now in progress, attempting to evaluate the efficacy of this approach to preventing the progression, or inducing regression, of "nonclinically significant" diabetic macular edema and of severe nonproliferative diabetic retinopathy.

Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression.

We hypothesize that poly(ADP-ribose) polymerase (PARP) activation is an important mechanism in the oxidative stress-related development of diabetic retinopathy. In the experiments reported here, we evaluated if: a) PARP activation is present in the retina in short-term diabetes; and b) PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, counteract diabetes- and hypoxia-induced retinal VEGF formation. In vivo studies were performed in control and streptozotocin-diabetic rats treated with/without 3-aminobenzamide or 1,5-isoquinolinediol (30 and 3 mg/kg per day, intraperitoneally, for 2 weeks after 2 weeks of diabetes). In vitro studies were performed in human retinal pigment epithelial cells exposed to normoxia or hypoxia with/without 3-aminobenzamide and 1,5-isoquinolinediol at 200 and 2 micro M. Retinal immunostaining for poly(ADP-ribose) was increased and NAD concentration reduced in diabetic rats, and both variables were corrected by PARP inhibitors. Retinal VEGF protein (ELISA, immunohistochemistry), but not mRNA (ribonuclease protection assay) abundance, was increased in diabetic rats, and this increase was corrected by both 3-aminobenzamide and 1,5-isoquinolinediol. PARP inhibitors did not affect retinal glucose, sorbitol pathway intermediates or lipid peroxidation in diabetic rats. Hypoxia caused a several-fold increase in both VEGF-mRNA and protein in retinal pigment epithelial cells. VEGF mRNA overexpression was only slighly blunted by PARP inhibitors whereas VEGF protein was corrected. In conclusion, PARP is involved in diabetes- and hypoxia-induced VEGF production at post-transcriptional level, downstream from the sorbitol pathway activation and oxidative stress. The results justify studies of PARP inhibitors in models of retinopathy of prematurity and diabetic retinopathy.

The influence of glucose concentration and hypoxia on VEGF secretion by cultured retinal cells.

PURPOSE: To study the relationship of oxygen level and glucose concentration on the secretion of vascular endothelial growth factor (VEGF) mRNA and protein in several types of cultured retinal cells. MATERIALS AND METHODS: Several types of human and bovine retinal cells were cultured in medium without glucose, or containing 5 mM or 25 mM D-glucose or 5 mM D-glucose and 20 mM D-galactose. Cells were cultured in 20% O(2) ("normoxia") or in 1% O(2) ("hypoxia"). After being cultured for 8-96 hr, we measured VEGF protein in the medium and VEGF mRNA in the cell layer, as well as the concentrations of glucose, lactate, and pyruvate in the medium. RESULTS: Hypoxia increased VEGF mRNA and protein in these cells. In normoxia, culture in high glucose medium had no significant effect on basal VEGF production in normal glucose. However, culture in hypoxia and high glucose significantly blunted hypoxic VEGF up-regulation. Culture in normoxia, with no glucose in the medium, significantly increased VEGF. Culture in high galactose medium did not significantly affect VEGF production. Despite considerable lactate production, especially in the presence of 25 mM glucose, addition of strong buffers to the medium had little effect on VEGF production. CONCLUSIONS: Cultured retinal cells up-regulate their VEGF production when their energy supply, including glucose and/or O(2), is inadequate. Supplying glucose to the cells in the presence of low O(2) reduces their VEGF production. We suggest that "early worsening" of retinopathy results when diabetic patients with minimal to moderate retinopathy, whose retinal circulation and, hence, retinal oxygen supply is compromised, are placed on a "tight" glucose control regimen and their major remaining retinal energy source is reduced, with VEGF up-regulation as a compensatory mechanism.