Predictive factors for treatment outcomes with intravitreal anti-vascular endothelial growth factor injections in diabetic macular edema in clinical practice.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice. METHODS: This was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models. RESULTS: There was a significant improvement in BCVA (p < 0.001) and CMT (p < 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a < 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive "early functional response" (p < 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p < 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an "early anatomical response", (p < 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response. CONCLUSIONS: The study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes. TRIAL REGISTRATION: The study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 - 067).

Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema.

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.

The effect of insulin on response to intravitreal anti-VEGF injection in diabetic macular edema in type 2 diabetes mellitus.

OBJECTIVES: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus. METHODS: This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. RESULTS: The mean final BCVA and CMT improved in both the insulin (N = 137; p < 0.001; p < 0.001, respectively) and the OHA group (N = 61; p = 0.199; p < 0.001, respectively). The two treatment groups were comparable for final BCVA (p = 0.263), BCVA change (p = 0.184), final CMT (p = 0.741), CMT change (p = 0.458), and the cumulative injections received (p = 0.594). The results were comparable between the two groups when stratified by baseline vision (p > 0.05) and baseline HbA1c (p > 0.05). CONCLUSION: Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.

Pericytes, inflammation, and diabetic retinopathy.

Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus, and a common cause of vision impairment and blindness in these patients, yet many aspects of its pathogenesis remain unresolved. Furthermore, current treatments are not effective in all patients, are only indicated in advanced disease, and are associated with significant adverse effects. This review describes the microvascular features of DR, and how pericyte depletion and low-grade chronic inflammation contribute to the pathogenesis of this common ophthalmic disorder. Existing, novel and investigational pharmacological strategies aimed at modulating the inflammatory component of DR and ameliorating pericyte loss to potentially improve clinical outcomes for patients with diabetic retinopathy, are discussed.

MicroRNA-Related Genetic Variants Are Associated With Diabetic Retinopathy in Type 1 Diabetes Mellitus.

Purpose: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). Methods: All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Results: Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Conclusions: Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: a population-based audit.

IMPORTANCE: Five-year survival rates in patients undergoing vitrectomy for diabetic retinopathy (DR) vary from 68% to 95%. No study has been conducted in an Australian population. BACKGROUND: We aimed to determine the survival rates of patients undergoing diabetic vitrectomy in an Australian population. DESIGN: Retrospective audit, tertiary centre hospitals and private practices. PARTICIPANTS: All individuals in South Australia and the Northern Territory who underwent their first vitrectomy for diabetic complications between January 1, 2007 and December 31, 2011. METHODS: An audit of all eligible participants has been completed previously. Survival status as of July 6, 2018 and cause of death were obtained using SA/NT DataLink. Kaplan-Meier survival curves and multivariate cox-regressions were used to analyse survival rates and identify risk factors for mortality. MAIN OUTCOME MEASURES: Five-, seven- and nine-year survival rates. RESULTS: The 5-, 7- and 9-year survival rates were 84.4%, 77.9% and 74.7%, respectively. The most common cause of death was cardiovascular disease. Associated with increased mortality independent of age were Indigenous ethnicity (HR = 2.04, 95% confidence interval [CI]: 1.17-3.57, P = 0.012), chronic renal failure (HR = 1.76, 95% CI: 1.07-2.89, P = 0.026) and renal failure requiring dialysis (HR = 2.32, 95% CI: 1.25-4.32, P = 0.008). CONCLUSIONS AND RELEVANCE: Long-term survival rates after diabetic vitrectomy in Australia are similar to rates reported in other populations. Indigenous ethnicity and chronic renal failure were the most significant factors associated with long-term mortality. This information can guide allocation of future resources to improve the prognosis of these high risk groups.

Mitochondrial haplogroups are not associated with diabetic retinopathy in a large Australian and British Caucasian sample.

Mitochondrial haplogroups H1, H2 and UK have previously been reported to be associated with proliferative diabetic retinopathy (PDR) in Caucasian patients with diabetes. We aimed to replicate this finding with a larger sample and expand the analysis to include different severities of DR, and diabetic macular edema (DME). Caucasian participants (n = 2935) with either type 1 or type 2 diabetes from the Australian Registry of Advanced Diabetic Retinopathy were enrolled in this study. Twenty-two mitochondrial single nucleotide polymorphisms were genotyped by MassArray and haplogroups reconstructed using Haplogrep. Chi square tests and logistic regressions were used to test associations between haplogroup and DR phenotypes including any DR, non-proliferative DR (NPDR), proliferative DR (PDR) and DME. After stratifying the samples in type 1 and type 2 diabetes groups, and adjusting for sex, age, diabetes duration, concurrent HbA1c and hypertension, neither haplogroups H1, H2, UK, K or JT were associated with any DR, NPDR, PDR or DME.

Presence of diabetic retinopathy is associated with worse 10-year mortality among Indigenous Australians in Central Australia: The Central Australian ocular health study.

IMPORTANCE: Diabetes mellitus (DM) is highly prevalent among Indigenous Australians and contributes greatly to premature death. The association of diabetic retinopathy (DR) with early mortality, however, has not previously been reported among Indigenous Australians. BACKGROUND: To investigate associations between 10-y mortality and the presence of DR among Indigenous Australians living in Central Australia. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 1257 individuals aged 40 y or older, living in one of 30 remote communities within Central Australia were recruited through outreach clinics. METHODS: Fundus examination was performed on all patients at recruitment. The presence of any DR was recorded. MAIN OUTCOME MEASURES: Mortality rate and cause were obtained at 10 y, and their association with any DR was determined. RESULTS: Ten-year all-cause mortality was found to be 29.3%. Of those with DM but no DR, 24.0% died during the 10 y after recruitment, compared with 40.1% for those with any DR (P < 0.0001). Those who had any DR were 75% more likely to die (hazard ratio [HR] 1.75; P < 0.0001) and were more likely to die from renal failure (HR 2.71; P = 0.004) or stroke (HR 5.91; P = 0.026). CONCLUSION AND RELEVANCE: The presence of any DR among those with DM, was associated with a 75% greater 10-y all-cause mortality rate and were more likely to die from renal failure or stroke. We recommend that whenever DR is noted among Indigenous Australians with DM, that they be immediately referred for investigation and management of risk factors, which might predispose to renal failure and stroke.

Visual outcomes following vitrectomy for diabetic retinopathy amongst Indigenous and non-Indigenous Australians in South Australia and the Northern Territory.

IMPORTANCE: Visual outcomes following diabetic vitrectomy have not previously been studied in an Australian population. BACKGROUND: This analysis aimed to determine the rate of, and factors associated with visual success following diabetic vitrectomy performed for Indigenous and non-Indigenous Australians, and investigate factors predisposing to early progression to diabetic retinopathy (DR) requiring vitrectomy. DESIGN: Retrospective, population-based audit. PARTICIPANTS: All patients undergoing vitrectomy for the complications of DR in South Australia (SA) and the Northern Territory (NT) between 2007 and 2011. METHODS: Medical records were audited and data collected, including demographics, diabetic history, past treatment for DR, indication for vitrectomy and visual acuity pre and postoperatively. MAIN OUTCOME MEASURES: Visual success (gain of ≥15 ETDRS letters) at 6 and 12 months, postoperatively. RESULTS: A total of 495 diabetic vitrectomies, for 404 eyes of 335 patients were performed in SA and NT between 2007 and 2011. 77 (23%) patients requiring diabetic vitrectomy were Indigenous Australians. 87% of patients undergoing diabetic vitrectomy had stable or improved vision at 1 year, postoperatively. There was no significant difference between indigenous and non-indigenous eyes achieving visual success (P = 0.929). Timely preoperative laser treatment (P = 0.03) and preoperative visual acuity (P = 0.01) were the predominant factors associated with visual success. CONCLUSIONS AND RELEVANCE: Indigenous patients are just as likely to have improved vision following diabetic vitrectomy as non-Indigenous Australians. However, the small subset of indigenous patients with blind eyes prior to vitrectomy are significantly less likely to improve from surgery. The underlying factors associated with poor outcomes in this group requires further exploration.

Diabetic macular oedema: clinical risk factors and emerging genetic influences.

Diabetic macular oedema is the major cause of visual impairment in type 1 and type 2 diabetes. As type 2 diabetes becomes more prevalent worldwide, the prevalence of diabetic macular oedema is also expected to rise. Current management of diabetic macular oedema is challenging, expensive and not optimal in a subset of patients. Therefore, it is important to increase our understanding of the risk factors involved and develop preventative strategies. While clinical risk factors for diabetic macular oedema have been identified, few studies have addressed potential genetic risk factors. Epidemiology and family studies suggest genetic influences are of importance. In this review, we summarise known clinical risk factors, as well as discuss the small number of genetic studies that have been performed for diabetic macular oedema.

Ten-year all-cause mortality and its association with vision among Indigenous Australians within Central Australia: the Central Australian Ocular Health Study.

BACKGROUND: No studies to date have explored the association of vision with mortality in Indigenous Australians. We aimed to determine the 10-year all-cause mortality and its associations among Indigenous Australians living in Central Australia. DESIGN: Prospective observational cohort study. PARTICIPANTS: A total of 1257 (93.0%) of 1347 patients from The Central Australian Ocular Health Study, over the age of 40 years, were available for follow-up during a 10-year period. METHODS: All-cause mortality and its associations with visual acuity, age and gender were analysed. MAIN OUTCOME MEASURES: All-cause mortality. RESULTS: All-cause mortality was 29.3% at the end of 10 years. Mortality increased as age of recruitment increased: 14.2% (40-49 years), 22.6% (50-59 years), 50.3% (60 years or older) (χ = 59.15; P < 0.00001). Gender was not associated with mortality as an unadjusted variable, but after adjustment with age and visual acuity, women were 17.0% less likely to die (t = 2.09; P = 0.037). Reduced visual acuity was associated with increased mortality rate (5% increased mortality per one line of reduced visual acuity; t = 4.74; P < 0.0001) after adjustment for age, sex, diabetes and hypertension. CONCLUSIONS: The 10-year all-cause mortality rate of Indigenous Australians over the age of 40 years and living in remote communities of Central Australia was 29.3%. This is more than double that of the Australian population as a whole. Mortality was significantly associated with visual acuity at recruitment. Further work designed to better understand this association is warranted and may help to reduce this disparity in the future.

A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients.

AIMS: This study aimed to investigate whether the single-nucleotide polymorphism (SNP) rs2910164 residing within microRNA-146a (miR-146a) is associated with diabetic microvascular complications diabetic nephropathy (DN), proliferative diabetic retinopathy (PDR) or diabetic macular oedema (DME) in either Caucasian patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus. METHODS: Caucasian patients with T1DM (n = 733) or T2DM (n = 2215) were recruited from ophthalmology, renal and endocrine clinics in Australia and the UK. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be on treatment with oral hypoglycaemic drugs or insulin. In total, 890 participants had DN (168 with T1DM and 722 with T2DM), 731 had PDR (251 with T1DM and 480 with T2DM) and 1026 had DME (170 with T1DM and 856 with T2DM). Participants were genotyped for SNP rs2910164 in miR-146a. Analyses investigating association were adjusted for relevant clinical covariates including age, sex, DM duration, HbA1c and hypertension. RESULTS: A significant association was found between the C allele of rs2910164 and DN in the T1DM group (OR 1.93; CI 1.23-3.03; P = 0.004), but no association found in the T2DM group (OR 1.05; CI 0.83-1.32; P = 0.691). In the subset of T2DM patients, the C allele was specifically associated with DME (OR 1.25; CI 1.03-1.53; P = 0.025). No association with DME was found in the T1DM group (OR 0.87; CI 0.54-1.42); P = 0.583), or with PDR for either type of DM. CONCLUSIONS: Rs2910164 is significantly associated with microvascular complications DN in patients with T1DM and DME in patients with T2DM.

Role of microglia and toll-like receptor 4 in the pathophysiology of delirium.

Delirium is a serious medical condition that commonly afflicts elderly inpatients. This is especially common in the post-operative setting where it increases mortality, length of hospital stay and health care costs. The exact mechanisms involved in its pathogenesis remain uncertain and there is currently no effective pharmacological therapy for treatment or prevention of delirium. We hypothesize that microglia-mediated neuroinflammation via toll-like receptor 4 signalling is a significant contributor to post-operative delirium. Based on our proposed mechanism, three novel pharmacological therapies have been suggested to be effective to prevent or treat delirium. Curcumin, ibudilast and minocycline have been shown to interfere with various steps in the proinflammatory microglial activation intracellular signalling pathway, disrupting the subsequent neuroinflammatory cascade. We hypothesize that these drugs could be a novel pharmacotherapy that could significantly improve the outcome of post-operative delirious patients.