Proteomic analysis of diabetic retinopathy identifies potential plasma-protein biomarkers for diagnosis and prognosis.

OBJECTIVES: To identify molecular pathways and prognostic- and diagnostic plasma-protein biomarkers for diabetic retinopathy at various stages. METHODS: This exploratory, cross-sectional proteomics study involved plasma from 68 adults, including 15 healthy controls and 53 diabetes patients for various stages of diabetic retinopathy: non-diabetic retinopathy, non-proliferative diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema. Plasma was incubated with peptide library beads and eluted proteins were tryptic digested, analyzed by liquid chromatography-tandem mass-spectrometry followed by bioinformatics. RESULTS: In the 68 samples, 248 of the 731 identified plasma-proteins were present in all samples. Analysis of variance showed differential expression of 58 proteins across the five disease subgroups. Protein-Protein Interaction network (STRING) showed enrichment of various pathways during the diabetic stages. In addition, stage-specific driver proteins were detected for early and advanced diabetic retinopathy. Hierarchical clustering showed distinct protein profiles according to disease severity and disease type. CONCLUSIONS: Molecular pathways in the cholesterol metabolism, complement system, and coagulation cascade were enriched in patients at various stages of diabetic retinopathy. The peroxisome proliferator-activated receptor signaling pathway and systemic lupus erythematosus pathways were enriched in early diabetic retinopathy. Stage-specific proteins for early - and advanced diabetic retinopathy as determined herein could be 'key' players in driving disease development and potential 'target' proteins for future therapies. For type 1 and 2 diabetes mellitus, the proteomic profiles were especially distinct during the early disease stage. Validation studies should aim to clarify the role of the detected molecular pathways, potential biomarkers, and potential 'target' proteins for future therapies in diabetic retinopathy.

Short-term outcomes of treatment switch to faricimab in patients with aflibercept-resistant neovascular age-related macular degeneration.

PURPOSE: To report short-term outcomes of treatment switch to faricimab in real-world patients with aflibercept-resistant neovascular age-related macular degeneration (AMD). METHODS: Single-center, retrospective cohort study with chart-review using electronic injection database, electronic medical records, and optical coherence tomography (OCT) data from May to September 2023. RESULTS: A total of 50 eyes of 46 patients were analyzed. Faricimab treatment led to absence of fluid in 32% of the eyes and a reduction of fluid in 84% of the eyes. There was a statistically significant decrease in central retinal thickness (CRT) and pigment epithelial detachment (PED) height in those that responded to the switch (median difference: - 31 µm, IQR: 55, p < 0.0001 and median difference: - 21 µm, IQR: 36, p < 0.0001, respectively) and a statistically significant increase in CRT (median difference: + 19 µm, IQR: 20, p = 0.0143) and no change in PED height (median difference: + 22 µm, IQR: 64, p = 0.1508) in those that did not. Best-corrected visual acuity (BCVA) showed marginal decrease with low statistical significance. No ocular or systemic safety events were observed. CONCLUSIONS: Our findings suggest that switching to faricimab is generally safe and effective in patients with neovascular AMD who are otherwise difficult to treat and have residual fluid despite frequent injections with aflibercept. We observed a high rate of morphological response to the treatment switch, improvement of anatomical parameters with about one-third of patients having dry macula following a single injection, and a marginal change in BCVA. Sustainability of these results requires further investigation. STUDY REGISTRATION: ClinicalTrials.gov registration number: NCT06124677. Date of registration: 09/11/2023, retrospectively registered.

Systemic adverse events and all-cause mortality following same-session bilateral intravitreal anti-VEGF injections: a systematic review.

PURPOSE: To review the risk of systemic adverse events and all-cause mortality following same-day bilateral anti-VEGF injections. METHODS: Twelve literature databases were searched for studies on same-session bilateral intravitreal anti-VEGF injections. Studies reporting on systemic adverse events and mortality were included. Data extraction was made independently by two authors and discussed afterwards until consensus was reached. RESULTS: Seven studies were included with a total of 13,406 intravitreal anti-VEGF injections (6703 bilateral injections sessions) given to 689 patients. Across all studies, mean age of patients ranged from 55.7 to 82.5 years, and mean follow-up times ranged from 1.3 to 41 months. Six studies reported on systemic adverse events: Two cases of non-fatal cardiac adverse events were reported after 12,964 injections (6482 bilateral injection sessions) in 626 patients. Four studies reported on death: 12 deaths were recorded after 6233 bilateral injection sessions in a total population of 554 subjects. CONCLUSIONS: We suggest that the risk of non-fatal systemic adverse events and death after same-session bilateral anti-VEGF injection is reasonably low, but larger studies with follow-ups of several years are needed to quantify the exact risk. STUDY REGISTRATION: Prospectively registered in PROSPERO, registration ID: CRD42023428254, registration date: 20/05/2023.

Endophthalmitis following same-day bilateral anti-VEGF injections: a systematic review.

PURPOSE: To review the risk of endophthalmitis in same-day bilateral anti-VEGF injections. METHODS: We searched 12 literature databases for studies on the risk of endophthalmitis after same-day bilateral intravitreal anti-VEGF injections. Data extraction was made independently by two authors and discussed afterward until reaching consensus. RESULTS: Seventeen studies were included with a total of 138,478 intravitreal anti-VEGF injections (69,239 bilateral injections sessions) given in at least 7579 patients. In total, 33 cases of endophthalmitis had occurred, and no cases were bilateral. The incidence of endophthalmitis ranged from 0 to 0.53% per intravitreal injection across studies. CONCLUSIONS: We suggest that clinicians can consider same-day treatment of both eyes of patients in need of bilateral intravitreal anti-VEGF injection therapy, but larger studies are needed to quantify the exact risk of endophthalmitis.

Prevalence and severity of diabetic retinopathy in pregnant women with diabetes-time to individualize photo screening frequency.

AIMS: To evaluate the prevalence and severity of diabetic retinopathy including macular oedema in pregnant women with diabetes and to identify women in whom the frequency of retinal screening can be reduced to minimize the burden of health care visits. METHODS: A cohort study of 348 women with pre-existing diabetes were routinely screened with retinal photo in early (12 weeks) and late pregnancy (27 weeks). Diabetic retinopathy was classified in five stages in accordance with National Danish Guidelines based on the eye with the highest retinopathy level. Sight-threatening retinopathy was defined as the presence of proliferative retinopathy and/or clinically significant macular oedema (CSMO). RESULTS: Retinopathy was present in 52% (116/223) vs. 14% (17/125), with sight-threatening retinopathy in 16% (35/223) vs. 6% (7/125) of women with type 1 and type 2, respectively. Women without retinopathy in early and late pregnancy were characterized by shorter diabetes duration (p < 0.0001 and p = 0.008) and predominance of type 2 diabetes. Amongst the 50% (175/348) of the cohort having no retinopathy in early pregnancy and HbA1c<53 mmol/mol (7.0%), none developed sight-threatening retinopathy and 94% (165/175) remained without any retinopathy during pregnancy. Development of sight-threatening retinopathy was mainly observed in women with retinopathy in early pregnancy. Treatment for sight-threatening retinopathy was given to a minority (2.7 and 2.4%, respectively). CONCLUSION: Good glycaemic control and no retinopathy was seen in a large proportion of women in early pregnancy and none of these women developed sight-threatening retinopathy. The frequency of retinal screening can probably be safely reduced during pregnancy in these women.

A nationwide study on the incidence of rhegmatogenous retinal detachment in Denmark, with emphasis on the risk of the fellow eye.

PURPOSE: To estimate the risk of developing rhegmatogenous retinal detachment (RRD) in the fellow eye in patients with RRD in the first eye and to identify potential risk factors. METHODS: We used the Danish National Patient Registry to identify all surgeries performed for RRD in Denmark in the period from January 2000 to July 2011. RESULTS: In 11,451 cases of RRD in the study period, 8,553 cases in 8,081 patients were identified as primary RRD with an annual incidence of 13.7 per 100,000 citizens. There was a significant increase in the number of cases with RRD during the study period that was mainly explained by an increase of cataract surgeries. Four hundred and seventy-one of 7,941 patients with primary RRD on one eye and no other previous eye disease developed an additional RRD in the fellow eye with an overall incidence of 1% per year. Cox analysis revealed male gender, surgery on the lens, and young age as significant risk factors (P < 0.0001). CONCLUSION: Patients with RRD on the first eye have a 100 times greater risk of developing RRD on the second eye, and the risk increases with male gender and surgery on the lens but decreases with age.

Prognostic modelling of number of patients with retinal vein occlusion in anti-VEGF therapy.

PURPOSE: The purpose of the study was to evaluate temporal changes in age- and sex-stratified incidence rates of retinal vein occlusion (RVO) commenced in anti-vascular endothelial growth factor (anti-VEGF) treatment, proportion of patients remaining in active anti-VEGF therapy over time, and to develop a forecasting model for future number of patients with RVO in active anti-VEGF therapy. METHODS: This was a registry-based study of patients with RVO in the Capital Region of Denmark from commenced in anti-VEGF therapy from 1 January 2007 to 30 June 2022. Census data were extracted from Statistics Denmark for incidence rate analyses and forecasting data of future demographics. RESULTS: A total of 2641 patients with RVO were commenced in anti-VEGF therapy, of which 2192 were later discontinued. Number of patients rose dramatically during the first years of introduction of anti-VEGF therapy, after which growth was slower and followed the demographic changes. Trend analyses revealed that the COVID-19 epidemics impacted with fewer referrals and more aggressive discontinuation practices. Annual incidence of RVO in 2012-2021 was 13.1 per 100 000 (95% CI: 12.6-13.6 per 100 000). Proportion of patients with RVO remaining in active anti-VEGF treatment was 55.0%, 40.1%, 30.8% and 12.1% after Years 1, 2, 3 and 8, respectively. According to our forecast, number of patients with RVO in active anti-VEGF therapy will grow slowly but continually at least until year 2035. CONCLUSION: Our study reports incidence rates and provides prognostic modelling of number of patients with RVO in anti-VEGF therapy.

Injection burden and treatment intervals of aflibercept in observe-and-plan regimen for neovascular age-related macular degeneration.

PURPOSE: The Observe-and-Plan (O&P) regimen allows for individualised treatment. In this study, we evaluated injection burden and intervals using aflibercept in an O&P regimen for eyes with neovascular age-related macular degeneration (AMD). METHODS: This was a retrospective registry-based study of treatment-naïve eyes with neovascular AMD. Treatment data were compiled for 3 years after commencement of intravitreal aflibercept therapy. We evaluated clinical consequences at the first follow-up after loading dose, the proportion of patients who obtained and kept dry macula after loading dose, number of injections and intervals between injections. RESULTS: Data were obtained for 1103 eyes. After loading dose, 0.4% were lost to follow-up, 7.5% discontinued, 50.9% booked for further injections and 41.3% booked for monthly observations. After loading dose, the macula remained dry in 49.2% at 3 months, 34.0% at 6 months, 23.7% at 12 months and 15.2% at 24 months. For the entire population, median cumulative total number of injections was 7, 12 and 15, after 1, 2 and 3 years, respectively. After the 3rd year, the proportion of eyes in the short 4-6 weeks treatment interval was 51.1%, 8 weeks interval was kept in 14.4% and the extended treatment intervals of 10 and 12 weeks was possible in 34.4%. CONCLUSION: After loading dose, one in two eyes required further injections. A large proportion required therapy with shorter intervals than the label-recommended 8 weeks. The large majority of those who obtained a dry macula after loading dose turned exudative again, mostly within the first 3 months.

Individualised screening for diabetic retinopathy with proliferative retinopathy and macular oedema as separate end points.

PURPOSE: A number of algorithms have been developed to calculate screening intervals for diabetic retinopathy on the basis of individual risk factors. However, these approaches have not considered proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DME) as separate end points and death as competing risk. METHODS: A multi-state survival model with death as competing risk was used to predict the screening interval for diabetic retinopathy based on information about all 2446 patients from a well-defined population who had started treatment for either PDR or DME during 25 years. The performance of the model was tested on the existing database and at seven screening sites on patients who had not developed a treatment requiring condition. RESULTS: Testing on the existing database showed that at a risk level of 2% the algorithm could predict a screening interval with a success rate higher than 90% and a 1.75 times average prolongation of the screening interval without failing to detect the development of verified PDR og DME. The model was limited to a diabetes duration shorter than 40 years and depended on knowledge of relevant risk factors. At the other participating screening sites the algorithm predicted shorter intervals than the screener. CONCLUSIONS: Algorithms for individualised screening for diabetic retinopathy can prolong screening intervals without losing patients who develop a vision threatening condition. The calculation of screening intervals requires access to relevant risk factors and should be developed on large data sets that reflect the population in which the algorithm should be used.

Effect of Needle Gauge Size on Pain During Intravitreal Anti-VEGF Injection: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Concerns related to pain from intravitreal injections are one of the key factors mentioned by patients when asked about therapy. In this systematic review and network meta-analysis, we evaluate the literature of comparative clinical trials on the relationship between needle gauge size and pain experience during intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. METHODS: We searched 12 literature databases on 14 October 2023 for comparative studies of gauge sizes for intravitreal anti-VEGF injections. The primary outcome of interest was the reported pain experience immediately after the injection. All outcomes of pain were transformed into standardized effect sizes using Cohen's d. Using a network meta-analysis approach, we were able to compare all gauge sizes and rank them according to the reported pain experience. RESULTS: We identified nine eligible studies with data on a total of 998 patients and 1004 eyes. Needle sizes studied were 26-gauge, 27-gauge, 29-gauge, 30-gauge, 32-gauge, 33-gauge, and 34-gauge. A complete network was present, which allowed for a network meta-analysis. We used the thickest (26-gauge) needle as the reference group and observed a clear trend of lower pain experience with thinner gauge sizes (d: -0.4, d: -2.7, d: -3.8, d: -4.8, d: -4.5, and d: -5.3; respectively, for 27-gauge, 29-gauge, 30-gauge, 32-gauge, 33-gauge, and 34-gauge). CONCLUSION: A gauge size of 30 or thinner may minimize patient discomfort related to intravitreal anti-VEGF therapy.

Topical non-steroidal anti-inflammatory drugs for central serous chorioretinopathy: A systematic review and meta-analysis.

Central serous chorioretinopathy (CSC) is a prevalent exudative maculopathy and the ongoing verteporfin shortage restricts current treatment possibilities. Topical non-steroidal anti-inflammatory drugs (NSAID) have previously been proposed as a treatment for CSC, although its exact efficacy remains unclear. In this systematic review and meta-analysis, we outlined the efficacy of topical NSAIDs for the treatment of CSC. We searched 11 literature databases on 13 December 2022, for any study describing topical NSAID treatment for CSC. Thirteen eligible studies were included with a total of 1001 eyes of 994 patients with CSC. Six studies were case reports, two were cohort studies and five were non-randomized comparative studies. Where specified, topical NSAIDs used were bromfenac 0.09%, diclofenac 0.1%, ketorolac 0.4% and 0.5%, pranoprofen 0.1%, and nepafenac 0.1% and 0.3%. Studies were predominantly of cases with acute CSC and several case studies reported treatment outcomes simultaneously with discontinuation of corticosteroid use, which complicated treatment evaluation. Meta-analyses of comparative studies revealed a statistically significant but clinically irrelevant best-corrected visual acuity improvement of -0.04 logMAR (95% CI: -0.07 to -0.01 logMAR; p = 0.01) at 1-month follow-up, which became statistically insignificant at 3-month follow-up (-0.03 logMAR; 95% CI: -0.06 to 0.003 logMAR; p = 0.08). Further, we found no benefit in complete subretinal fluid resolution at 1-month follow-up (OR: 1.20; 95% CI: 0.81-1.76; p = 0.37) or 3-month follow-up (OR: 1.17; 95% CI: 0.86 to 1.59; p = 0.33). Taken together, available evidence does not support the use of topical NSAIDs for the treatment of CSC.

Risk of Diabetic Retinopathy According to Subtype of Type 2 Diabetes.

Type 2 diabetes is a heterogeneous disease that can be subdivided on the basis of ß-cell function and insulin sensitivity. We investigated the presence, incidence, and progression of diabetic retinopathy (DR) according to subtypes of type 2 diabetes. In a national cohort, we identified three subtypes of type 2 diabetes: classical, hyperinsulinemic, and insulinopenic type 2 diabetes, based on HOMA2 measurements. From the Danish Registry of Diabetic Retinopathy we extracted information on level of DR. We used several national health registries to link information on comorbidity, medications, and laboratory tests. We found individuals with hyperinsulinemic type 2 diabetes were less likely to have DR at entry date compared with those with classical type 2 diabetes, whereas individuals with insulinopenic type 2 diabetes were more likely to have DR. In multivariable Cox regression analysis, individuals with hyperinsulinemic type 2 diabetes had a decreased risk of both incidence and progression of DR compared to those with classical type 2 diabetes. We did not find any clear difference in risk of incident or progression of DR in individuals with insulinopenic compared to classical type 2 diabetes. These findings indicate that subcategorization of type 2 diabetes is important in evaluating the risk of DR.

Presence and development of diabetic retinopathy in 16 999 patients with type 1 diabetes in the Danish Registry of Diabetic Retinopathy.

PURPOSE: To evaluate the five-year incidence of diabetic retinopathy (DR) and associated risk markers in patients with type 1 diabetes in the national Danish DR-screening programme. METHODS: Based on national data, we included all 16 999 patients with type 1 diabetes in the Danish Registry of Diabetic Retinopathy, who attended the national screening programme in the period 2013-2018. According to the worse eye at first screening, DR was classified (levels 0-4) and linked with various national health registries to retrieve information on diabetes duration, systemic comorbidity, and medication. RESULTS: At first screening, median age and duration of diabetes were 45.0 and 16.7 years, and 57.5% were males. The prevalence and five-year incidences for DR and progression to proliferative DR (PDR) were 44.2%, 8.9% and 2.0%, respectively. In multivariable Cox models, the incidence endpoints were associated with duration of diabetes (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.63-1.89, and HR 2.04, 95% CI 1.73-2.40 per 10 years), moderately low Charlson Comorbidity Index score (HR 1.27, 95% CI 1.10-1.47, and HR 2.80, 95% CI 2.23-3.51), and use of blood pressure lowering medication (HR 1.20, 95% CI 1.05-1.36, and HR 1.98, 95% CI 1.53-2.57). CONCLUSION: In a study of all patients with type 1 diabetes from the Danish DR-screening programme, we identified duration of diabetes, systemic disease and use of anti-hypertensive treatment as consistent risk markers for incident and progressive DR.

Exudative Progression of Treatment-Naïve Nonexudative Macular Neovascularization in Age-Related Macular Degeneration: A Systematic Review With Meta-Analyses.

PURPOSE: To systematically review and report the rate of exudative progression over time in patients with nonexudative macular neovascularization (MNV) in age-related macular degeneration (AMD). DESIGN: Systematic review with prevalence meta-analyses and individual participant meta-analysis. METHODS: We searched 10 literature databases on March 26, 2023, for studies of consecutive patients with treatment-naïve nonexudative MNV in AMD. The primary outcome of interest was time from diagnosis to exudative progression. We conducted meta-analyses on the prevalence of exudative progression at 1 and 2 years. Where possible, we extracted individual participant data from studies and conducted an individual participant meta-analysis and explored the exudative progression using a time-to-event curve. RESULTS: We identified 16 eligible studies with a total of 384 eyes with nonexudative MNV. Exudative progression had occurred in 20.9% (95% CI 13.1%-29.8%) of eyes at 1 year and in 30.7% (95% CI 21.8%-40.4%) at 2 years. Similar results were observed in the individual participant meta-analysis, showing exudative progression in 18.9% (95% CI 13.5%-26.3%) of eyes at 1 year and 31.3% (95% CI 24.2%-40.0%) at 2 years. Risk factors for a fast exudative progression were the presence of subretinal lipid globules, large MNV areas, rapid MNV growth, growth in pigment epithelium detachment height and width, appearance of a branching pattern, and development of a hyporeflective halo around the MNV. CONCLUSIONS: Nonexudative MNVs in AMD are at high risk of exudative progression. Recognition of these lesions may allow for better individualized follow-up regimens in which closer monitoring may facilitate earlier diagnosis of exudative progression.

Diabetic retinopathy as an independent marker of cardiovascular disease in type 1 diabetes: Results from a nationwide longitudinal matched case-cohort study.

PURPOSE: To investigate diabetic retinopathy (DR) as a potential marker of cardiovascular disease (CVD) in adults with type 1 diabetes attending the Danish DR-screening programme and non-diabetes adults. METHODS: In this registry-based matched case-cohort study, we identified 16 547 adults with type 1 diabetes, who were registered in the Danish Registry of Diabetic Retinopathy (DiaBase). Each case was age- and sex-matched by five non-diabetes individuals (n = 82 399), and odds ratios (ORs) and hazard ratios (HRs) were estimated for incident and upcoming CVD in multivariable models. RESULTS: Adults with type 1 diabetes (median age 44.5 years, 57.6% male) were more likely to have prevalent CVD (OR 1.29; 95% CI, 1.20-1.38) and to develop CVD within 5 years (HR 1.19; 95% CI, 1.08-1.30) as compared to non-diabetes control. However, adults without DR were less likely to develop CVD (HR 0.84; 95% CI, 0.72-0.97) compared to the reference population. For adults with type 1 diabetes, there was an increasing risk for incident CVD for increasing levels of DR (HR 1.33, 1.95, 1.71 and 2.39 for DR-levels 1-4, respectively). Patients with CVD at the time of the first screening had a higher risk to develop DR during follow-up (HR 1.23; 95% CI, 1.02-1.49). CONCLUSION: In a nationwide matched case-cohort study adjusted for potential confounders, DR was identified as an independent marker of prevalent and incident CVD in type 1 diabetes with increasing risk demonstrated for higher levels of DR. Likewise, CVD also independently predicted the risk of incident DR.

Association of continuous subcutaneous insulin therapy and diabetic retinopathy in type 1 diabetes: A national cohort study.

AIM: This study aimed to investigate the short-and long-term effect on diabetic retinopathy (DR) in individuals with type 1 diabetes treated with continuous subcutaneous insulin injections (CSII) compared to those using multiple daily injections (MDI). METHODS: We conducted a register-based matched cohort study utilizing data from the Danish Registry of Diabetic Retinopathy as well as several other national Danish health registers. Our cohort consisted of all individuals with type 1 diabetes who attended the Danish screening program for DR from 2013 to 2022. We included individuals registered with CSII treatment, and compared them to individuals using MDI, matched by age, sex, and DR level. Cox regression analysis was performed to evaluate the outcomes. RESULTS: The study included 674 individuals treated with CSII and 2006 matched MDI users. In our cohort 53.4 % were female and median age was 36 (IQR 27-47). Average follow-up risk-time was 4.8 years. There was no difference in the risk of DR worsening between the CSII group and MDI group (HR 1.05 [95%CI 0.91; 1.22], p = 0.49). However, an increased risk of focal photocoagulation was observed in the CSII group (HR 2.40 [95%CI 1.11; 5.19], p = 0.03). CONCLUSIONS: Our findings indicate that CSII treatment does not confer a significant difference in the overall short- and long-term risk of DR worsening or ocular intervention compared to MDI treatment. These results provide insights into the DR outcomes of CSII treatment in individuals with type 1 diabetes.

Anti-VEGF Treatment of Diabetic Macular Edema in Denmark: Incidence, Burden of Therapy, and Forecasting Analyses.

BACKGROUND: The aim of this study was to analyze demographically stratified incidence rates of patients with diabetic macular edema (DME) commenced in anti-VEGF therapy, to study temporal trends, to report the proportion of patients in active therapy over time, and to develop a model to forecast the future number of patients in active treatment. METHODS: This was a retrospective registry-based study of all patients with DME who received at least one intravitreal anti-VEGF treatment from 1 January 2007 to 30 June 2022. Population data were extracted from Statistics Denmark. RESULTS: This study included 2220 patients with DME who were commenced in anti-VEGF therapy. Demographic analyses revealed higher incidence rates among males than females and among those aged 60-80 years. The number of patients in active treatment followed an exponential decay curve; hence, this was used to mathematically model the number of patients in active therapy. The number of patients in active treatment is expected to stay relatively stable with a minimal increase until the year 2023. CONCLUSIONS: This study provides insight into the practical aspects of the anti-VEGF treatment of DME that allow the planning of adequate health services.

Presence and development of diabetic retinopathy in 153 238 patients with type 2 diabetes in the Danish Registry of Diabetic Retinopathy.

PURPOSE: The purpose of the study was to evaluate the prevalence and incidence of diabetic retinopathy (DR) along with associated markers in patients with type 2 diabetes in the Danish DR-screening programme. METHODS: We included all persons with type 2 diabetes in the Danish Registry of Diabetic Retinopathy, who had attended at least one episode of DR screening in 2013-2018. DR was classified as levels 0-4 indicating increasing severity. Data were linked with various national health registries to retrieve information on diabetes duration, marital status, comorbidity and systemic medication. RESULTS: Among 153 238 persons with type 2 diabetes, median age and duration of diabetes were 66.9 and 5.3 years and 56.4% were males. Prevalence and 5-year incidences of DR, 2-step-or-more progression of DR and progression to proliferative DR (PDR) were 8.8%, 3.8%, 0.7% and 0.2%, respectively. In multivariable models, leading markers of incident DR and progression to PDR were duration of diabetes (HR 1.98, 95% CI 1.87-2.09; HR 2.89, 95% CI 2.34-3.58 per 10 years of duration) and use of insulin (HR 1.88, 95% CI 1.76-2.01; HR 2.40, 95% CI 1.84-3.13), while the use of cholesterol-lowering medicine was a protecting marker (HR 0.87, 95% CI 0.81-0.93; HR 0.70, 95% CI 0.52-0.93). From 2013 to 2015, 3-year incidence rates of PDR decreased from 1.22 to 0.45 events per 1000 person-years. CONCLUSION: Nationally, among Danish individuals with type 2 diabetes attending DR screening, we identified duration of diabetes and use of insulin as the most important predictor for the development of DR, while cholesterol-lowering medicine was a protective factor.

Inter-grader reliability in the Danish screening programme for diabetic retinopathy.

PURPOSE: The Danish Registry of Diabetic Retinopathy includes information from >200 000 patients who attends diabetic retinopathy (DR) screening in Denmark. Screening of patients with uncomplicated type 2 diabetes is often performed by practicing ophthalmologists, while patients with type 1 and complicated type 2 diabetes attends screening at hospitals. We performed a clinical reliability study of retinal images from Danish screening facilities to explore the inter-grader agreement between the primary screening ophthalmologist and a blinded, certified grader. METHODS: Invitations to participate were sent to screening facilities across Denmark. The primary grader uploaded fundus photographs with information on estimated level of DR (International Clinical Diabetic Retinopathy scale as 0 [no DR], 1-3 [mild, moderate or severe nonproliferative DR {NPDR}], or 4 [proliferative DR {PDR}]), region of screening, image style, and screening facility. Images were then regraded by a blinded, certified, secondary grader. Weighted kappa analysis was performed to evaluate agreement. RESULTS: Fundus photographs from 230 patients (458 eyes) were received from practicing ophthalmologists (52.6%) and hospital-based grading centres (47.4%) from all Danish regions. Reported levels of DR by the primary graders were 66.8%, 12.2%, 13.1%, 1.3% and 5.5% for DR levels 0-4. The overall agreement between primary and secondary graders was 93% (κ = 0.83). Based on screening facility agreement was 96% (κ = 0.89) and 90% (κ = 0.76) for practicing ophthalmologists and hospital-based graders. CONCLUSION: In this nationwide study, we observed a high overall inter-grader agreement and based on this, it is reasonable to assume that reported DR gradings in the screening programme in Denmark, accurately reflect the truth.

Prevalence of geographic atrophy in Nordic countries and number of patients potentially eligible for intravitreal complement inhibitor treatment: A systematic review with meta-analyses and forecasting study.

We systematically reviewed the literature on the prevalence of geographic atrophy (GA) in Nordic populations, conducted meta-analyses on age-stratified estimates, and calculated current and future number of patients and those potentially eligible for intravitreal complement inhibitor treatment. We followed the PRISMA guidelines, and our protocol was registered in PROSPERO. Ten databases were searched on 22 April 2023 for population-based studies of GA prevalence. Based on clinical descriptive analyses of GA and eligibility criteria of the phase III studies for intravitreal pegcetacoplan (complement C3 and C3b inhibitor), we were able to calculate the proportion of patients with GA potentially eligible for therapy. Finally, we extracted population data for Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) from Eurostat, applied prevalence statistics to the extracted census and forecasting data to estimate the number of patients with GA, and then applied the proportion eligible for intravitreal pegcetacoplan therapy. We identified six studies with a total of 10 159 individuals. Prevalence of GA was estimated to 0.4% (95% confidence intervals [CI]: 0.2%-0.8%), 1.5% (95% CI: 0.7%-2.6%), and 7.6% (95% CI: 4.6%-11.3%) for individuals aged 60-69, 70-79, and 80+ years, respectively. In Nordic countries, we estimate a total of 166 307 individuals with GA in 2023, increasing to 277 893 in 2050. Of these, 90 803 individuals in 2023, increasing to 151 730 in 2050, are potentially eligible for intravitreal complement inhibitor treatment. Considering these large numbers, our study highlights the importance of this topic in the coming years and its potential to significantly impact our clinical practice, organization, and staffing.