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    Research Update 564


    Association of Metformin With the Development of Age-Related Macular Degeneration.

    JAMA Ophthalmology. 2022 Dec 22.

    Domalpally A, Whittier SA, Pan Q, Dabelea DM, Darwin CH, Knowler WC, Lee CG, Luchsinger JA, White NH, Chew EY; Diabetes Prevention Program Research (DPPOS) Group.

    Importance: Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD.

    Objective: To investigate the association between metformin use and age-related macular degeneration (AMD).

    Design, Setting, And Participants: The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicentre randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022.

    Interventions: Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.

    Main Outcomes And Measures: Prevalence of AMD in the treatment arms.

    Results: Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02).

    Conclusions And Relevance: These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.

    DOI: 10.1001/jamaophthalmol.2022.5567


    SCORE2 Report 20: Relationship of Treatment Discontinuation with Visual Acuity and Central Subfield Thickness Outcomes.

    American journal of Ophthalmology. 2022 Dec 27

    Scott IU, Oden NL, VanVeldhuisen PC, Ip MS, Blodi BA; SCORE2 Investigator Group.

    Purpose: To investigate the relationship of anti-VEGF treatment discontinuation with baseline factors and outcomes in eyes treated initially with aflibercept or bevacizumab for macular edema from central or hemiretinal vein occlusion.

    Design: Long-term follow-up after a randomized clinical trial from 64 US centers. METHODS: Analysis included 150 SCORE2 Month 60 completers classified into three groups: discontinued treatment early, treated intermittently, and treated continuously. Outcomes included visual acuity (VA) and central subfield thickness (CST).

    Results: Those who discontinued treatment early were younger (60.9 years, versus 66.7 and 70.5 for the treated intermittently and treated continuously groups; P=0.001), and 17.4% were black, compared to 19.5% and 4.7% for the treated intermittently and treated continuously groups (P=0.006). At Month 60, the discontinued treatment early group had a higher proportion with complete resolution of macular edema (69.6%) than those treated intermittently (15.0%) and treated continuously (15.7%) (P<0.001). Least squares means analyses over follow-up demonstrated that the discontinued treatment early group had lower mean CST (257µm) than the treated intermittently (CST=303µm, P=0.02) and treated continuously (CST=300µm, P=0.01) groups.

    Conclusions: Compared to those treated continuously, those who discontinued treatment early were younger and more likely black. The discontinued treatment early group had a higher proportion with complete resolution of macular edema at Month 60, and lower mean CST over follow-up, but not better VA, than the treated continuously and treated intermittently groups. Results support the need for continued monitoring and individualized treatment for patients treated with anti-VEGF for macular edema from central or hemiretinal vein occlusion.

    Trial Registration: Clinical trial identifier at NCT01969708.

    DOI: 10.1016/j.ajo.2022.12.026

    Treatment results of diabetic macular edema with different choroidal thickness with intravitreal anti vascular endothelial growth factor.

    BMC Ophthalmology. 2022 Dec 22

    Savur F, Kaldırım H, Atalay K, Öğreden T, Hayat ŞÇ.

    Purpose: To compare the results of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in patients with diabetic macular edema (DME) with different choroidal thicknesses.

    Methods: The files of patients diagnosed with DME and treated with intravitreal anti-VEGF were reviewed retrospectively. The best-corrected visual acuity (BCVA), choroidal thickness (CT), and macular thickness (MT) measurements were recorded before and after treatment. All patients included in the study were divided into 3 groups according to the initial sub foveal choroidal thickness (SFCT). Group 1 included 35 patients with SFCT ≤ 220, group 2 included 27 patients with SFCT > 220 ≤ 270, and group 3 included 30 patients with SFCT > 270. The total number of anti-VEGF administered during the follow-up at the last examination, baseline and post-treatment CT, MT, and BCVA measurements were statistically compared in all 3 groups.

    Results: The mean age of the patients was 61.9 ± 10.2 in group 1, 58.7 ± 8.7 in group 2, and 57.0 ± 6.5 in group 3. The mean anti-VEGF count in group 1 was significantly lower than group 2 and group 3 (p = 0.004, p = 0.006). In Group 1, BCVA improved significantly after treatment compared to baseline (p = 0.001). In Groups 2 and 3, BCVA did not change significantly after treatment compared to baseline (p = 0.320, p = 0.104). After treatment, central macular thickness decreased significantly in group 1 compared to baseline, while central macular thickness did not show a significant change from baseline in group 2 and group 3 after treatment (p = 0.003, p = 0.059, p = 0.590).

    Conclusion: In our study, we observed that the treatment needs of our DME patients with different choroidal thicknesses were different. In patients with DME, the initial choroidal thickness may help determine the need for follow-up and treatment.

    DOI: 10.1186/s12886-022-02721-3


    Small hard drusen and associated factors in early seniority.

    PloS One. 2022 Dec 22

    Belmouhand M, Rothenbuehler SP, Dabbah S, Bjerager J, Sander B, Hjelmborg JB, Dalgård C, Jensen R, Larsen M.

    Purpose: The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 μm in diameter).

    Methods: This single-center, cross-sectional study of 176 same-sex twin pairs aged 30 to 80 (median 60) years was a component of a framework study of the transition from not having age-related macular degeneration to having early AMD. Drusen categories assessed using fundus photography and optical coherence tomography included small hard drusen (diameter < 63 μm), intermediate soft drusen (63-125 μm), and large soft drusen (> 125 μm), of which the soft drusen are compatible with a diagnosis of AMD.

    Results: Having ≥ 20 small hard drusen within or outside the macula was associated with increasing age, lower body mass index, shorter axial length, hyperopia, female sex, increasing high-density lipoprotein (HDL), high alcohol consumption, and with the presence of soft drusen.

    Conclusions: Having ≥ 20 small hard drusen was associated with some AMD-related risk factors, but not with smoking, increasing body mass index, and higher blood pressure. Having ≥ 20 small hard drusen was also associated with soft drusen, in agreement with previous studies. These findings suggest that small hard drusen are not an early manifestation of AMD but the product of a distinct process of tissue alteration that promotes the development of AMD or some subtype thereof.

    DOI: 10.1371/journal.pone.0279279


    Albuminuria as a biomarker of severity in diabetic retinopathy and in the response to intravitreal treatment in diabetic macular edema.

    International Ophthalmology. 2022 Dec 13.

    Gibelalde A, Amenabar Alonso A, Pinar-Sueiro S, Bilbao-Garay I, Juaristi Eizmendi , Sampedro.

    Purpose: Diabetic macular edema (DME) presents a suboptimal response to antiangiogenic treatment in approximately 30% of patients. We analysed the relationship between renal function and response to antiangiogenic therapy in patients with DME.

    Methods: A total of 367 patients were collected and distributed into three main groups: uncomplicated diabetic retinopathy (DR) group (n = 97), proliferative diabetic retinopathy (PDR) group (n = 94) and DME group (n = 175). Likewise, patients with DME were divided into two groups: responders to antiangiogenic drugs (n = 96) and non-responders to antiangiogenic drugs (n = 79). Age, type of diabetes, arterial hypertension (AHT), creatinine, HbA1c, albuminuria and glomerular filtration rate were analyzed. In the statistical analysis, chi-square test and t student were used to compare each group. The relationship between albuminuria and response to treatment in the DME group was studied with a binary logistic regression model, estimating odds ratio and their confidence intervals.

    Results: There are differences between the three main groups in terms of the presence or not of albuminuria. The presence of albuminuria is greater in the group of patients with more severe DR (PDR and DME), compared to the uncomplicated DR group (p < 0.009). In the logistic regression analysis model, a positive relationship was found and the odds ratio for the albuminuria variable and is 2.78 (CI: 1.42-5.36).

    Conclusions: The presence of albuminuria is associated with a higher degree of DR and worse response to antiangiogenic therapy in patients with DME in our series. Multidisciplinary teams would be necessary to reduce albuminuria and thus optimize the treatment of patients with DME.

    DOI: 10.1007/s10792-022-02604-y

    Hyperpigmentary abnormalities in age-related macular degeneration: association with progression and impact on visual sensitivity.

    The British journal of Ophthalmology. 2022 Dec 23

    Goh KL, Kumar H, Hadoux X, Jannaud M, Abbott C, Hodgson L, Robman L, Makeyeva G, Van Wijngaarden P, Guymer R, Wu Z.

    Background/Aims: To investigate the additional prognostic value of quantifying the extent of colour fundus photography (CFP)-defined hyperpigmentary abnormalities (HPAs) compared with their presence alone for predicting progression to late-stage age-related macular degeneration (AMD) and to understand their association with visual sensitivity in individuals with intermediate AMD.

    Methods: 140 participants with bilateral large drusen underwent multimodal imaging and microperimetry at baseline and then every 6 months for up to 3 years. Baseline CFPs were graded for the presence of HPAs and their extent was quantified. Optical coherence tomography (OCT) scans were used to quantify drusen volume. Predictive models for progression to late AMD (including OCT signs of atrophy) were developed using either HPA presence or extent. The association between HPA extent with mean visual sensitivity (both overall and sector based) was also evaluated. All models were adjusted for the confounders of baseline age and drusen volume.

    Results: The predictive performance for late AMD development was not significantly different for HPA presence or extent (p=0.92). Increasing HPA extent in each sector, but not its overall extent in an eye, was associated with reduced sector-based visual sensitivity (p<0.001 and p=0.671, respectively).

    Conclusion: In a cohort with bilateral large drusen, quantifying HPA extent did not improve the prediction of late AMD development compared with presence alone. HPA extent was associated with more local, rather than generalised, reductions in visual sensitivity. These findings suggest that quantification of HPA extent adds little to the prediction of AMD progression, but that it provides an imaging biomarker of visual dysfunction.

    DOI: 10.1136/bjo-2022-322676


    Subretinal fluid may protect against macular atrophy in neovascular age-related macular degeneration: 5 years of follow-up from Fight Retinal Blindness registry.

    Acta Ophthalmologica. 2022 Dec 19

    Sánchez-Monroy J, Nguyen V, Puzo M, Calvo P, Arruabarrena C, Monaco P, Chilov M, Keegan D, Barthelmes D, Gillies M.

    Purpose: The purpose of the study was to assess the association of macular atrophy (MA) according to the activity of macular neovascularization (MNV) (inactive, only subretinal fluid [SRFL], or active, i.e. including intraretinal fluid [IRFL]) using optical coherence tomography (OCT) in patients with neovascular age-related macular degeneration (nAMD).

    Methods: Multicentric observational study. Treatment-naïve nAMD eyes without sub foveal MA or subretinal fibrosis (SF) at baseline were included since 1st January 2010 and 30th September 2016 to allow up to 5 years of treatment follow-up. Eyes were grouped based on their predominant activity status as: (1) mostly inactive, (2) mostly active non-SRFL only [IRFL] or (3) mostly active-SRFL only [onlySRFL]. Kaplan-Meier survival curves estimated the time to development of MA or SF. Cox proportional hazards models evaluated predictors of developing sub foveal MA or SF. The main outcome measure was the risk of developing MA according to predominant MNV activity.

    Results: A total of 973 eyes were eligible for analysis. OnlySRFL eyes had lower risk of developing sub foveal MA (HR [95% CI]: 0.56 [0.36, 0.88]; p = 0.024) and extrafoveal MA (HR [95% CI]: 0.41 [0.27, 0.61]; p < 0.001) than IRFL eyes. IRFL eyes had lower visual acuity (VA) (54.5 letters) and the highest proportion of eyes with vision ≤35 letters (25%) at 5 years while only eyes had comparable 5-year VA (63.7 letters) to inactive eyes (63.7 letters).

    Conclusion: Subretinal fluid appears to protect against MA. Distinguishing the compartment of retinal fluid and understanding its relationship with MA and SF can guide the management of nAMD.

    DOI: 10.1111/aos.15309


    Association of Dietary Nitrate and a Mediterranean Diet With Age-Related Macular Degeneration Among US Adults: The Age-Related Eye Disease Study (AREDS) and AREDS2.

    JAMA Ophthalmology. 2022 Dec 22

    Broadhead GK, Agrón E, Peprah D, Keenan TDL, Lawler TP, Mares J, Chew EY; AREDS/AREDS2 Investigators.

    Importance: Low dietary nitrate intake has previously been suggested to be a risk factor for age-related macular degeneration (AMD) progression; however, this finding has not been replicated in other cohorts or adjusted for dietary patterns.

    Objective: To determine whether there is an association between dietary nitrate intake and AMD progression.

    Design, Setting, And Participants: This cohort study analyzed data from the prospective Age-Related Eye Disease Study (AREDS) and AREDS2 randomized clinical trial cohorts and their extended follow-up studies, which were conducted in multicenter outpatient retinal practices. Participants in both trials had non-late AMD in at least 1 eye. Data were analyzed from March 1, 2020, to September 30, 2022. EXPOSURE: Dietary nitrate intake.

    Main Outcomes And Measures: Association between dietary nitrate intake and development of late AMD (neovascular AMD [nAMD] or geographic atrophy [GA]) or large drusen. The interactions of dietary patterns, with common at-risk single-nucleotide polymorphisms, were also assessed. RESULTS: In the combined AREDS/AREDS2 cohort of 7788 participants (4288 AREDS participants and 3610 AREDS2 participants [110 of whom participated in both studies]), there were 13 511 eligible eyes. The combined cohort comprised 4396 women (56%) and 3392 men (44%), and the combined mean (SD) age was 71.1 (6.6) years. Dietary nitrate intake was associated with a decreased risk of progression to late AMD in the combined AREDS/AREDS2 cohort (hazard ratio [HR], 0.77 [95% CI, 0.69-0.86] for quartile 4 vs quartile 1 of intake) and a decreased risk of GA (HR, 0.71 [95% CI, 0.61-0.83]) and nAMD (HR, 0.85 [95% CI, 0.73-0.99]). In AREDS, increased nitrate intake (quartile 4 vs quartile 1) was associated with a decreased risk of late AMD (HR, 0.77 [95% CI, 0.65-0.91]) and GA (HR, 0.80 [95% CI, 0.65-0.97]) but not nAMD; in AREDS2, there was no association between nitrate intake (quartile 4 vs quartile 1) and late AMD (HR, 0.90 [95% CI, 0.80-1.02]) or nAMD (HR, 0.93 [95% CI, 0.78-1.11]). There was a correlation between Mediterranean dietary patterns and dietary nitrate intake (r = 0.52, P < .001).

    Conclusions And Relevance: The findings of this cohort study suggest that dietary nitrate intake was associated with lower AMD risk. However, this association disappeared after adjusting for Mediterranean dietary patterns. These results are subject to potential bias and are hypothesis-generating in nature; therefore, they are insufficient to support new clinical recommendations. Previously described associations between dietary nitrate intake and AMD may in fact represent overall dietary patterns. Further research is needed before dietary nitrate intake can be recommended as a therapy for AMD.

    DOI: 10.1001/jamaophthalmol.2022.5404


    Subretinal Transplant of Human Amniotic Membrane in Advanced Age-Related Macular Degeneration.

    Life (Basel, Switzerland). 2022 Nov 30

    Caporossi T, Scampoli A, Baldascino A, Gambini G, Pacini B, Governatori L, Bacherini D, Carlà MM, Crincoli E, Rizzo C, Kilian R, Rizzo S.

    Macular neovascularization (MNV) and geographic atrophy can complicate age-related macular degeneration (AMD) and lead to severe visual acuity reduction. Despite the medical treatments available, with a defect in the retinal pigmented epithelium (RPE) there is no possibility of restoring acceptable visual acuity. We evaluated postoperative outcomes in patients affected by advanced AMD who underwent subretinal implant of the human amniotic membrane (hAM) as a source of pluripotent stem cells. This retrospective, consecutive, non-randomized interventional study included 23 eyes of 21 patients affected by AMD complicated by MNV, and five eyes of five patients affected by geographic atrophy. All eyes underwent a pars plana vitrectomy, neovascular membrane removal for the MNV group, a subretinal implant of hAM, and gas tamponade, and were followed for 12 months. The primary study outcome was visual acuity improvement. Secondary outcomes were postoperative complications, OCT-angiography parameters correlated with best-corrected visual acuity (BCVA) and MNV recurrence. The mean preoperative BCVA was 1.9 logMAR, and the mean final BCVA value was 1.2 logMAR. In the MNV group, the mean BCVA improved from 1.84 logMAR to 1.26 logMAR, and from 1.84 logMAR to 1.32 logMAR in the geographic atrophy group. No MNV recurrence was evident in 12 months of follow-up. An OCT-angiography scan was used to evaluate the retinal vascularization in the treated eye, which showed a high correlation between BCVA and deep vascular density. This study demonstrates the hAM potential and safety in promoting a partial restoration of retinal function together with an increase in visual acuity.

    DOI: 10.3390/life12121998


    Future perspectives for treating patients with geographic atrophy.

    Graefes archive for clinical and experimental Ophthalmology . 2022 Dec 15.

    Loewenstein A, Trivizki O.

    Purpose: Geographic atrophy (GA) is a late-stage form of age-related macular degeneration (AMD) characterized by the expansion of atrophic lesions in the outer retina. There are currently no approved pharmacological treatments to prevent or slow the progression of GA. This review describes the progression and assessment of GA, predictive imaging features, and complement-targeting investigational drugs for GA.

    Methods: A literature search on GA was conducted.

    Results: Expansion of atrophic lesions in patients with GA is associated with a decline in several measures of visual function. GA lesion size has been moderately associated with measures obtained through microperimetry, whereas GA lesion size in the 1-mm diameter area centered on the fovea has been associated with visual acuity. Optical coherence tomography (OCT) can provide 3-dimensional quantitative assessment of atrophy and is useful for identifying early atrophy in GA. Features that have been found to predict the development of GA include certain drusen characteristics and pigmentary abnormalities. Specific OCT features, including hyper-reflective foci and OCT-reflective drusen substructures, have been associated with AMD disease progression. Lesion characteristics, including focality, regularity of shape, location, and perilesional fundus autofluorescence patterns, have been identified as predictors of faster GA lesion growth. Certain investigational complement-targeting drugs have shown efficacy in slowing the progression of GA.

    Conclusion: GA is a progressive disease associated with irreversible vision loss. Therefore, the lack of treatment options presents a significant unmet need. OCT and drugs under investigation for GA are promising future tools for disease management.

    DOI: 10.1007/s00417-022-05931-z