The Association Between Metformin Use and New-Onset ICD Coding of Geographic Atrophy.

Purpose: Metformin has been suggested to protect against the development of age-related macular degeneration (AMD) in multiple observational studies. However, the association between metformin and geographic atrophy (GA), a debilitating subtype of AMD, has not been analyzed. Methods: We conducted a case-control study of patients ages 60 years and older with new-onset International Classification of Diseases (ICD) coding of GA in the Merative MarketScan Commercial and Medicare Databases between 2017 and 2021. Cases were matched with propensity scores estimated by age, region, hypertension, and Charlson Comorbidity Index to a control without GA of the same year. Exposure to metformin was assessed for cases and controls in the year prior to their index visit. Conditional multivariable logistic regression, adjusting for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals (CIs). This study design and analysis were repeated in a sample of patients without diabetes. Results: In the full sample, we identified 10,505 cases with GA and 10,502 matched controls without GA. In total, 1149 (10.9%) cases and 1277 (12.2%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 12% (95% CI, 0.79-0.99). In the sample of patients without diabetes, we identified 7611 cases with GA and 7608 matched controls without GA. Twenty-nine (0.4%) cases and 63 (0.8%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 47% (95% CI, 0.33-0.83). Conclusions: Metformin may hold promise as a noninvasive, alternative agent to prevent the development of GA. This finding is notable due to shortcomings in recently approved therapeutics for GA and metformin's overall ease of use and few adverse effects. Additional studies are required to explore our findings further and motivate a clinical trial.

Metformin Use and Age-Related Macular Degeneration in Patients Without Diabetes.

Importance: Metformin use may protect against the development of age-related macular degeneration (AMD) based on results from observational studies. However, its potential effectiveness among patients without diabetes remains unclear. Objective: To assess the association between metformin use and the development of AMD in patients without diabetes. Design, Setting, and Participants: This case-control study used data from 2006 to 2017 in the Merative MarketScan Research Database, a nationwide insurance claims database that includes between 27 and 57 million patients in the US with primary or Medicare supplemental health insurance. Cases with AMD and controls without AMD aged 55 years or older were matched 1:1 by year, age, anemia, hypertension, region, and Charlson Comorbidity Index score. Then, cases and matched controls without a diagnosis of diabetes were selected. In subgroup analyses, cases with dry AMD and their matched controls were identified to explore the association between metformin use and AMD staging in patients without diabetes. Data were analyzed between March and September 2023. Exposures: Exposure to metformin in the 2 years prior to the index date (ie, date of AMD diagnosis in cases and date of a randomly selected eye examination for controls) was assessed from the claims database and categorized into quartiles based on cumulative dose (1-270, 271-600, 601-1080, and >1080 g/2 y). Exposure to other antidiabetic medications was also noted. Main Outcomes and Measures: Odds of new-onset AMD development as assessed by multivariable conditional logistic regression after adjusting for known risk factors for AMD, including female sex, hyperlipidemia, smoking, and exposures to other antidiabetic medications. Asymptotic Cochran-Armitage tests for trend were also performed. Results: We identified 231 142 patients with any AMD (mean [SD] age, 75.1 [10.4] years; 140 172 females [60.6%]) and 232 879 matched controls without AMD (mean [SD] age, 74.9 [10.5] years; 133 670 females [57.4%]), none of whom had a diagnosis of diabetes. The sample included 144 147 cases with dry AMD that were matched to 144 530 controls. In all, 2268 (1.0%) cases and 3087 controls (1.3%) were exposed to metformin in the 2 years before their index visit. After data adjustment, exposure to any metformin was associated with reduced odds of any AMD development (adjusted odds ratio [AOR], 0.83; 95% CI, 0.74-0.87), specifically in the dosing quartiles of 1 to 270, 271 to 600, and 601 to 1080 g/2 y. Any metformin use was also associated with a reduced odds of developing dry AMD (AOR, 0.85; 95% CI, 0.79-0.92), specifically in the dosing quartiles of 1 to 270 and 271 to 600 g/2 y. Adjusted odds ratios for any AMD and dry AMD development did not differ across the dosing quartiles. Asymptotic Cochran-Armitage tests for trend revealed 2-sided P = .51 and P = .66 for the any and dry AMD samples, respectively. Conclusions and Relevance: In this case-control study of a population without a diagnosis of diabetes, metformin use was associated with reduced odds of developing AMD. This association does not appear to be dose dependent. These findings provide further impetus to study metformin's usefulness in protecting against AMD in prospective clinical trials.

Potential for Treatment Interval Extension in Eyes with nAMD Disease Activity Post Loading Phase in HAWK and HARRIER.

INTRODUCTION: The HAWK and HARRIER studies evaluated the efficacy and safety of brolucizumab versus aflibercept in treatment-naïve eyes with neovascular age-related macular degeneration. Based on the study design, brolucizumab-treated eyes adjusted to a q8w regimen because the presence of disease activity (DA) at the end of the matched loading phase (Week 16) could not subsequently extend to a q12w interval. The aim of this post hoc analysis was to assess subsequent DA in this subgroup to determine the potential for interval extensions during the first year of treatment. METHODS: Pooled data from the brolucizumab 6 mg arms and aflibercept arms of HAWK and HARRIER were included. Presence of DA was determined by the masked investigator based on their assessment of functional and anatomical parameters measured by optical coherence tomography. DA was compared at DA assessments, conducted at Weeks 16, 20, 32, and 44; fluid was also assessed at the primary analysis at Week 48. RESULTS: Fewer brolucizumab- (22.8%) than aflibercept-treated (32.2%) eyes had DA at the first DA assessment at Week 16. In eyes with investigator-identified DA at Week 16, BCVA change from baseline to Week 96 was comparable between treatment arms. Fewer brolucizumab- than aflibercept-treated eyes had DA at each subsequent DA assessment in Year 1: 31.8% vs 39.1% (Week 20), 27.3% vs 43.5% (Week 32), and 17.3% vs 31.2% (Week 44). Fewer eyes treated with brolucizumab than aflibercept had intraretinal and/or subretinal fluid: 35.3% vs 43.5% (Week 20), 55.8% vs 69.6% (Week 32), 30.0% vs 43.1% (Week 44), and 48.6% vs 68.6% (Week 48). CONCLUSION: These findings indicate that, in eyes that still had DA 8 weeks after the final dose of loading phase, brolucizumab-treated eyes had improved fluid resolution and higher potential for treatment interval extension than aflibercept-treated eyes during the first year of treatment.

Review on the Safety and Efficacy of Brolucizumab for Neovascular Age-Related Macular Degeneration From Major Studies and Real-World Data.

Frequent antivascular endothelial growth factor injections in neovascular age-related macular degeneration (nAMD) often lead to poor compliance and suboptimal outcomes. A longer-acting agent has been a pressing unmet need until recently. Brolucizumab, an antivascular endothelial growth factor agent, is a single-chain antibody fragment approved by the US Food and Drug Administration (FDA) on October 8, 2019, for treating nAMD. It delivers more molecules at equivalent volumes of aflibercept, thus achieving a longer-lasting effect. We reviewed literature published in English between January 2016 and October 2022 from MEDLINE, PubMed, Cochrane database, Embase, and Google scholar using the keywords: "Brolucizumab, real-world data, intraocular inflammation (IOI), safety, and efficacy". Brolucizumab showed reduced injection frequency, better anatomic outcomes, and noninferior vision gains compared with aflibercept in HAWK and HARRIER studies. However, post hoc studies on brolucizumab revealed a higher-than-expected incidence of IOI, leading to the early termination of 3 studies: MERLIN, RAPTOR, and RAVEN for nAMD, branch retinal vein occlusion, and central retinal vein occlusion, respectively. Contrastingly real-world data showed encouraging outcomes in terms of fewer IOI cases. The subsequent amendment of the treatment protocol resulted in reduced IOI. Thereafter US FDA approved its use in diabetic macular edema on June 1, 2022. Based on major studies and real-world data, this review shows that brolucizumab is effective for treating naive and refractory nAMD. The risk of IOI is acceptable and manageable, but proper preinjection screening and high-vigilance care of IOI are needed. More studies are warranted to evaluate further the incidence, best prevention, and treatment measures for IOI.

The 0.19-mg Fluocinolone Acetonide Implant for the Treatment of Diabetic Macular Edema: An Expert Consensus.

BACKGROUND AND OBJECTIVE: To better understand the level of agreement among retina specialists on the role of inflammation in diabetic retinopathy (DR) and diabetic macular edema (DME), and the use of 0.19-mg fluocinolone acetonide (FAc) implant in DME treatment, a consensus survey was drafted and disseminated to retina specialists across the United States. MATERIALS AND METHODS: Using the modified Delphi method, a list of 12 consensus statements were generated by the coauthors based on short-answer responses to an initial survey. In total, 56 retina specialists completed the entire consensus survey. Except for two multiple-choice questions, there were 10 consensus statements that used a modified Likert scale to indicate their level of agreement to the statement: Agree = 3, Mostly Agree = 2, Mostly Disagree = 1, Disagree = 0. Percentage agreement and 95% confidence intervals (CIs) were calculated, and a consensus threshold was set at > 80% agreement for each statement. RESULTS: Seven of 10 consensus statements using the modified Likert scale reached consensus, including those on the role of inflammation in pathophysiology of DR/DME, injection burden and patient adherence, and efficacy and safety of the FAc implant. The remaining three statements displayed high agreement with average scores > 80%, but the 95% CIs were below threshold. These included the impact of the FAc implant on DR progression, FAc as baseline therapy for DME, and the effectiveness of the steroid challenge to mitigate intraocular pressure risk after FAc use. Two multiple-choice questions focused on clinical situations in which corticosteroids would be used as baseline therapy for DME (pseudophakic eye [73%], recent stroke/myocardial infarction [66%], and pregnancy/breastfeeding [66%]) and which delivery route satisfies the steroid challenge for the FAc implant (intravitreal [100%], sub-tenon/periocular [73%], and topical [57%]). CONCLUSIONS: Physicians highly agreed on the role of inflammation in pathophysiology of DR/DME, injection burden and patient adherence, and efficacy and safety of the FAc implant. However, full consensus was not found on the impact of the FAc implant on DR progression, FAc as baseline therapy for DME, and the effectiveness of the steroid challenge to mitigate intraocular pressure risk after FAc use. [Ophthalmic Surg Lasers Imaging Retina. 2023;54(3):166-173.].

Update on Current Microbiological Techniques for Pathogen Identification in Infectious Endophthalmitis.

Infectious endophthalmitis is a vision-threatening medical emergency that requires prompt clinical diagnosis and the initiation of treatment. However, achieving precision in endophthalmitis management remains challenging. In this review, we provide an updated overview of recent studies that are representative of the current trends in clinical microbiological techniques for infectious endophthalmitis.

Suprachoroidal Injection of Triamcinolone Acetonide Injectable Suspension for the Treatment of Macular Edema Associated With Uveitis in the United States: A Cost-Effectiveness Analysis.

OBJECTIVES: Suprachoroidal injection of triamcinolone acetonide is the first Food and Drug Administration-approved treatment for macular edema associated with uveitis. A cost-effectiveness analysis was performed comparing this treatment with best supportive care (BSC) for the management of this indication from US Medicare and commercial payer perspectives. METHODS: A patient-level simulation was developed per the patient characteristics and changes in best-corrected visual acuity letter scores observed in a phase III study of triamcinolone acetonide (PEACHTREE). The wholesale acquisition cost of triamcinolone acetonide was $1650/injection; suprachoroidal injection cost was assumed at $200/injection. Healthcare costs were informed by a US claims-based analysis. Mortality risk associated with severe vision loss and blindness was modeled by applying a hazard ratio to all-cause mortality rates of the US general population. Health-related quality of life weights, obtained from a regression model fitted to the Visual Function Questionnaire-25 data from PEACHTREE, were applied based on the best-corrected visual acuity scores of both eyes. Costs (2020 US dollar) and benefits were discounted at 3% annually. Incremental cost-effectiveness ratios were estimated over a 10-year horizon. RESULTS: In the base-case, the incremental cost-effectiveness ratio comparing triamcinolone acetonide with BSC was $28 479 per quality-adjusted life-year gained. The wholesale acquisition cost for triamcinolone acetonide for suprachoroidal use was ∼68%, ∼56%, and ∼27% below the willingness-to-pay thresholds of $150 000, $100 000, and $50 000 per quality-adjusted life-year gained, respectively. Results were robust in sensitivity and scenario analyses. CONCLUSIONS: Triamcinolone acetonide for suprachoroidal use is cost-effective compared with BSC for patients with macular edema associated with uveitis.

Use of OCT Angiography to Diagnose and Manage Atypical Presentations of Macular Telangiectasia Type 2.

Macular telangiectasia Type 2 (MacTel) is a bilateral acquired retinal disease characterized by both vascular changes and atrophy of the retina. The purpose of this case series is to highlight the use of optical coherence tomography angiography (OCTA) as a non-invasive imaging modality to distinguish atypical MacTel from other macular conditions with similar presentations. We performed a retrospective review of patients referred to our academic retinal practice with unconfirmed or misdiagnosed MacTel between July 2017 and July 2021. Patients' OCTA imaging findings were reviewed to guide the appropriate diagnosis and management of atypical MacTel. Fifteen eyes from eight patients were included in this study. Six patients were referred with previous diagnoses of either full-thickness macular hole, lamellar hole, vitreomacular traction (VMT), postoperative cystoid macular edema (CME), or diabetic macular edema (DME). Two patients were referred to us to confirm the diagnosis of MacTel. OCTA revealed telangiectatic vessels in the temporal parafovea of all 15 eyes. OCTA also highlighted previously undiagnosed subretinal neovascularization (SRNV) in seven eyes. OCTA imaging is a valuable imaging modality to distinguish MacTel from other macular conditions, whose treatment courses vary substantially. Due to its ease of use, it holds immense potential in the future as treatments for non-proliferative MacTel emerge.

High-Fat Diet Alters the Retinal Pigment Epithelium and Choroidal Transcriptome in the Absence of Gut Microbiota.

Relationships between retinal disease, diet, and the gut microbiome have started to emerge. In particular, high-fat diets (HFDs) are associated with the prevalence and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR). These effects are thought to be partly mediated by the gut microbiome, which modulates interactions between diet and host homeostasis. Nevertheless, the effects of HFDs on the retina and adjacent retinal pigment epithelium (RPE) and choroid at the transcriptional level, independent of gut microbiota, are not well-understood. In this study, we performed the high-throughput RNA-sequencing of germ-free (GF) mice to explore the transcriptional changes induced by HFD in the RPE/choroid. After filtering and cleaning the data, 649 differentially expressed genes (DEGs) were identified, with 616 genes transcriptionally upregulated and 33 genes downregulated by HFD compared to a normal diet (ND). Enrichment analysis for gene ontology (GO) using the DEGs was performed to analyze over-represented biological processes in the RPE/choroid of GF-HFD mice relative to GF-ND mice. GO analysis revealed the upregulation of processes related to angiogenesis, immune response, and the inflammatory response. Additionally, molecular functions that were altered involved extracellular matrix (ECM) binding, ECM structural constituents, and heparin binding. This study demonstrates novel data showing that HFDs can alter RPE/choroid tissue transcription in the absence of the gut microbiome.

An Introduction to Biosimilars for the Treatment of Retinal Diseases: A Narrative Review.

Biological therapies have revolutionized the treatment of disease across a number of therapeutic areas including retinal diseases. However, on occasion, such treatments may be relatively more expensive compared to small molecule therapies. This can restrict patient access and treatment length leading to suboptimal clinical outcomes. Several biosimilar candidates of ranibizumab and aflibercept are currently in development and the first biosimilar of ranibizumab received EMA approval in August and FDA approval in September 2021. Biosimilars are biological medicines that are highly similar to an already-approved biological medicine (reference product). The physicochemical and clinical similarity of a biosimilar is determined by a rigorous analytical and clinical program, including extensive pharmacokinetic and pharmacodynamic analysis with phase III equivalence studies where appropriate. These phase III studies are carried out in a patient population that is representative of all of the potential approved therapeutic indications of the originator product and the most sensitive for detecting potential differences between the biosimilar and the reference product. Biosimilars have been used successfully across a wide range of therapeutic areas for the past 15 years where they have achieved substantial cost savings that can be reinvested into healthcare systems without affecting the quality of patient care. The current review provides an introduction to biosimilars with the aim of preparing retinal specialists for discussing these products with their patients.