Long-term natural history of ellipsoid zone width in USH2A-retinopathy.

AIMS: To investigate the long-term natural history of ellipsoid zone (EZ) width in USH2A-retinopathy. METHODS: EZ width measurements from optical coherence tomography were retrospectively obtained from 110 eyes of 55 participants with molecularly confirmed biallelic USH2A-retinopathy. We used a hierarchical Bayesian method to construct and compare different mathematical models describing the long-term decline of EZ width. RESULTS: Compared with linear and quadratic models, exponential decline best represented the long-term loss of EZ width based on the deviance information criterion score. Log-transformed EZ width declined linearly over 30 years of inferred disease duration (median: 0.063 (IQR: 0.040-0.086) log (µm)/year). Compared with the raw EZ width decline rate, the log-transformed EZ width decline rate required 48% fewer patients to achieve an identically powered 1-year trial (38 vs 73 participants). Log EZ width decline rate was uncoupled from baseline EZ width (Spearman ρ=-0.18, p=0.06) and age (ρ=-0.10, p=0.31). Eyes with Usher syndrome exhibited earlier median onset ages of macular EZ width loss (18.8 (IQR: 13.1-24.7) vs 28.1 (IQR: 18.5-35.8) years, p<0.001) but comparable log EZ width decline rates (0.060 (IQR: 0.035-0.100) vs 0.065 (IQR: 0.050-0.079) log (µm)/year; p=0.42). CONCLUSIONS: EZ width follows an exponential decline in USH2A-retinopathy. Compared with raw EZ width decline rate, log-transformed EZ width decline rate may be a superior endpoint for clinical trials. Syndromic eyes exhibit an earlier onset of macular EZ width loss but progress at comparable rates to non-syndromic eyes.

Geographic Atrophy Natural History Versus Treatment: Time to Fovea.

BACKGROUND AND OBJECTIVE: The Food and Drug Administration recently approved treatments of geographic atrophy (GA). Our study aims to quantify the time for a lesion to reach the central fovea based on reduction of GA growth rates from therapeutics compared to the natural history. PATIENTS AND METHODS: A previously published study calculates local border expansion rate of GA lesions at varying retinal eccentricities. In this study, we use these rates to model GA expansion toward the fovea and the effects of treatments that reduce growth in GA area by 15% to 45% on lesions of varying sizes with posterior margin 250, 500, 750, 1000, 1250, 1500, and 3000 µm from the fovea. RESULTS: Lesions with an area 8 mm2 and posterior edge 500 µm from the fovea will reach the fovea in 5.08 years with no treatment, but the same lesions will reach the fovea in 5.85, 6.52, 7.36, and 8.46 years with a treatment that reduces growth in GA area by 15%, 25%, 35%, and 45%, respectively. CONCLUSIONS: Distance of the posterior edge of the lesion was the primary factor in GA growth toward the fovea, and lesion size only minimally affects growth rates of GA. Based on the efficacy of current and future therapeutics and distance of GA to the fovea, our study provides the marginal time benefit of treatment to guide patients and clinicians, placing both the natural history of GA and the effects of current and future treatments into clinical context. [Ophthalmic Surg Lasers Imaging Retina 2024;55:576-585.].

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.