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.

Purpose

To investigate the association between rim area focal hyperautofluorescence (RAFH) signals and geographic atrophy (GA) growth rates, as well as the impact of oral metformin on the longitudinal change of RAFH.

Design

Secondary analysis of a randomized controlled trial.

Participants

Seventy-one eyes from 44 participants with GA and ≥6 months of follow-up in the METformin for the MINimization of geographic atrophy progression study.

Methods

Fundus autofluorescence images were captured using a 488 nm excitation wavelength. Two masked graders identified and measured RAFH lesions using proprietary semiautomatic segmentation software and ImageJ. We calculated RAFH by dividing the areas of hyperautofluorescence within a 450-μm rim circumscribing the GA by the total area enclosed within this rim.

Main outcome measures

Longitudinal changes in RAFH and GA area.

Results

Baseline RAFH was positively associated with the baseline square root of GA area 0.065/year (P < 0.001). In the entire study cohort, higher baseline RAFH was associated with a faster GA area growth rate in mm²/year (Spearman's ρ = 0.53; P < 0.001). The association became weaker in square root-transformed GA area growth (ρ = 0.19, P = 0.11) and perimeter-adjusted GA growth rate (ρ = 0.28, P = 0.02), achieving statistical significance only in the latter. When this analysis was stratified into 3 baseline GA tertiles, the first and second tertiles showed weak to moderate association with statistical significance in all 3 modes of GA growth rates. Rim area focal hyperautofluorescence increased slightly but significantly over time at 0.020/year (P < 0.01). Rim area focal hyperautofluorescence increased slightly but significantly over time at 0.020/year (P < 0.01). The use of oral metformin was not significantly associated with the change in RAFH over time compared with the observation group (0.023/year vs. 0.016/year; P = 0.29).

Conclusions

Increased baseline RAFH is associated with faster GA area progression. However, the effect size of this association may depend on the baseline GA lesion size such that small to medium-sized GA lesions display this relationship regardless of the mode of the calculation of GA growth rate.

Financial disclosures

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose

To investigate the relationship between geographic atrophy (GA) progression and change in best-corrected visual acuity (BCVA) over 4 years and identify factors associated with faster BCVA loss.

Design

Secondary analysis of 2 randomized controlled clinical trials.

Participants

Age-Related Eye Disease Study (AREDS) and AREDS2 participants with GA secondary to nonexudative age-related macular degeneration.

Methods

Baseline and annual color fundus photographs were assessed for GA area and proximity to the foveal center. Best-corrected visual acuity was measured using Early Treatment Diabetic Retinopathy Study logarithm of the minimum angle of resolution (logMAR) charts. Analyses included BCVA change over 4 years, with the relationship of BCVA decline with GA progression and other baseline factors examined using multivariable linear mixed-effects models.

Main outcome measures

The primary outcome was BCVA change over 4 years. Secondary outcomes included BCVA change from baseline to years 1, 2, and 3.

Results

We included 1351 eyes from 994 participants, including 594 eyes from 464 participants with 4-year BCVA follow-up. Higher baseline BCVA, smaller baseline GA proximity to the foveal center, and greater GA growth rate were each independently associated with larger BCVA loss over 4 years (each P < 0.001). Among the 594 eyes with 4-year BCVA data, 69 eyes with a baseline BCVA < 40 letters (Snellen equivalent of 20/160 or worse) and 42 eyes with baseline GA located more than 1 mm from the foveal center did not experience significant BCVA loss over 4 years. In contrast, 483 eyes that met both criteria of baseline BCVA ≥ 40 letters and GA lesions involving or within 1 mm of the foveal center showed significant BCVA loss over 4 years (mean change = -11.33 letters [95% confidence interval = -12.80 to -9.84]), with faster GA progression associated with larger BCVA loss (P < 0.001).

Conclusions

In this cohort, eyes with GA involving or within 1 mm of the foveal center and a baseline BCVA of ≥ 40 letters appeared more likely to experience significant BCVA loss, suggesting these eyes may benefit more from therapies that slow GA progression. Our findings support a personalized approach to managing patients with GA, potentially guiding the design of future GA trials.

Financial disclosure(s)

Proprietary or commercial disclosure may be found after the references.

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.