Anatomical–Functional Dissociation in Diabetic Macular Edema: Five-Year Outcomes of Treat-and-Extend Versus Pro Re Nata Anti-VEGF Regimens

Objectives: To determine whether the superior anatomical control achieved with a treat-and-extend (T&E) anti-VEGF regimen translates into better five-year visual outcomes than a pro re nata (PRN) regimen in treatment-naïve center-involving diabetic macular edema (CI-DME), and to characterize the anatomical–functional relationship. Methods: In this retrospective propensity-score–matched survivor cohort, one eye per patient was analyzed. One-to-one nearest-neighbor matching balanced 14 baseline covariates. Longitudinal best-corrected visual acuity (BCVA) and central subfield thickness (CST) were analyzed using linear mixed-effects models with matched-pair clustering. Absence of a clinically meaningful visual difference was evaluated using two one-sided tests (TOST) with a prespecified ±5-letter equivalence margin. The anatomical–functional relationship was assessed by segmented regression. Sensitivity analyses included inverse probability of treatment weighting, doubly robust estimation, inverse probability of censoring weighting, best-/worst-case imputation, interval-censored recurrence modeling, and E-value analysis. Results: Both regimens improved BCVA, with no clinically meaningful difference at five years (T&E +6.2 ± 14.6 vs. PRN +6.9 ± 14.0 letters; difference −0.7 letters; 90% CI, −2.4 to 1.0; TOST p < 0.001). T&E achieved greater CST reduction (−172.3 vs. −114.2 µm; difference −58.1 µm; p < 0.001), higher dry-macula rates (73.8% vs. 59.5%; p < 0.001), fewer recurrences (2.2 vs. 3.9; p < 0.001), and fewer monitoring-only visits (14.6 vs. 28.4; p < 0.001), but required 53% more injections (25.1 vs. 16.4; p < 0.001). Segmented regression identified a breakpoint at 148 µm CST reduction; additional thinning beyond this threshold was not associated with further visual improvement. Baseline BCVA, ellipsoid zone disruption, and diabetic retinopathy severity, but not treatment regimen, independently predicted five-year vision. Results were consistent across sensitivity analyses. Conclusions: Among patients completing five years of therapy, additional anatomical drying beyond an exploratory, cohort-specific breakpoint of approximately 150 µm CST reduction was not associated with further measurable visual gain in this observational cohort. Regimen selection should therefore reflect treatment burden, monitoring requirements, and patient preference rather than anticipated visual superiority. Because the cohort included only patients completing five years of follow-up, these findings apply to adherent patients and should not be generalized to unselected populations.