Abstract
The primary aim of therapy for center-involved diabetic macular edema (DME) is to achieve a long-lasting dry macula. High therapeutic efficacy correlates with targeting the underlying pathogenesis. Recent discoveries have identified two additional tractional pathogeneses that are undetectable by standard optical coherence tomography (OCT). These indicated that all “diffuse” DME in non-ischemic maculae is tractional in origin. Consequently, DME may be classified by pathogenesis as tractional DME and microaneurysm-related DME.
Faricimab (Vabysmo) inhibits vascular endothelial growth factor-A and angiopoietin-2, and is highly effective in abolishing leaking microaneurysms, altering their turnover. In the pivotal YOSEMITE and RHINE trials, two outcome assessments were reported. The first applied a numerical definition in which central subfield thickness <325µm was considered “no DME” ("dry" macula), irrespective of OCT anatomy. Using <325µm and visual criteria, injection intervals were extended to 12 and 16 weeks, and <325µm was found in ~83% of eyes over the 2-year trial. The second assessment was anatomical: at year-1 and -2, approximately half, ~40% and 47%, respectively, achieved ≥8 weeks of dry, fluid-free maculae. Hence, injection intervals were extended in 43% (83%-40%) and 36% of eyes, respectively, with edematous maculae, instead of prompt treatment.
Uniquely, analysis revealed a sharp clinical separation between two response patterns: (1) anatomical drying for ≥8 weeks, consistent with faricimab’s effect in microaneurysm-related DME, and (2) partial or absent response, consistent with tractional DME. Had DME been stratified before treatment and faricimab used only for microaneurysm-related disease, dryness could likely have been achieved for ≥8 weeks, while futile injections could have been avoided in tractional DME. Concerns regarding outcomes following missed stratification might also be relevant, in retrospect, to most earlier trials and real-world practice.
In conclusion, the well-defined clinical separation between the two DME pathogeneses supports identical earlier claims, and seems a landmark moment for DME therapy after decades. It follows the conduct: Never mix two different items for calculations. After excluding microaneurysm-related DME, the benchmarks for long-lasting resolution remain pars plana vitrectomy in treatment-naïve eyes or following failed grid laser photocoagulation; grid laser photocoagulation is efficacious in specific early conditions. Aligning future trials and clinical practice with pathogenetic enrollment, consistent with the Declaration of Helsinki, and anatomy-based endpoints is essential to move toward an effective, potentially curative therapy.