There have been many clinical trials of anti-VEGF agents (and laser therapy) for the treatment of diabetic macular edema (DME) over the years – but still, some questions are unanswered; for example, what is the relationship between anatomic and functional responses to anti-VEGF therapy? Remember Protocol I (Figure 1a [1])? The Phase III multicenter, randomized trial (Figure 1a) showed that ranibizumab (with prompt or deferred focal/grid laser) resulted in superior visual acuity (VA)outcomes compared with laser alone through two years (1).

An early post-hoc analysis showed that sustained and early reduction of central retinal thickness (CRT) with ranibizumab therapy was associated with better long-term VA outcomes (2). And yet, asking a similar question, Phase III RIDE/RISE trial (Figure 1b) investigators saw a dissociation between early CRT reductions and visual outcomes (3). As RIDE/RISE also showed that delayed intervention with anti-VEGF therapy limits the scope for future vision improvement, Dugel and colleagues returned to the Protocol I dataset (4) to further characterize the anatomic response of the retina to ranibizumab, as determined by the average extent of edema over the 156-week period post-treatment initiation.