**13. Glycemic control**

There is controversy on the correlation of HbA1c and visual response to anti-VEGF from large phase 3 trials. An analysis of ranibizumab-treated patients from the RISE and RIDE trials did not find an association between mean change in BCVA at weeks 52 and 100, with the baseline HbA1c [60]. This is in contrast to an analysis of aflibercept-treated patients from the VISTA and VIVID trials, which found that the mean improvement in VA at 2 years was dependent on HbA1c levels [61]. An exploratory analysis of DRCR.net Protocol T, in which participants were randomized to receive bevacizumab, ranibizumab, or aflibercept, found that the magnitude of vision improvement after anti-VEGF treatment decreased by 1 letter for each 1% increase in HbA1c levels at baseline [9]. More recently, lower HbA1c levels at baseline (7% or less) were significantly associated with greater reduction in central macular subfield thickness at one month after injection of bevacizumab or ranibizumab, however the change in BCVA after treatment did not have any correlation with the glycemic control [62]. Chen et al. reported that after one year of treatment on ranibizumab, only in the responder group the baseline level of HbA1c was significantly associated with the changes in BCVA and the final BCVA [63]. The common methodological issue with these trials and cohorts under observation is the estimate of glycemic control – HbA1c at baseline, only. There is a significant variability in the glucose plasma levels in diabetic patients. Its impact on microvascular complications in type 2 diabetes was investigated in a post-hoc analysis of 12 042 participants in both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Veteran Affairs Diabetes Trial (VADT) that were observed for 84 to 87 months. Variability measures included coefficient of variation and average real variability for fasting glucose. Both indices were associated with development of future microvascular outcomes - higher risk of developing PDR that requires laser treatment - even after adjusting for other risk factors, including measures of average glycemic control (ie, cumulative average of HbA1c). Meta-analyses of these 2 trials confirmed these findings and indicated fasting plasma glucose variation may be more harmful in those with less intensive glucose control [64]. A patient with DME and significant fluctuations in the plasma glucose, hypoglycaemic episodes and HbA1c over 7.5% needs close monitoring – even though the edema may respond structurally to intravitreal treatment, the visual outcome will be limited and very unstable. In addition to the ubiquitous dietary mistakes and sedentary lifestyle, often there are problems associated with ongoing infections, diabetic foot ulcers, non-ocular surgeries and systemic steroid treatment (**Figures 2** and **4**) Dynamic fasting and random plasma glucose and HbA1c re-assessment at the clinic and prior to intravitreal treatment are easy and useful in identifying these patients, particularly during worsening of the DME and diabetic retinopathy after periods of stabilization.
