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Diabetic Macular Oedema


with standard-of-care treatment in patients with visual impairment due to DME. Long-term results are awaited to evaluate the outcomes of laser treatment alone and in combination with ranibizumab. The study has a limited follow-up to allow a real efficacy comparison with laser treatment, the latter being slower in producing its effects.


by decreasing the release of arachidonic acid derivatives such as prostaglandins, responsible for altered retinal vascular permeability and by inhibiting VEGF production. In order to provide further clarity on the effectiveness of treatments based on administration of steroidal or anti-VEGF drugs in comparison with conventional laser treatment, the Diabetic Retinopathy Clinical Research Network (DRCRnet) designed a randomised, multicentre clinical trial.21,22


It is well known that corticosteroids play an important role in reducing DME19,20


The study (two years follow-up) recruited 691 patients


and examined a total of 854 eyes randomised in four groups receiving: laser photocoagulation treatment alone (293 eyes), 0.5 mg ranibizumab + prompt laser (187 eyes), 0.5 mg ranibizumab + deferred laser (at least 24 weeks, 188 eyes), or intravitreal triamcinolone 4 mg + prompt laser (186 eyes). At one-year examination, the mean change in the VA letter score with respect to the baseline value showed a statistically significant improvement in the ranibizumab + prompt laser group (+9 ± 11 letters) and ranibizumab + deferred laser group (+9 ± 12), but not in the triamcinolone + prompt laser group (+4 ± 13), compared with the laser group (+3 ± 13). Over the two years of follow-up, a different correlation between VA change and retinal thickness was observed in each group. A progressive reduction in mean CST was noted in the laser group during the 24 months of follow-up; however, the mean change in VA did not continue to increase from the one- to two-year visit as noted during the first year of follow-up. In the triamcinolone + laser group, during the first year of follow-up, an improvement of visual function was associated with a significant reduction in CST, whereas, from the one- to two-year examination, the mean CST increased in parallel with a VA reduction. Ranibizumab groups showed a parallel VA improvement associated with a CST reduction from baseline to the 12-month visit and, following this period, the optical coherence tomography (OCT) results remained relatively stable up to the 24-month examination and paralleled the VA outcomes. Intraocular hypertension and cataract surgery were more frequently noted in the triamcinolone + prompt laser group in comparison with groups receiving ranibizumab + laser or laser alone. This trial confirms the promising preliminary results in the treatment of DME, suggesting that a combined therapy might offer a more efficient approach considering the multifactorial pathogenesis of the disorder. Moreover, it is once again demonstrated that laser treatment requires many months to become active on DME.


The Study of ranibizumab injection in subjects with clinically significant macular oedema with centre involvement secondary to diabetes mellitus ([RISE] [n= 377] and [RIDE] [n=382]) trials are Phase III, double-masked, multicentre, randomised, sham injection-controlled trials evaluating the efficacy and safety of ranibizumab injections in patients with DME.23


Patients were


randomised into three groups: sham injections (RISE [n=127], RIDE [n=130]), ranibizumab 0.3 mg injections (RISE [n=125], RIDE [n=125]), and ranibizumab 0.5 mg injections (RISE [n=125], RIDE [n=127]). The primary outcomes assessed are the percentage of subjects who gain at least 15 letters in BCVA compared with baseline, mean change from baseline in BCVA and mean change from baseline in central


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foveal thickness (CFT). The preliminary results report that patients gaining at least three lines compared with baseline were 18.1, 44.8 and 39.2 % in RISE and 12.3, 33.6 and 45.7 % in RIDE, in the sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab groups, respectively. Patients achieving a VA of at least 20/40 were 37.8, 60, and 63.2 % in RISE and 34.6, 54.4, and 62.2 % in RIDE, in the sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab groups, respectively. Two-year data analysis from the two studies showed an ocular and general safety profile similar to previous trials, with no systemic AEs due to ranibizumab injections.


Pegaptanib


Pegaptanib is a pegylated 28-nucleotide RNA aptamer that binds to the VEGF164/165 isoform at high affinity. VEGF165 is present in human eyes affected by diabetic retinopathy with increased concentration and plays an active role in promoting angiogenesis and in enhancing vascular permeability.The Macugen diabetic retinopathy study was a phase II randomised, sham-controlled, double-masked, dose-finding trial designed to evaluate the effect of three doses of intravitreal pegaptanib versus sham injection in patients affected by clinically significant DME.24


One hundred seventy-two patients were


randomised to receive 0.3 mg (n=44), 1.0 mg (n=44), or 3.0 mg (n=42) pegaptanib, or sham injection (n=42), at baseline and at week six and week 12. If needed, additional injections were administered every six weeks up to a maximum of three additional injections. Retinal laser photocoagulation could be delivered if the investigators judged it necessary. At the final visit at week 36, the group of patients receiving pegaptanib 0.3 mg was significantly superior to the sham injection group, as measured by mean change in VA (+4.7 letters versus -0.4 letters, p=0.04), proportion of patients gaining >10 letters of VA (34 versus 10 %, p=0.003), change in mean CRT (68 µm reduction versus 3.7 µm increase, p=0.02). Moreover, only 25 % of patients receiving pegaptanib required retinal photocoagulation, in comparison with 40 % of patients receiving sham injection (p=0.04). Patients receiving 1.0 or 3.0 mg did not show a significant improvement compared with 0.3 mg as regards BCVA or CRT changes. Adverse events were noted in all treatment arms and were transient, procedure-related and mild or moderate (such as eye pain, vitreous floaters, eye discharge and conjunctival haemorrhage).


Recently, the results of a sham-controlled, multicentre, parallel-group study were reported.25


The aim of this study was to demonstrate the


efficacy of 0.3 mg pegaptanib intravitreal injection to improve VA more than 10 Early treatment of diabetic retinopathy study (ETDRS) letters from baseline compared with sham injection. During the study, focal/grid laser photocoagulation was allowed, starting at week 18, if necessary. Two hundred and sixty and 207 patients, respectively, concluded one or two years of follow-up. The authors reported an improvement in VA ≥10 ETDRS letters at week 54 in 36.8 % of subjects in the pegaptanib group and in 19.7 % of the sham group compared with baseline values. A better VA in the pegaptanib group was also reported at the end of the two-year follow-up period. Moreover, fewer pegaptanib-treated subjects received laser treatment compared with sham-treated subjects (23.3 versus 41.7 % at week 54, 25.2 versus 45.0 % at week 102). The incidence of adverse events was lower in the pegaptanib group compared with the sham group.


Bevacizumab


Bevacizumab is a full-length recombinant humanised antibody active against all isoforms of VEGF. Short-term effects of bevacizumab for


EUROPEAN ENDOCRINOLOGY


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