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Diabetic Macular Oedema


improvement in the bevacizumab group was significantly greater than in the other groups. With a longer follow-up, however, bevacizumab turned out to be superior to bevacizumab/triamcinolone and macular laser photocoagulation only in the eyes with initial CMT of ≥350 μm, indicating that in the primary treatment of DME, initial CMT may be an important factor in decision-making.


Recently, the results of a retrospective, multicentre, interventional comparative case series involving 115 consecutive patients (139 eyes) with DME receiving primary treatment with 1.25 or 2.5 mg bevacizumab were published.34


have been shown to determine excessive vascular permeability. This higher affinity will most probably allow lower doses to be employed and a longer duration of action to be maintained.37,38


A Phase I study


exploring the safety and bioactivity of a single injection of 4.0 mg VEGF Trap-Eye in subjects with DME demonstrated a reduction in CRT and significant improvement in VA.39


In a recent study, 221 diabetic patients


Patients received re-injections whenever there was a recurrence of DME (defined by a decrease in BCVA associated with the presence of intraretinal fluid on OCT or fluorescein angiography). In the first month after the initial bevacizumab injection, improvements in BCVA and CMT measurements were recorded and these significant changes continued throughout the 24-month follow-up. BCVA analysis at 24 months showed that 62 (44.6 %) eyes remained stable, 72 (51.8 %) eyes improved by two or more ETDRS lines and five (3.6 %) eyes decreased by two or more ETDRS lines.


The Bevacizumab or laser therapy in the management of diabetic macular edema (BOLT) study recruited 80 patients (80 eyes) affected by centre-involving clinically significant DME and at least one previous macular laser treatment. Subjects were randomised to two groups receiving intravitreal bevacizumab (n=42) or laser treatment according to ETDRS guidelines (n=38). Subjects in the bevacizumab arm underwent an injection at their baseline visit (1.25 mg in 0.05 ml). Patients were reviewed every six weeks with an end-of-year visit at 52 weeks. After the baseline injection, patients received two further injections at six and 12 weeks. Additional injections were programmed according to a specific OCT-based retreatment protocol. Subjects in the laser arm underwent modified ETDRS laser treatment at their baseline visit and were reviewed every four months with an end-of-year visit at 52 weeks. Retreatment was performed according to ETDRS guidelines. The primary endpoint was the difference in ETDRS BCVA at 12 months between the two arms. The baseline characteristics of the two treatment groups were comparable; the only significant difference in the groups was the duration of DME (median of 24 and 36 months in the bevacizumab and laser arms, respectively). Two patients in the laser group did not complete the 12 months of follow-up, while all 42 patients in the bevacizumab arm completed the study. The bevacizumab group gained a median of eight ETDRS letters, compared with the laser group which lost 0.5 ETDRS letters (p=0.0002). Mean CRT changes from baseline were -130 and -67 in the bevacizumab and laser groups, respectively (p=0.06). The median number of treatments was nine in the bevacizumab arm and three in the laser treatment arm. The findings of this study support the use of bevacizumab for DME. However, to confirm these results a larger trial with a longer follow-up period and a treatment arm that includes laser + bevacizumab therapy is needed.


The one-year results of a prospective randomised trial were recently reported.35


Vascular Endothelial Growth Factor Trap VEGF Trap-Eye (Regeneron) is a 115 kDa recombinant fusion protein of portions of VEGF receptors 1 and 2 and the Fc region of human immunoglobulin-G (IgG) which binds all VEGF-A isoforms with higher affinity in comparison with other anti-VEGF substances, including bevacizumab and ranibizumab.36


Moreover, VEGF Trap-Eye has a longer


half-life in the eye after intraocular injection and it binds other members of the VEGF family including placental growth factors 1 and 2, which


40


with DME were enrolled and assigned to five different groups characterised by different dosing regimens of intravitreal VEGF Trap (monthly injection of 0.5 or 2 mg VEGF Trap, three monthly injections followed by other injections every eight weeks or on PRN regimen, or macular laser photocoagulation alone).40


The four VEGF Trap groups


gained from 8.5 to 11.4 ETDRS letters versus only 2.5 letters in the laser group (p=0.0085) and obtained a reduction in CRT by 127.3–194.5 µm, compared with the 67.9 µm of the laser group (p=0.0066).


Bevasiranib


Small interfering RNA (siRNA) molecules are able to inactivate mRNA and suppress RNA translation. Bevasiranib is a specific siRNA designed to reduce the levels and activity of VEGF mRNA and may have a role in the treatment of diabetic retinopathy.41–43


The RNAi


administered monthly for three months. The study showed a reduction in macular thickness between weeks 8 and 12 and improvement of VA. A Phase III, randomised, double-masked clinical trial evaluating the efficacy of bevasiranib in patients affected by wet age-related macular degeneration was recently terminated. Subjects received bevasiranib either every eight weeks or every 12 weeks after an initial pre-treatment with three injections of ranibizumab, compared with ranibizumab given every four weeks. Preliminary results after 60 weeks suggest that bevasiranib is efficacious, even though slightly inferior to ranibizumab. Average VA remained positive through week 60 and a lower proportion of patients avoided visual loss on the more frequent bevasiranib dosing arm.45 Results from randomised clinical trials evaluating the use of bevasiranib in the treatment of DME are awaited.


assessment of bevasiranib in diabetic macular edema (RACE) trial investigated the use of different doses of bevasiranib (0.2, 1.5, or 3.0 mg)44


Rapamycin


Rapamycin (also known as sirolimus) is a macrocyclic antibiotic (produced by Streptomyces hygroscopicus) that specifically binds FK-binding protein-12 (FKBP12); the active complex inhibits the mammalian target of rapamycin (mTOR), a kinase which integrates growth factor-activated signals, including signals that promote angiogenesis mediated by VEGF. Moreover, mTOR is an activator of hypoxia-inducible factor-1a (HIF-1a), which upregulates the transcription of VEGF. In hypoxic cells, rapamycin can interfere with HIF-1a activation by increasing the rate of its degradation.46–48 Therefore, rapamycin may have a meaningful role as therapy for retinal disorders characterised by pathological vascular permeability and proliferation. Preliminary results of the application of rapamycin for DME were presented at the Association of Research in Vision and Ophthalmology (ARVO) Meeting 2008 by Blumenkranz et al.49


showing


Five adult participants with DME involving the centre of the fovea and best corrected ETDRS VA score of ≤74 letters received 20 μl (440 μg) of subconjunctival rapamycin at baseline, month two, and every two months thereafter, unless there was resolution of either retinal thickening on OCT or leakage on fluorescein angiography. The main outcomes were BCVA, CRT and safety outcomes. The results


a significant improvement in BCVA and CRT reduction. The most recent results come from a Phase I/II prospective, open-label pilot study.50


EUROPEAN ENDOCRINOLOGY


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