Key points:<\/strong><\/p>\n

The pathophysiology of DMO results from: <\/p>\n
\n
• Retinal vascular disease Vasoregression and retinal ischaemia\n
• VEGF and inflammatory factors induced by ischaemia and tissue damage\n
• Loss of the BRB
  Paracellular transport \u2013 small molecules
  Transcellular transport \u2013 large molecules
  Starling equation: hydrostatic versus osmotic pressures affect oedema
  Role of abnormal vascular structures
  Chronic DMO may be a separate condition <\/ul>\n<\/ul><\/div>\n
  Managing the Patient with Diabetic Macular Oedema <\/b>
  Mr Ian Pearce
  Royal Liverpool University Hospital, UK
  <\/center><\/p>\n

  The primary objective of diabetes management is to regain control of blood glucose levels and to optimise blood pressure and blood lipid levels.^{5<\/sup> Despite these interventions, over time patients develop multiple diabetesrelated complications, of which they are often unaware of until they have progressed significantly.11<\/sup> Patients with diabetes are 25x more likely to be blind than patients without diabetes30 and many patients fear blindness more than premature death. Ophthalmologists therefore have an important role in educating patients in the need to control hyperglycaemia, the major driver of retinopathy. Ophthalmologists are also likely to be the first healthcare professionals to observe end-organ damage in these patients and are responsible for reporting it to their treating physicians. <\/p>\n}

  If diabetes is well managed, the risk of macro- and micro-vascular complications can be reduced.^{5,31<\/sup> This has been demonstrated in several large-scale clinical studies including the Diabetes Control and Complications Trial (DCCT),32<\/sup> the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study33<\/sup> and the UK Prospective Diabetes Study (UKPDS).34<\/sup> The DCCT showed that rates of DR rise steeply in patients whose glycated haemoglobin (HbA_{1c<\/sub>) levels are not maintained at approximately 7 % (see Figure 2<\/i>).32<\/sup> For every 1 % reduction in HbA1c<\/sub> there is a 30 % reduction in the progression of DR. However, too rapid a reduction in HbA1c<\/sub> can also result in DR and so no more than a 1 % reduction in 6 months is advised. <\/p>\n}}

  Clinical studies also show that controlling blood pressure in patients with diabetes is vital. The UKPDS showed that treating to target a blood pressure of <150\/85 mmHg (preferably 140\/80) substantially reduces the risk of death and complications due to diabetes.^{34<\/sup> In another large study, DMO was reduced over a 4-year period when patients with diabetes received blood pressure-lowering treatment.35<\/sup> Lipidaemia is also influential in DR but not as important as glycaemia and blood pressure. An analysis of data from the DCCT showed that higher serum lipids (total lipids, low-density lipoprotein [LDL] and highdensity lipoprotein [LDL] cholesterol, total-to-HDL cholesterol ratio and triglycerides) are associated with an increased risk of clinically significant MO (CSMO) and retinal hard exudate.36<\/sup> In addition, other clinical studies have shown reductions in the progression of retinopathy following treatment with atorvostatin37<\/sup> or fibrates.38<\/sup> <\/p>\n}

  The successful management of diabetes and avoidance of DR requires a systematic approach in which all of the risk parameters are adequately controlled. An analysis of data from the National Health and Nutrition Examination Surveys (NHANES) in the US found that only 19 % of patients with diabetes met all their targets for HbA_{1c<\/sub>, blood pressure and LDL cholesterol, indicating a substantial need for improvement.^{39<\/sup> To counter this problem, multifactorial treatments are needed to provide intensive control of all risk factors. This approach was evaluated in a Danish study (Steno-2) in which patients with diabetes received tight glucose regulation, renin-angiotensin system blockers, aspirin and lipid-lowering agents.40<\/sup> This intense treatment regimen produced a risk reduction of 43 % for the progression of DR compared with controls given standard treatment (p=0.01).40<\/sup> <\/p>\n}}

  Until recently, laser photocoagulation was the \u2018gold standard\u2019 therapy in DMO and had been for 3 decades. Focal laser photocoagulation targets specific areas whereas macular grid photocoagulation applies a localised pattern to treat areas of diffuse leakage. Despite the emergence of medications, laser therapy still has a role in the treatment of DMO. The classic Early Treatment in Diabetic Retinophy Study (ETDRS) that commenced during the 1980s demonstrated that macular (focal\/macular grid) laser photocoagulation was more effective when administered early rather than deferred.^{41<\/sup> In this study, laser treatment reduced the risk of moderate vision loss by approximately 50 %, and was effective at preserving vision\/preventing further vision loss. 41 <\/sup><\/p>\n}

  More recently, intravitreal corticosteroid and anti-VEGF agents have become available for the treatment of DMO and these can be used as alternatives to or in combination with laser therapy.^{6,42,43<\/sup> Extended-release implants of dexamethasone or fluocinolone acetonide are effective and more convenient than injections.44,45<\/sup> In some countries such as the UK, however, their use is currently restricted to pseudophakic patients who are unresponsive to anti-VEGF agents due to their side effects.46<\/sup> <\/p>\n}

  Since VEGF is a major factor in the inflammation that drives DMO, several anti-VEGF medications have been used effectively to treat DMO.^{20<\/sup> These are used alone or in combination with or before laser therapy or with other treatments. Ranibizumab (Lucentis\u00ae) is a humanised fragment, a mouse monoclonal antibody and also binds VEGF-A.47<\/sup> Aflibercept (Eylea\u00ae) is a fully human, recombinant fusion protein that tightly and stably binds VEGF-A and also binds placenta growth factor (PlGF).48<\/sup> Bevacizumab (Avastin\u00ae) is a humanised, recombinant monoclonal antibody with high affinity for VEGF-A. It is widely approved for systemic treatments of various cancers but is also used extensively off-label for ocular diseases including DMO.49,50<\/sup> Pegatanib (Macugen\u00ae) is a 28-base RNA aptamer covalently linked to two branched 20 kDa polyethylene glycol moieties that binds potently to VEGF. It is approved for the treatment of wet AMD but is also used for off-label treatment of DMO.51<\/sup> <\/p>\n}

  Both aflibercept and ranibizumab have shown significant efficacy against DMO in clinical trials. The efficacy of aflibercept is discussed in the next section. In the ranibizumab for macular oedema (RIDE and RISE) phase III studies, patients with DMO were randomized to ranibizumab 0.3 mg\/ day, 0.5 mg\/day or sham treatment.^{7 <\/sup>In both studies there was a gradual improvement in VA in terms of BCVA scores in both ranibizumab-treated groups. At 24 months there was a substantially greater improvement in VA for the ranibizumab-treated groups compared with the controls (RIDE: 12.0, 10.9 and 2.3 letters; RISE: 12.5, 11.9 and 2.6 letters). At this stage, patients receiving sham injections were switched to ranibizumab 0.5 mg\/day. Over the following 12 months, however, these patients showed slight gains but did not achieve the improvements in VA as those who had been treated with ranibizumab from the outset. This suggests that patients with DMO should be treated early to avoid vision losses. <\/p>\n}

  \n

  Key points:<\/strong><\/p>\n

  \n
  • Systematic management is central to limiting progression of DR\n
  • Anti-VEGF agents have demonstrated the most-significant improvements in VA:
    Improvements in VA are greater than with steroids
    Considered by some guidelines to be the current \u2018gold
    standard\u2019 treatment for DMO in the presence of reduced visual function\n
  • Challenges:
    Injection frequency and interval between visit frequency
    A longer-acting agent may address both these concerns <\/ul><\/div>\n
    VIVID and VISTA \u2013 Clinical Trial Results and Implications <\/b>
    Professor Jean-Fran\u00e7ois Korobelnik
    University Hospital, Bordeaux, France
    <\/center> <\/p>\n

    The VIVID and VISTA trials are two similarly designed phase III head-tohead comparisons of the efficacy and safety of intravitreal aflibercept and laser therapy. These are double-masked, randomized, activecontrolled trials conducted at multiple centres in Europe, Asia, Australia, (VIVID) and the US (VISTA).^{8<\/sup> A total of 872 patients with type 1 or 2 diabetes who presented with DMO with central involvement and ETDRS BCVA 20\/40 to 20\/320 were recruited. Patients were then randomised to receive either intravitreal aflibercept injection, 2 mg every 4 weeks (2q4), 2 mg every 8 weeks after five initial monthly doses (2q8), or macular laser photocoagulation. <\/p>\n}

    Baseline characteristics were similar between groups within each study; central retinal thickness (CRT) was slightly greater in VIVID but the proportion who had received prior anti-VEGF therapy was markedly greater in VISTA (in the US) as was the duration of disease (see Table 1<\/i>). The primary endpoint results show that VA rapidly improved during the first 4 weeks of treatment with aflibercept and then improved more steadily up to 52 weeks in both the VIVID and VISTA trials and this was substantially greater than improvements seen with laser treatment. BCVA letter improvement for aflibercept 2q8, 2q4 and laser treatment were 10.7, 10.5 and 1.2, respectively (p<0.0001), in the VIVID trial and 10.7, 12.5 and 0.2 (p<0.0001) in the VISTA trial (see Figure 3<\/).^{8<\/sup> This shows that less-frequent dosing of aflibercept at 8-week intervals rather than 4-week intervals has little effect on visual outcomes and both are markedly more effective than laser treatment. Early reports of data from extended follow-up in these trials indicate that the benefits in VA in aflibercept-treated groups subsequently stabilised and the similarities between dosing regimens and improvements over laser treatment were maintained to 100 weeks.9<\/sup> <\/p>\n}

    For secondary endpoints, the aflibercept treatment regimens showed greater improvements in retinal pathology compared with laser treatment. Mean reductions in CRT at 52 weeks, as determined by optical coherence tomography (OCT), for aflibercept 2q8, 2q4 versus laser were: 192.4, 195.0 and 66.2 \u03bcm, respectively, (p<0.0001) in the VIVID study and 183.1, 185.9 and 73.3 \u03bcm, respectively, (p<0.0001) in the VISTA study (see Figure 4<\/i>). <\/p>\n

    The aflibercept treatments were well tolerated and there were no newsafety signals compared with laser treatment. The frequency of ocular and non-ocular adverse events were similar in the three treatment groups in both studies. Treatment emergent, Anti-Platelet Trialists\u2019 Collaborationdefined arterial thromboembolic events occurred at similar frequencies in the aflibercept 2q8, 2q4 and laser groups (3.5 %, 3.1 % and 2.8 %). These events were non-fatal myocardial infarction, non-fatal stroke and vascular death. Serious adverse events (SAEs) occurred in 1.7 % of aflibercept 2q8-treated patients, 1.7 % of aflibercept 2q4-treated patients and 4.2 % of laser-treated patients. SAEs included mainly cataract, DR and vitreous haemorrhage.^{8<\/sup> Early reports indicate that no new safety concerns were identified in the additional period to week 100.9<\/sup> <\/p>\n}

    \n

    Key points:<\/strong><\/p>\n

    \n
    • In DMO clinical trials to date, proactive treatment regimens resulted in higher VA gains than reactive pro re nata treatment\n
    • In the VIVID (Europe, Asia, Australia) and VISTA (US) trials, in a large patient population, aflibercept demonstrated a greater ability than laser to improve vision and CRT in DMO\n
    • Aflibercept administered 2 mg every 8 weeks performed similarly to the 2 mg every 4 weeks\n
    • Proactive aflibercept 2 mg every 8 weeks provides excellent efficacy, and safety with low patient and clinic burden <\/ul><\/div>\n
      Conclusion<\/b> <\/center> <\/p>\n

      In DMO, hyperglycaemia drives vascular dysfunction and low-grade inflammation that is mediated by numerous cytokines among which VEGF is central. These processes result in disrupted fluid transport, a breakdown in the BRB and leakage into retinal tissues causing fluid accumulation and macular cysts. Inhibition of VEGF action therefore is a key approach to managing DMO and preventing retinal damage and eyesight loss. <\/p>\n

      In patients with diabetes, prevention of DR progression to DMO requires a systematic approach. Management should involve good glycaemic control as well as control of blood pressure and lipid levels (especially LDL-cholesterol). Maintaining these parameters below set limits markedly reduces the risk of DR and DMO progression but this requires intensive monitoring and treatment. Such individual attention may not be available to all patients for durations of approximately 10 years that DMO takes to develop after diabetes onset. <\/p>\n

      For patients who have developed DMO, until recently, laser photocoagulation was the only treatment available.^{52<\/sup> However, anti- VEGF agents, especially aflibercept and ranibizumab, are now becoming established as the \u2018standard of care\u2019 as first-line treatments for a subset of patients with DMO. In the RIDE and RISE trials, ranibizumab showed significant improvements in VA and retinal thickness versus sham treatment and was well tolerated in such patients. This efficacy was markedly better than can be achieved with corticosteroid treatments. The VIVID and VISTA trials, in which aflibercept was directly compared with laser-only treatment, showed significant improvements in efficacy over laser treatment. It is notable that the lower frequency (2q8) regimen provided similar efficacy to the higher frequency (2q4) and there were no safety differences between these two regimens. Aflibercept was very well tolerated and no retinal atrophy was seen in either of the VIVID or VISTA trials. In cases in which DMO occurs in both eyes of a patient, at some clinics, intravitreal treatment of the second eye is not given at the same time but may be delayed by hours or days. This ensures that there are no adverse events following the first injection; there is little evidence that consecutive injections of an anti-VEGF agent into each eye could cause clinically relevant blood levels of the medication. Use of the 2q8 regimen may be more suitable in cases of bilateral administration. It should be emphasised that anti- VEGF medications have not replaced laser therapy but can be used prior to, or in combination with, laser treatment especially in cases of focal leakage. <\/p>\n}

      The disease stage at which different intravitreal medications should be used and how long they should be administered in DMO is not universally agreed. In the past, it was normal practice to wait until HbA_{1c<\/sub> levels and blood pressure were under control before initiating treatment. This strategy, however, costs time and may lead to retinal damage so now treatments increasingly commence earlier before these targets are reached. Anti-VEGF agents are indicated for first-line use in DMO when the fovea is involved and when vision is impaired. Corticosteroid injections and implants are mainly used second-line and are restricted to patients who fail to respond to anti-VEGF agents. Patients with a CRT of approximately 420 \u03bcm should be given anti-VEGF agents but those with a CRT of 370 \u03bcm may be given laser, corticosteroid or bevacizumab treatment. Treatment decisions are, however, challenging in DMO and therapy is often stopped too early. A 6-month course of anti-VEGF treatment is the absolute minimum but further treatment should be based on individual requirements.^{53,54<\/sup> It is important when treating DMO that the clinician takes an interest in the patients\u2019 diabetes history and adjusts the treatment strategy appropriately. <\/p>\n}}

      Aflibercept and ranibizumab are both approved for use in DMO. They have proved effective in clinical trials and as experience of their regular clinical use increases it is likely that they will be used in a wider population of patients as a first-line treatment. Such strategies are likely to help control this increasingly prevalent threat to vision worldwide. <\/p>\n

      \n

      This article has been produced on behalf of Bayer Healthcare and reports on a Bayer funded and organised symposium.<\/strong><\/p>\n<\/p><\/div>\n

      Eylea\u00ae ▼<\/font><\/sub>40 mg\/ml solution for injection in a vial (aflibercept) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing)<\/b> <\/p>\n

      Presentation:<\/b> 1 ml solution for injection contains 40 mg aflibercept. Each vial contains 100 microlitres, equivalent to 4 mg aflibercept. Indication(s):<\/b> Treatment of neovascular (wet) age-related macular degeneration (AMD),macular oedema secondary to central retinal vein occlusion (CRVO) and visual impairment due to diabetic macular oedema (DMO) in adults. Posology & method of administration:<\/b> For intravitreal injection only. Must be administered according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. Each vial should only be used for the treatment of a single eye. The vial contains more than the recommended dose of 2 mg. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Refer to SmPC for full details. Adults:<\/b> The recommended dose is 2 mg aflibercept, equivalent to 50 microlitres. For wAMD treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, treatment interval may be extended based on visual and anatomic outcomes. In this case the schedule for monitoring may be more frequent than the schedule of injections. For CRVO, after the initial injection, treatment is given monthly at intervals not shorter than one month, and continues until visual and anatomic outcomes are stable for three monthly assessments. Thereafter the need for continued treatment should be reconsidered. Treatment may be continued with gradually increasing treatment intervals to maintain a stable visual and anatomic outcome. Continued treatment is not recommended if no improvement in visual and anatomic outcomes over the first three injections. If treatment is discontinued, monitor visual and anatomic outcomes and resume treatment if these deteriorate. Usually, monitoring should be done at the injection visits. During treatment interval extension until therapy completion, the monitoring schedule should be determined by the treating physician based on the individual patient\u2019s response and may be more frequent than the schedule of injections. For DMO, initiate treatment with one injection\/month for 5 consecutive doses, followed by one injection every two months. No requirement for monitoring betweeninjections. After the first 12 months of treatment, the treatment interval may be extended based on visual and anatomic outcomes. The schedule for monitoring should be determined by the treating physician. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, treatment should be discontinued. Hepatic and\/or renal impairment: <\/b> No specific studies have been conducted. Available data do not suggest a need for a dose adjustment. Elderly population:<\/b> No special considerations are needed. Limited experience in those with DMO over 75years old. Paediatric population:<\/b> No data available. Contra-indications:<\/b> Hypersensitivity to active substance or any excipient; active or suspected ocular or periocular infection; active severe intraocular inflammation. Warnings & precautions: <\/b>As with other intravitreal therapies endophthalmitis has been reported. Aseptic injection technique essential. Patients must report any symptoms of endophthalmitis without delay. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection; special precaution is needed in patients with poorly controlled glaucoma (do not inject while the intraocular pressure is \u2265 30 mmHg). Immediately after injection, monitor intraocular pressure and perfusion of optic nerve head and manage appropriately. There is a potential for immunogenicity as with other therapeutic proteins; patients should report any signs or symptoms of intraocular inflammation e.g pain, photophobia or redness, which may be a clinical sign of hypersensitivity. Reports of systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events following intravitreal injection of VEGF inhibitors. Safety and efficacy of concurrent use in both eyes have not been systemically studied. Caution in patients with risk factors for development of retinal pigment epithelial tears including large and\/ or high pigment epithelial retinal detachment. Withhold treatment in patients: with rhegmatogenous retinal detachment or stage 3 or 4 macular holes; with retinal break and do not resume treatment until the break is adequately repaired. Withhold treatment and do not resume before next scheduled treatment if there is: decrease in best-corrected visual acuity of \u226530 letters compared with the last assessment; central foveal subretinal haemorrhage, or haemorrhage \u226550%, of total lesion area. Do not treat in the 28 days prior to or following performed or planned intraocular surgery. Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection. Populations with limited data: There is limited experience of treatment with Eylea in patients with ischaemic, chronic CRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended. There is limited experience in DMO due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy. Eylea has not been studied in patients with active systemic infections, concurrent eye conditions such as retinal detachment or macular hole, or in diabetic patients with uncontrolled hypertension. This lack of information should be considered when treating such patients. Interactions: <\/b> No available data. Fertility, pregnancy & lactation: <\/B> Not recommended during pregnancy unless potential benefit outweighs potential risk to the foetus. No data available in pregnant women. Studies in animals have shown embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection. Not recommended during breastfeeding. Excretion in human milk: unknown. Male and female fertility impairment seen in animal studies with high systemic exposure not expected after ocular administration with very low systemic exposure. Effects on ability to drive and use machines:<\/B> Possible temporary visual disturbances. Patients should not drive or use machines if vision inadequate. Undesirable effects:<\/B> Very common: conjunctival haemorrhage (phase III studies: increased incidence in patients receiving anti-thrombotic agents), eye pain, visual acuity reduced. Common: retinal pigment epithelium tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, corneal oedema, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival or ocular hyperaemia. Uncommon: Injection site irritation, abnormal sensation in eye, eyelid irritation. Serious: cf. CI\/W&P – in addition: endophthalmitis, cataract, transient increased intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (incl. allergic reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect\/erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare, blindness. Consult the SmPC in relation to other side effects. Overdose:<\/B> Monitor intraocular pressure and treat if required. Incompatibilities:<\/b> Do not mix with other medicinal products. Special Precautions for Storage:<\/b> Store in a refrigerator (2\u00b0C to 8\u00b0C). Do not freeze. Unopened vials may be kept at room temperature (below 25\u00b0C) for up to 24 hours before use. Legal Category:<\/B> POM. Package Quantities & Basic NHS Costs:<\/b> Single vial pack \u00a3816.00. MA Number(s):<\/b> EU\/1\/12\/797\/002. Further information available from:<\/b> Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone: 01635 563000. Date of preparation: March 2015 <\/b><\/p>\n

      Eylea\u00ae is a trademark of the Bayer Group <\/p>\n

      Adverse events should be reported. Reporting forms and information can be found at www. mhra.gov.uk\/yellowcard. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@ bayer.co.uk <\/b> <\/p>\n

      L.GB.11.2014.8880b; April 2015 <\/p><\/div>\n","protected":false},"excerpt":{"rendered":"

      Diabetic macular oedema (DMO) is an increasingly common visionthreatening disease that results from retinal vascular dysfunction and low-grade inflammation, developing into diabetic retinopathy (DR) and then to DMO over 10 or more years following the onset of diabetes.1 Areas of retinal tissue lose capillary vasculature and become ischaemic, stimulating secretion of vascular endothelial growth factor […]<\/p>\n","protected":false},"author":53489,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_relevanssi_hide_post":"","_relevanssi_hide_content":"","_relevanssi_pin_for_all":"","_relevanssi_pin_keywords":"","_relevanssi_unpin_keywords":"","_relevanssi_related_keywords":"","_relevanssi_related_include_ids":"","_relevanssi_related_exclude_ids":"","_relevanssi_related_no_append":"","_relevanssi_related_not_related":"","_relevanssi_related_posts":"","_relevanssi_noindex_reason":"","rank_math_lock_modified_date":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1119","post","type-post","status-publish","format-standard","hentry","category-uncategorized","vocabulary_1-diabetic-macular","vocabulary_1-retina-vitreous"],"acf":{"wpcf-article_introduction":"","wpcf-article_abstract":"A satellite symposium entitled \u2018Aflibercept* \u2013 Setting Its Sights On Diabetic Macular Oedema (DMO)\u2019 was chaired by Jean-Fran\u00e7ois Korobelnik and was convened at the 2014 European Association for Vision and Eye Research (EVER) Congress. The symposium discussed the science behind DMO, in particular, the role of vascular endothelial growth factor (VEGF) and associated inflammatory mechanisms that alter fluid transport from capillaries into retinal tissues leading to focal leakage, fluid accumulation, macular damage and eventual blindness. This discussion of the pathophysiology emphasised the importance of VEGF as a target for DMO treatments. Management of diabetes and prevention of progression of diabetic retinopathy leading to DMO requires strict control of glycated haemoglobin (HbA<sub>1c<\/sub>), blood pressure and lipid levels. Once DMO has developed and vision is impaired, the anti-VEGF agents have emerged as vital components of disease management and are becoming the first-line standard of care. Aflibercept (EYLEA\u00ae ▼<\/font><\/sub>) and ranibizumab (Lucentis\u00ae) are approved agents for DMO and have shown significant efficacy in clinical trials in terms of visual acuity gains, decreased retinal thickness and have good safety profiles. The symposium finally focused on the use of aflibercept in DMO. In large-scale trials (VIVID and VISTA), this treatment has been compared head-to-head with laser treatment and during 1 year of treatment, showed substantial efficacy benefits, no new safety signals and the potential for lower frequency intravitreal dosing at 8- rather than 4-week intervals for monitoring and pro re nata dosing. ","wpcf-article_keywords":"Diabetic macular oedema, VEGF, anti-VEGF agents, aflibercept","wpcf-article_citation_override":"European Ophthalmic Review, <\/i>2014;8(2):152\u20138 DOI: http:\/\/doi.org\/10.17925\/EOR.2014.08.02.152<\/a>","wpcf-compliance-with-ethics":"","wpcf-article_disclosure":"Jean-Fran\u00e7ois Korobelnik is a consulant for Alcon, Alimera, Allergan, Bayer, Horus, Novartis, Roche, Th\u00e9a and Zeiss. Ian Pearce has engaged in consultancies,\r\nadvisory boards, speaking engagements, conducted clinical research or owns shares in Alcon, Alimera, Allergan, Bayer and Novartis. Reinier Schlingemann is a consultant, has engaged in advisory boards and received speaker fees from Astellas, Bayer and Novartis.","wpcf-review_process":"","wpcf-authorship":"","wpcf-article_correspondence":"Jean-Fran\u00e7ois Korobelnik, Department of Ophthalmology, CHU de Bordeaux, Hopital Pellegrin, Bordeaux, France. E: jean-francois.korobelnik@chu-bordeaux.fr","wpcf-article_support":"The publication of this article was supported by Bayer Healthcare. The views and opinions expressed are those of the authors and not necessarily those of\r\nBayer Healthcare.","wpcf-open_access":"","wpcf-article_pdf":"http:\/\/touchophthalmology.com\/wp-content\/uploads\/sites\/16\/2015\/07\/EU_Ophth_8.2_NEW-10.6.15-1_0.pdf","wpcf-article_pdf-gated":true,"wpcf-article_doi":"","wpcf-old_nid":"","wpcf-article_image":"http:\/\/touchophthalmology.com\/wp-content\/uploads\/sites\/16\/2016\/10\/imag6-2_3.png","wpcf-editor_choice":false,"wpcf-old_author_ids":"","wpcf-article_references":"*EYLEA\u00ae▼<\/font><\/sub> (aflibercept solution for injection). Prescribing information can be found below the references. <\/i>
      
      This article is a write up of a promotional meeting organised and funded by Bayer Healthcare. The speakers were paid honoraria towards this meeting. Bayer HealthCare checked the content for factual accuracy, to ensure it is fair and balanced, and that it complies with the ABPI Code of Practice<\/i>
      
      \r\n</sub>

      \r\n\r\n
      1. Progression of retinopathy with intensive versus conventional\r\ntreatment in the Diabetes Control and Complications Trial.\r\nDiabetes Control and Complications Trial Research Group,\r\nOphthalmology, 1995;102:647\u201361.\r\n
      2. Joussen AM, Smyth N, Niessen C, Pathophysiology of diabetic\r\nmacular edema, Dev Ophthalmol, 2007;39:1\u201312.\r\n
      3. Scholl S, Augustin A, Loewenstein A, et al., General\r\npathophysiology of macular edema, Eur J Ophthalmol,\r\n2011;21 Suppl. 6:S10\u20139.\r\n
      4. Stem MS, Gardner TW, Neurodegeneration in the pathogenesis\r\nof diabetic retinopathy: molecular mechanisms and\r\ntherapeutic implications, Curr Med Chem, 2013;20:3241\u201350.\r\n
      5. American Diabetes Association. Standards of medical care in\r\ndiabetes \u2013 2012, Diabetes Care, 2012;35 Suppl. 1:S11\u201363.\r\n
      6. Ford JA, Lois N, Royle P, et al., Current treatments in diabetic\r\nmacular oedema: systematic review and meta-analysis,\r\nBMJ Open, 2013;3:e002269.\r\n
      7. Brown DM, Nguyen QD, Marcus DM, et al., Long-term\r\noutcomes of ranibizumab therapy for diabetic macular\r\nedema: the 36-month results from two phase III trials: RISE\r\nand RIDE, Ophthalmology, 2013;120:2013\u201322.\r\n
      8. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al., Intravitreal\r\nAflibercept for Diabetic Macular Edema, Ophthalmology,\r\n2014;121:2247\u201354.\r\n
      9. Midena E, Korobelnik JF, 2014, Intravitreal aflibercept for\r\ndiabetic macular edema (DME): 100-week results from the\r\nVIVID-DME and VISTA-DME studies, 14th EURETINA Congress,\r\nLondon, UK.\r\n
      10. Klein R, Knudtson MD, Lee KE, et al., The Wisconsin\r\nEpidemiologic Study of Diabetic Retinopathy XXIII: the twentyfive-\r\nyear incidence of macular edema in persons with type 1\r\ndiabetes, Ophthalmology, 2009;116:497\u2013503.\r\n
      11. International Diabetes Federation, 2013; Diabetes Atlas: 6th\r\nEdition. Available at: http:\/\/www.idf.org\/sites\/default\/files\/\r\nEN_6E_Atlas_Full_0.pdf (accessed 8 October 2014).\r\n
      12. International Diabetes Federation, 2011; Diabetes and\r\nblindness due to DME. Available at: https:\/\/www.idf.org\/sites\/\r\ndefault\/files\/IDF%2520Toolkit_Backgrounder_FINAL.pdf date\r\n(accessed 8 October 2014).\r\n
      13. Antonetti DA, Klein R, Gardner TW, Diabetic retinopathy,\r\nN Engl J Med, 2012;366:1227\u201339.\r\n
      14. Klein R, Kein BK, The epidemiology of diabetic retinopathy\r\n(5th Edition). In: SJ Ryan, S Sadda and D Hinton (eds.), Retina,\r\nPhiladelphia: Elsevier-Saunders, 2013.\r\n
      15. Shaya FT, Aljawadi M, Diabetic retinopathy, Clin Ophthalmol,\r\n2007;1:259\u201365.\r\n
      16. Kinyoun J, Barton F, Fisher M, et al., Detection of diabetic\r\nmacular edema. Ophthalmoscopy versus photography \u2013 Early\r\nTreatment Diabetic Retinopathy Study Report Number 5. The\r\nETDRS Research Group, Ophthalmology, 1989;96:746\u201350;\r\ndiscussion 50\u20131.\r\n
      17. Miller JW, Le Couter J, Strauss EC, et al., Vascular\r\nendothelial growth factor a in intraocular vascular disease,\r\nOphthalmology, 2013;120:106\u201314.\r\n
      18. Penn JS, Madan A, Caldwell RB, et al., Vascular endothelial\r\ngrowth factor in eye disease, Prog Retin Eye Res,\r\n2008;27:331\u201371.\r\n
      19. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al.,\r\nPrimary intravitreal bevacizumab (Avastin) for diabetic\r\nmacular edema: results from the Pan-American Collaborative\r\nRetina Study Group at 6-month follow-up, Ophthalmology,\r\n2007;114:743\u201350.\r\n
      20. Boyer DS, Hopkins JJ, Sorof J, et al., Anti-vascular endothelial\r\ngrowth factor therapy for diabetic macular edema, Ther Adv\r\nEndocrinol Metab, 2013;4:151\u201369.\r\n
      21. Funatsu H, Noma H, Mimura T, et al., Association of vitreous\r\ninflammatory factors with diabetic macular edema,\r\nOphthalmology, 2009;116:73\u20139.\r\n
      22. Yoshimura T, Sonoda KH, Sugahara M, et al., Comprehensive\r\nanalysis of inflammatory immune mediators in vitreoretinal\r\ndiseases, PLoS One, 2009;4:e8158.\r\n
      23. Al Dhibi HA, Arevalo JF, Clinical trials on corticosteroids for\r\ndiabetic macular edema, World J Diabetes, 2013;4:295\u2013302.\r\n
      24. Stewart MW, Corticosteroid use for diabetic macular edema:\r\nold fad or new trend?, Curr Diab Rep, 2012;12:364\u201375.\r\n
      25. Starling EH, On the absorption of fluids from the connective\r\ntissue spaces, Journal of Physiology, 1896;19:312\u201326.\r\n
      26. Zhang X, Zeng H, Bao S, et al., Diabetic macular edema: new\r\nconcepts in patho-physiology and treatment, Cell Biosci,\r\n2014;4:27.\r\n
      27. Klaassen I, Van Noorden CJ, Schlingemann RO, Molecular\r\nbasis of the inner blood-retinal barrier and its breakdown in\r\ndiabetic macular edema and other pathological conditions,\r\nProg Retin Eye Res, 2013;34:19\u201348.\r\n
      28. Klaassen I, Hughes JM, Vogels IM, et al., Altered expression\r\nof genes related to blood-retina barrier disruption in\r\nstreptozotocin-induced diabetes, Exp Eye Res, 2009;89:4\u201315.\r\n
      29. Hofman P, Blaauwgeers HG, Tolentino MJ, et al., VEGF-A\r\ninduced hyperpermeability of blood-retinal barrier\r\nendothelium in vivo is predominantly associated with\r\npinocytotic vesicular transport and not with formation of\r\nfenestrations. Vascular endothelial growth factor-A, Curr Eye\r\nRes, 2000;21:637\u201345.\r\n
      30. National Society to Prevent Blindness Operational Research\r\nDepatment 1980. Vision problems in the United States: a\r\nstatistical analysis , National Society to Prevent Blindness:\r\nNew York, US, 1\u201346.\r\n
      31. Inzucchi SE, Bergenstal RM, Buse JB, et al., Management\r\nof hyperglycaemia in type 2 diabetes: a patient-centered\r\napproach. Position statement of the American Diabetes\r\nAssociation (ADA) and the European Association for the\r\nStudy of Diabetes (EASD), Diabetologia, 2012;55:1577\u201396.\r\n
      32. The relationship of glycemic exposure (HbA1c) to the risk of\r\ndevelopment and progression of retinopathy in the diabetes\r\ncontrol and complications trial, Diabetes, 1995;44:968\u201383.\r\n
      33. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, et\r\nal., Effects of medical therapies on retinopathy progression in\r\ntype 2 diabetes, N Engl J Med, 2010;363:233\u201344.\r\n
      34. Intensive blood-glucose control with sulphonylureas or\r\ninsulin compared with conventional treatment and risk\r\nof complications in patients with type 2 diabetes (UKPDS\r\n33). UK Prospective Diabetes Study (UKPDS) Group, Lancet,\r\n1998;352:837\u201353.\r\n
      35. Beulens JW, Patel A, Vingerling JR, et al., Effects of blood\r\npressure lowering and intensive glucose control on the\r\nincidence and progression of retinopathy in patients with\r\ntype 2 diabetes mellitus: a randomised controlled trial,\r\nDiabetologia, 2009;52:2027\u201336.\r\n
      36. Miljanovic B, Glynn RJ, Nathan DM, et al., A prospective study\r\nof serum lipids and risk of diabetic macular edema in type 1\r\ndiabetes, Diabetes, 2004;53:2883\u201392.\r\n
      37. Gupta A, Gupta V, Thapar S, et al., Lipid-lowering drug\r\natorvastatin as an adjunct in the management of diabetic\r\nmacular edema, Am J Ophthalmol, 2004;137:675\u201382.\r\n
      38. Morgan CL, Owens DR, Aubonnet P, et al., Primary prevention\r\nof diabetic retinopathy with fibrates: a retrospective, matched\r\ncohort study, BMJ Open, 2013;3:e004025.\r\n
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      40. Gaede P, Lund-Andersen H, Parving HH, et al., Effect of a\r\nmultifactorial intervention on mortality in type 2 diabetes,\r\nN Engl J Med, 2008;358:580\u201391.\r\n
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      46. National Institute for Health and Care Excellence, 2014;\r\nFluocinolone acetonide intravitreal implant for treating\r\nchronic diabetic macular oedema after an inadequate\r\nresponse to prior therapy (rapid review of technology\r\nappraisal guidance 271). Available at: https:\/\/www.nice.org.\r\nuk\/guidance\/TA301 (accessed 21 October 2014).\r\n
      47. Gupta N, Mansoor S, Sharma A, et al., Diabetic retinopathy\r\nand VEGF, Open Ophthalmol J, 2013;7:4\u201310.\r\n
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      52. Zur D, Loewenstein A, Combination Therapy for diabetic\r\nmacular edema, J Ophthalml, 2012;2012:484612.\r\n
      53. Boras I, Lazic R, Gabric N, et al., Anti-VEGF in treatment of\r\ndiabetic macular edema, Coll Antropol, 2011;35(Suppl. 2):15\u201354.\r\n
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          \r\n\r\nEylea\u00ae <sub>▼<\/font><\/sub>40 mg\/ml solution for injection in a vial (aflibercept) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing)<\/b>
          
          Presentation:<\/b> 1 ml solution for injection contains 40 mg aflibercept. Each vial contains 100 microlitres, equivalent to 4 mg aflibercept. Indication(s):<\/b> Treatment of neovascular (wet) age-related macular degeneration (AMD),macular oedema secondary to central retinal vein occlusion (CRVO) and visual impairment due to diabetic macular oedema (DMO) in adults. Posology & method of administration:<\/b> For intravitreal injection only. Must be administered according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. Each vial should only be used for the treatment of a single eye. The vial contains more than the recommended dose of 2 mg. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Refer to SmPC for full details. Adults:<\/b> The recommended dose is 2 mg aflibercept, equivalent to 50 microlitres. For wAMD treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, treatment interval may be extended based on visual and anatomic outcomes. In this case the schedule for monitoring may be more frequent than the schedule of injections. For CRVO, after the initial injection, treatment is given monthly at intervals not shorter than one month, and continues until visual and anatomic outcomes are stable for three monthly assessments. Thereafter the need for continued treatment should be reconsidered. Treatment may be continued with gradually increasing treatment intervals to maintain a stable visual and anatomic outcome. Continued treatment is not recommended if no improvement in visual and anatomic outcomes over the first three injections. If treatment is discontinued, monitor visual and anatomic outcomes and resume treatment if these deteriorate. Usually, monitoring should be done at the injection visits. During treatment interval extension until therapy completion, the monitoring schedule should be determined by the treating physician based on the individual patient\u2019s response and may be more frequent than the schedule of injections. For DMO, initiate treatment with one injection\/month for 5 consecutive doses, followed by one injection every two months. No requirement for monitoring betweeninjections. After the first 12 months of treatment, the treatment interval may be extended based on visual and anatomic outcomes. The schedule for monitoring should be determined by the treating physician. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, treatment should be discontinued. Hepatic and\/or renal impairment: <\/b> No specific studies have been conducted. Available data do not suggest a need for a dose adjustment. Elderly population:<\/b> No special considerations are needed. Limited experience in those with DMO over 75years old. Paediatric population:<\/b> No data available. Contra-indications:<\/b> Hypersensitivity to active substance or any excipient; active or suspected ocular or periocular infection; active severe intraocular inflammation. Warnings & precautions: <\/b>As with other intravitreal therapies endophthalmitis has been reported. Aseptic injection technique essential. Patients must report any symptoms of endophthalmitis without delay. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection; special precaution is needed in patients with poorly controlled glaucoma (do not inject while the intraocular pressure is \u2265 30 mmHg). Immediately after injection, monitor intraocular pressure and perfusion of optic nerve head and manage appropriately. There is a potential for immunogenicity as with other therapeutic proteins; patients should report any signs or symptoms of intraocular inflammation e.g pain, photophobia or redness, which may be a clinical sign of hypersensitivity. Reports of systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events following intravitreal injection of VEGF inhibitors. Safety and efficacy of concurrent use in both eyes have not been systemically studied. Caution in patients with risk factors for development of retinal pigment epithelial tears including large and\/ or high pigment epithelial retinal detachment. Withhold treatment in patients: with rhegmatogenous retinal detachment or stage 3 or 4 macular holes; with retinal break and do not resume treatment until the break is adequately repaired. Withhold treatment and do not resume before next scheduled treatment if there is: decrease in best-corrected visual acuity of \u226530 letters compared with the last assessment; central foveal subretinal haemorrhage, or haemorrhage \u226550%, of total lesion area. Do not treat in the 28 days prior to or following performed or planned intraocular surgery. Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection. Populations with limited data: There is limited experience of treatment with Eylea in patients with ischaemic, chronic CRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended. There is limited experience in DMO due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy. Eylea has not been studied in patients with active systemic infections, concurrent eye conditions such as retinal detachment or macular hole, or in diabetic patients with uncontrolled hypertension. This lack of information should be considered when treating such patients. Interactions: <\/b> No available data. Fertility, pregnancy & lactation: <\/B> Not recommended during pregnancy unless potential benefit outweighs potential risk to the foetus. No data available in pregnant women. Studies in animals have shown embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection. Not recommended during breastfeeding. Excretion in human milk: unknown. Male and female fertility impairment seen in animal studies with high systemic exposure not expected after ocular administration with very low systemic exposure. Effects on ability to drive and use machines:<\/B> Possible temporary visual disturbances. Patients should not drive or use machines if vision inadequate. Undesirable effects:<\/B> Very common: conjunctival haemorrhage (phase III studies: increased incidence in patients receiving anti-thrombotic agents), eye pain, visual acuity reduced. Common: retinal pigment epithelium tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, corneal oedema, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival or ocular hyperaemia. Uncommon: Injection site irritation, abnormal sensation in eye, eyelid irritation. Serious: cf. CI\/W&P - in addition: endophthalmitis, cataract, transient increased intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (incl. allergic reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect\/erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare, blindness. Consult the SmPC in relation to other side effects. Overdose:<\/B> Monitor intraocular pressure and treat if required. Incompatibilities:<\/b> Do not mix with other medicinal products. Special Precautions for Storage:<\/b> Store in a refrigerator (2\u00b0C to 8\u00b0C). Do not freeze. Unopened vials may be kept at room temperature (below 25\u00b0C) for up to 24 hours before use. Legal Category:<\/B> POM. Package Quantities & Basic NHS Costs:<\/b> Single vial pack \u00a3816.00. MA Number(s):<\/b> EU\/1\/12\/797\/002. Further information available from:<\/b> Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone: 01635 563000. Date of preparation: March 2015 <\/b>
          
          Eylea\u00ae is a trademark of the Bayer Group
          
          Adverse events should be reported. Reporting forms and information can be found at www. mhra.gov.uk\/yellowcard. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@ bayer.co.uk <\/b>
          
          L.GB.11.2014.8880b; April 2015","wpcf-article_received_date":"2014-10-22T00:00:00","wpcf-article_accepted_date":"2014-11-14T00:00:00","wpcf-article_published_online":null,"wpcf-podcast":"","wpcf-ogg":"","wpcf-article_end_page":"","wpcf-article_start_page":"","wpcf-acknowledgements":" Editorial assistance was provided by James Gilbart at Touch Medical Media, London, UK.","wpcf-errata_pdf":"","wpcf-article_flipper_image":"http:\/\/touchophthalmology.com\/wp-content\/uploads\/sites\/16\/2016\/10\/Flipper-Files3_8.png","wpcf-corrected_online":null,"wpcf-supplementary_information":"","wpcf-article_highlight_pdf":"","data_availability":"","digital_features":""},"_links":{"self":[{"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/posts\/1119","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/users\/53489"}],"replies":[{"embeddable":true,"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/comments?post=1119"}],"version-history":[{"count":0,"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/posts\/1119\/revisions"}],"wp:attachment":[{"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/media?parent=1119"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/categories?post=1119"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/touchophthalmology.com\/wp-json\/wp\/v2\/tags?post=1119"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}</sub>