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Review New technologies and drugs in the management of diabetic retinopathy Hamish MA Towler Abstract MD, FRCPEd, FRCSEd, FRCOphth, Consultant Ophthalmologist, NELEEA Ltd, Spire Roding Hospital, Ilford, UK Diabetic retinopathy remains one of the most common and most feared causes of blindness and visual impairment in adults of working age despite the availability of effective treatment for more than 30 years. Sight-threatening diabetic retinopathy consists of two distinct clinical entities: proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DMO or maculopathy) which may coexist, both of which can be detected by clinical or photographic screening before vision is affected, thereby allowing treatment to be offered before visual impairment has developed. Laser photocoagulation has been the mainstay of treatment of PDR and DMO since landmark studies in the 1980s proved its effectiveness. The more recent elucidation of the role of vascular endothelial growth factor (VEGF) in the pathogenesis of both types of diabetic retinopathy, and the ability to specifically inhibit VEGF effects by the intraocular injection of blocking agents offer new options of non-destructive treatment with better visual outcomes than laser. Diabetic macular oedema may also respond to intraocular steroid therapy, and the development of slow-release delivery systems can now provide drug delivery for three years from a single injection. The assessment of DMO has been revolutionised by non-invasive imaging with ocular coherence tomography (OCT) which allows microscopic visualisation of macular detail and serial quantitative measurement of the structural response to treatment. These new therapeutic options are improving visual outcomes for DMO, but are also creating enormous logistical problems for both patients and eye clinics as they are much more demanding in terms of frequent clinic visits and use of ophthalmology imaging services than conventional but less effective laser treatment. Copyright © 2014 John Wiley & Sons. Practical Diabetes 2014; 31(7): 275–280 Correspondence to: Hamish MA Towler, MD, FRCPEd, FRCSEd, FRCOphth, Consultant Ophthalmologist, NELEEA Ltd, Spire Roding Hospital, Roding Lane South, Ilford IG4 5PZ, UK; email: [email protected] Received: 2 May 2014 Accepted in revised form: 12 June 2014 Key words anti-VEGF; intravitreal fluocinolone; ocular coherence tomography; diabetic maculopathy Introduction Diabetic retinopathy (DR) is a chronic progressive and potentially sight-threatening disease of the retinal microcirculation associated with prolonged hyperglycaemia resulting from diabetes mellitus, which may be aggravated by other associated conditions such as hypertension and hyperlipidaemia. This retinal microvascular damage manifests in two non-exclusive ways: breakdown of the blood-retina barrier resulting in retinal oedema, and capillary occlusion which leads to retinal ischaemia, hypoxia, and subsequent neovascularisation. The concept of a growth factor released by hypoxic retina was first postulated by Michaelson in 19481 and eventually characterised as a family of vascular endothelial growth factors (VEGF) in the 1990s.2 VEGF plays a crucial role in DR by stimulating the growth of new blood vessels but also increases vascular permeability, resulting in retinal oedema which is highly detrimental to visual PRACTICAL DIABETES VOL. 31 NO. 7 function when the macula and fovea are affected. The recognition of the importance of VEGF in both proliferative retinopathy and macular oedema has led to treatment with intravitreal injection of agents which block the effects of VEGF. Anti-VEGF therapy was first applied in the eye for the treatment of neovascular (or ‘wet’) age-related macular degeneration (AMD) where the clinical impact has been almost miraculous,3,4 and current options include ranibizumab, bevacizumab and, more recently, aflibercept. The experience with anti-VEGF therapy for AMD has confirmed the safety and effectiveness of repeated intravitreal injections, with low rates of endophthalmitis (less than 1:1000 injections), with no significant risk of inducing cataract or increasing intraocular pressure, but the need for regular and continuing treatment has created enormous logistical problems in treatment delivery. Diabetic retinopathy is classified according to its clinical features as either proliferative (PDR) or COPYRIGHT © 2014 JOHN WILEY & SONS 275 Review New technologies and drugs in the management of diabetic retinopathy non-proliferative (NPDR).5,6 NPDR in the presence of a healthy macula and normal visual acuity is commonly called background diabetic retinopathy (BDR). Macular involvement is classified separately and with greater difficulty since the clinical features may be much less apparent than expected for the degree of visual loss. The detailed photographic grading systems which underpinned the landmark clinical trials proving the effectiveness of laser photocoagulation (such as the DRS and ETDRS)6–8 have evolved into simpler classifications9–13 used in population screening to identify eyes at risk from DR which require further ophthalmic assessment and possible treatment. No single standardised international grading system for DR screening has been universally adopted and, even within the UK, there are variations in the screening methodology, terminology, grading levels, and referral criteria used in the English, Northern Ireland, Scottish and Welsh grading systems.10–13 Although all the UK screening systems specify the use of non-mydriatic digital cameras, pupil dilation practice varies between regions. Pupil dilation is, however, mandatory for the assessment and treatment of DR in eye clinics. Ocular coherence tomography Ocular coherence tomography (OCT) utilises non-invasive laser interferometry to provide high resolution cross-sectional or topographic images of the retina in microscopic detail. This allows serial, quantitative analysis of retinal structural changes and has transformed the understanding and management of macular diseases in general and the vitreoretinal interface. The third generation of Figure 1a. Focal leakage near fovea, visual acuity (VA) 6/6 276 PRACTICAL DIABETES VOL. 31 NO. 7 OCT scanners and software provide faster image acquisition, wider field of view, better imaging of the choroid, and visualisation of the retinal capillaries without the need for intravenous dye injection.14 Fundus fluorescein angiography (FFA) remains a very valuable investigational tool for retinal vascular disease as it can reveal neovascularisation and retinal capillary occlusion as well as leakage, but it does not provide the same exquisite structural detail and quantitative analysis as OCT. FFA is more labour intensive and requires an intravenous injection of fluorescein, the administration of which carries some associated morbidity. Foveal thickness can now be measured with such unparalleled precision that it is likely that OCT will be utilised in screening for diabetic macular oedema (DMO) as an adjunct to digital retinal photography. Central foveal thickness (FTH) as measured by OCT is now routinely used to determine when to undertake further treatment. Wide field retinal imaging Advances in digital retinal imaging using wide field scanning laser ophthalmoscopes provides a much more extensive view of the retina with sensitivity and specificity similar to standard screening employing central one or two field protocols,15 but with a higher technical failure rate of around 11% compared with around 6% for standard imaging. This is too high for routine community screening but the ability to undertake wide field fluorescein angiography may be helpful in predicting and managing retinal ischaemia and neovascularisation.16 Wide field imaging can be undertaken through a normal undilated pupil. Figure 1b. Normal ocular coherence tomography (OCT) with no retinal oedema Prevention of diabetic retinopathy DR develops approximately 5–10 years after the onset of diabetes and potentially can be prevented or retarded in type 1 diabetes by ensuring tight diabetes control.17–21 The insidious development of type 2 diabetes often results in DR being detectable at diagnosis, and in this group good blood pressure control appears to be more effective than tightening diabetes control in retarding progression of DR.20,21 Good early glycaemic control also appears to have long-term legacy benefits even where subsequent control is less stringent. Improving diabetes control, blood pressure, and hyperlipidaemia may result in the regression or amelioration of DR without the need for specific ophthalmic treatment (Figure 1). Rapid tightening of diabetes control may paradoxically result in an initial worsening of retinopathy features,22,23 thus necessitating close ophthalmic surveillance, although ultimately the long-term visual prognosis is improved in these patients. Pioglitazone has been associated with an increased risk of DMO and this should be avoided or used with caution in patients with more severe background changes,24 who should have OCT undertaken to identify early macular thickening and oedema which may not be clinically evident. Laser developments Panretinal laser photocoagulation (PRP) remains the standard first-line treatment for PDR. Gas lasers (argon green and krypton red/yellow) have largely been superseded by solid state diode lasers including 810nm infrared, 577nm yellow, and 647nm Figure 1c. Resolution of lipid exudates one year later COPYRIGHT © 2014 JOHN WILEY & SONS Review New technologies and drugs in the management of diabetic retinopathy red, as well as 532nm green frequency doubled Nd:YAG lasers. Modern lasers can be programmed to deliver multiple spots in variable patterns with shorter pulse duration (20ms rather than the conventional 100ms) which produces less ocular discomfort for the patient and more rapid and even laser application.25 Consideration of the laser spot diameter is very important in planning the total amount of treatment applied, as smaller spots may result in significant under-treatment and failure to control neovascularisation. 1200 x 500mm diameter spots will treat an area of retina of 236mm2 (area treated = 1200 x ¼π x 0.52) and this is often sufficient to induce new vessel regression in mild to moderate PDR, whereas use of a 400mm spot would require 1875 applications to treat the same area of retina. Reducing the pulse duration from 100ms single spot delivery to 20ms multi-spot pattern delivery also requires a commensurate increase in power or area treated to ensure adequate clinical treatment. PRP treatment is continued until new vessel regression is achieved. Macular laser treatment has also benefited from modulation of the laser pulse duration of the diode laser to multiple short bursts of 100ms (compared with a conventional 100ms burst) which reduces collateral damage to the retina. This ‘micropulse’ delivery26 is as effective as conventional macular laser but produces no clinically visible scarring or retinal pigment epithelial disturbance and minimises the risk of inadvertent foveal burns which can have a devastating impact on visual acuity. Although macular laser treatment is effective at stabilising visual acuity, it is less successful in improving visual acuity which has already deteriorated. Intravitreal drug therapy of macular oedema is better than laser in improving visual acuity, but adjuvant macular laser may still have a role in providing long-term stability with reduced need for repeated intravitreal injections. The DRCR.net study27 has shown no additional visual benefit of immediate laser compared with deferred laser over three years’ ranibizumab treatment although the laser treated group had three fewer injections (median 11 vs 14 injections). PRACTICAL DIABETES VOL. 31 NO. 7 Intravitreal drug delivery Drug delivery into the eye by direct intravitreal drug injection was for many years considered an act of desperation. This dramatically changed during the HIV/AIDS era when the treatment of cytomegalovirus retinitis (CMVR) with intravitreal ganciclovir28 showed the route to be remarkably effective, safe, and repeatable. The need for regular injections to maintain control of CMVR led to the development of a sustained-release intravitreal device29 (Vitrasert®) which delivered adequate therapeutic drug levels for about 30 weeks, and which could then be replaced if necessary. The need for continuous intravitreal therapy for CMVR has since diminished with improvements in systemic HIV treatment and restoration of immune competence, but the safety and effectiveness of sustained release intravitreal drug delivery had been established. Ozurdex® is a polylactic-co-glycolic acid biodegradable polymer injected through a 22G applicator needle which releases dexamethasone for about four to six months. It has been shown to be effective in treating macular oedema secondary to retinal vein occlusion40 and uveitis, and more recently DMO.41 Iluvien® is a non-erodible intravitreal device releasing 0.2mg fluocinolone acetonide daily for about 36 months,42,43 which is injected into the vitreous cavity through a 25G applicator. It has recently been approved in England for the treatment of refractory DMO by NICE44 but only for use in eyes which have already undergone cataract surgery because cataract is an otherwise inevitable consequence. Like other intravitreal steroids, raised intraocular pressure may occur and nearly 5% of Iluvien treated eyes may need glaucoma surgery over three years.43 Intravitreal steroids for diabetic macular oedema The safety of intravitreal injection of the crystalline long-acting steroid triamcinolone acetonide was recognised in the early 1980s,30 but it was nearly 15 years before clinical studies of its use for macular disease were reported. Intravitreal triamcinolone acetonide (IVTA) use was first investigated in neovascular age-related macular degeneration31 where it showed modest benefits before being eclipsed by anti-VEGF therapy. IVTA was then shown to be very effective in the treatment of cystoid macular oedema due to intraocular inflammation (uveitis),32,33 and application of IVTA to diabetic macular oedema quickly followed.34,35 Anecdotal case reports, uncontrolled retrospective studies and the DRCR.net have subsequently shown modest benefits but also confirmed the significant complications of raised intraocular pressure and cataract.36–38 A sustained release fluocinolone device (Retisert®) which delivers clinically effective drug levels for approximately three years has been successfully used in uveitis,39 but like the Vitrasert requires surgical placement thereby engendering higher risks of vitreous haemorrhage and retinal detachment than a single pass injection through the pars plana. Intravitreal anti-VEGF therapy for DMO and PDR Pegaptanib was the first intravitreal anti-VEGF agent to be shown to be effective for DMO,45 and was quickly followed and replaced by bevacizumab,46 ranibizumab,47 and aflibercept48 as they became available and proved to be more clinically effective. Only ranibizumab and aflibercept have been licensed for intraocular injection, but bevacizumab has been used extensively throughout the world ‘off-label’ and shown to be as clinically effective as ranibizumab49 and significantly cheaper.50–52 Repeated treatment with these agents is necessary because of the shorter duration of action than intravitreal steroids, but long-term visual results are better than for laser treatment alone or combined with anti-VEGF therapy,53,54 and without the risks of raised intraocular pressure or cataract associated with steroids. The number of treatments reduces over time, the DRCR.net reporting nine, three, and two injections in the first, second, and third years respectively in patients allocated to deferred laser treatment.50 There are no published studies to date of ‘head to head’ randomised clinical trials of Ozurdex® or Iluvien with intravitreal anti-VEGF therapy, although Ozurdex/Lucentis® and COPYRIGHT © 2014 JOHN WILEY & SONS 277 Review New technologies and drugs in the management of diabetic retinopathy Ozurdex/Avastin® trials55,56 are in progress. These trials will be essential to determine the most appropriate treatment for DMO, in terms of visual recovery, complications, overall cost, and acceptability to patients. Revascularisation of the retina: intravitreal activated protein C Retinal neovascularisation which results from retinal ischaemia can currently be successfully treated by laser photocoagulation, but this is a destructive process which may compromise peripheral vision. The intriguing possibility of stimulating retinal revascularisation using intravitreal activated protein C has been recently reported in two cases of central retinal vein occlusion but further evaluation is clearly required.57 Drug licensing, treatment options, and personalised health budgets The modern era of intravitreally injected drug therapy has been plagued by the dilemma of the availability of drugs licensed to be used in this way. Ranibizumab is licensed for intravitreal administration whereas bevacizumab, a much cheaper but almost equally effective alternative,48 is not. In the UK, doctors are obliged by the GMC to use licensed drugs where available and not to choose a drug primarily because of its lower cost. As a result, the cumulative drug cost of these new and effective therapies threatens to burgeon out of control. Intravitreal therapy is more effective in treating DMO than laser with better visual outcomes, so who should determine which treatment option is selected? From October 2014, anyone receiving NHS continuing health care in England will have a right to have a personal health budget, and potentially the choice of therapy. to regression of sight-threatening retinopathy without the necessity for specific eye treatment. Engaging patients with OCT images of their retinal changes and subsequent progress has, in the author’s experience, been very helpful in encouraging patients to address control issues without the need for hectoring. It is essential that patients appreciate that their longterm contribution to the control of their diabetes and contributory risk factors is as important as any treatment which their ophthalmologist can provide. Focal DMO in eyes with good visual acuity and no foveal thickening on OCT should be treated with focal laser photocoagulation which is effective, safe, economical, and with good long-term results particularly where improved diabetes control is achieved. Diffuse macular oedema associated with reduced visual acuity ideally requires intravitreal therapy, which may be augmented by macular grid laser to reduce the need for additional drug injections. Intravitreal anti-VEGF therapy appears to be slightly more clinically effective in improving visual acuity than intravitreal steroids, without the complications of cataract or raised intraocular Optimising the management of PDR and macular oedema Panretinal laser photocoagulation remains the cornerstone of management of proliferative diabetic retinopathy, and the innovations in laser delivery described earlier have made this a little more comfortable for patients although doubling the cost of the hardware. Treatment of DMO requires a more selective and individualised patient approach, which has been greatly assisted by OCT retinal imaging. All patients need to be reminded of the importance of good diabetes, blood pressure and lipid control, implementation of which may lead Generic name (proprietary name) Mechanism of action Ranibizumab (Lucentis) Blocks VEGF-A Yes Yes Yes 4 £742.17 230µl 3 £247.39 66% £10 390.38 (£3463.46) Bevacizumab (Avastin) Blocks VEGF-A No Yes Yes 4 £242.66 4ml 40 £6.07 50% £3397.24 (£84.98) Aflibercept (Eylea) Blocks VEGF-A Yes and VEGF-B Yes Yes 6–8 £816.00 250µl 4 £204.00 75% £11 424.00 (£2856.00) Triamcinolone (Kenalog) Steroid No Yes No 16–18 £1.49 1ml 1 £1.49 90% £13.41 Dexamethasone Steroid (Ozurdex) Yes Yes No 16–18 £870.00 solid 1 £870.00 0% £7830.00 Fluocinolone (Iluvien) Yes Yes No 150 £5500.00 solid 1 £5500.00 0% £5500.00 Steroid Licensed Effective Effective Duration BNF cost/ Potential Potential Dose Three-year for IVT? for DMO? for PDR? of effect volume doses minimum wasted drug cost* (weeks) unit cost *Based on 14 anti-VEGF injections from DCRC.net or 9 triamcinolone or Ozurdex injections, with potential minimal drug cost shown in parentheses. IVT = intravitreal therapy; DMO = diabetic macular oedema; PDR = proliferative diabetic retinopathy; BNF = British National Formulary; VEGF = vascular endothelial growth factors. Table 1. Intravitreal drugs for treating diabetic retinopathy in the UK 278 PRACTICAL DIABETES VOL. 31 NO. 7 COPYRIGHT © 2014 JOHN WILEY & SONS Review New technologies and drugs in the management of diabetic retinopathy pressure, but requiring more frequent injections over a period of years. Anti-VEGF therapy has the additional benefit of inhibiting retinal and iris neovascularisation. The longer duration of effect of intravitreal steroids is, however, more attractive to patients. The higher affinity of aflibercept to VEGF extends its therapeutic effect, and the da Vinci trial48 showed that, after the first three onemonthly injections, reducing the injection frequency to every two months was as clinically effective as monthly treatment, requiring seven injections over the year compared with 11 monthly injections. In comparison, nine ranibizumab injections were utilised in the first year of the DRCR.net study27 which would appear to make aflibercept the more cost effective although price discounting through confidential NHS patient access schemes makes direct price comparisons unreliable. Utilising BNF prices, the drug cost of aflibercept is nearly £1000 cheaper over one year when used in this way, with further significant savings accruing from fewer clinic attendances and investigations. The specific choice of intravitreal agent should be determined primarily by clinical effectiveness, notwithstanding licensing issues. Although trials in neovascular AMD have shown that bevacizumab is not inferior to ranibizumab in clinical effectiveness,49 there may be individual patients who respond to one agent better than another, so it is important that clinicians can switch to an alternative agent without delays imposed by cost considerations alone. As in AMD treatment, the drug costs of treating DMO are beginning to escalate and clinicians are not immune to the impact of this on overall health budgets. There is considerable wastage in the administration of ranibizumab and aflibercept, whose unit costs could be significantly reduced (Table 1) if aliquotted under appropriate aseptic conditions as employed for bevacizumab. Adoption of bevacizumab as a firstline anti-VEGF agent would have an even greater impact in reducing costs, although this has the potential to lead to legal challenge by the pharmaceutical industry as a consequence PRACTICAL DIABETES VOL. 31 NO. 7 Right eye Figure 2a. Macula before treatment, VA 6/36 Left eye Figure 2b. Macula before treatment, VA 6/30 Figure 2d. OCT after third ranibizumab treatment Figure 2c. OCT topographic map before treatment Figure 2f. OCT after first intravitreal (IVT) triamcinolone Figure 2e. Macula OCT before treatment Figure 2g. OCT after third IVT ranibizumab Figure 2i. OCT after IVT triamcinolone, VA 6/30 Figure 2h. Fluocinolone implant in situ Figure 2j. OCT after IVT fluocinolone, VA 6/19 COPYRIGHT © 2014 JOHN WILEY & SONS 279 Review New technologies and drugs in the management of diabetic retinopathy of current drug licensing advice by the GMC. Illustrative cases Case 1. (Figure 2.) A 62-year-old woman with type 2 diabetes of 13 years duration presented to her optometrist with reduced visual acuity of 6/30 in both eyes. Significant diabetic retinopathy was detected and she was immediately referred for further management. Retinal examination and photography showed microvascular changes with dot haemorrhages and microaneurysms at both maculae but very little lipid exudate (Figure). Slit lamp biomicroscopy showed macular oedema, confirmed by OCT scan with central macular thickness of >400mm (Figure). An incidental finding of shallow anterior chambers with narrow drainage angles but normal intraocular pressures was also made. In view of the extensive and diffuse bilateral macular oedema, poor visual acuity, and concerns about glaucoma, intravitreal therapy with ranibizumab was undertaken, with three injections at monthly intervals to both eyes resulting in improvement in the clinical features of retinopathy, a 50% reduction in macular thickness but deterioration in visual acuity to 6/48 right eye and no improvement in the left acuity. Treatment was then switched to intravitreal triamcinolone in the right eye, with further reduction in macular thickness and improvement in acuity of two lines to 6/30. In view of the better clinical response to intravitreal steroid than ranibizumab, intravitreal fluocinolone (Iluvien) injection was subsequently undertaken in the left eye, with visual acuity improving to 6/19 three months after injection. Right intravitreal fluocinolone injection is planned when the triamcinolone effect has dissipated. Lesson: a poor or modest response to one intravitreal agent does not preclude a good response to an alternative even if the clinical situation appears hopeless – ‘try, try, try again!’ Case 2. (Figure 3.) A 64-year-old man presented with a non-ischaemic left central retinal vein occlusion and macular oedema reducing visual 280 PRACTICAL DIABETES VOL. 31 NO. 7 Right eye Left eye Figure 3a. Right macula after laser, VA 6/15 Figure 3b. Left macula after laser, VA 6/30 Figure 3c. Right macula OCT after laser, VA 6/15 Figure 3d. Left macula OCT after laser, VA 6/30 Figure 3e. Right OCT after IVT fluocinolone, VA 6/19 Figure 3f. Left OCT after IVT triamcinolone, VA 6/15 acuity to 6/19. The right eye was normal with visual acuity of 6/9. Risk factor investigations revealed hypertension and type 2 diabetes, control of the latter proving less than ideal. The left macular oedema was treated successfully with intravitreal antiVEGF (bevacizumab or ranibizumab) therapy over the next two years, during which he was observed to develop non-proliferative diabetic retinopathy followed by diabetic macular oedema in the right eye, the latter also treated successfully with intravitreal ranibizumab. Laser photocoagulation was undertaken after two years to reduce the frequency of intravitreal injections. Visually significant cataracts developed in both eyes, which were treated successfully by phacoemulsification and intraocular lens implants combined with intravitreal triamcinolone to prevent recurrence of macular oedema. The macular oedema in both eyes resolved completely one month after the intravitreal triamcinolone injections, so when the oedema recurred intravitreal fluocinolone implants were administered to both eyes. No oedema has recurred yet in the right eye but has reappeared in the left eye one month after the fluocinolone implant injection, which may reflect the additional vascular damage from the original vein occlusion. Lesson: poor diabetes control can confound the best attempts to arrest the progression of the ocular complications of diabetes despite innovations in therapy. Declaration of interests There are no conflicts of interest declared. References References are available online at www.practicaldiabetes.com. COPYRIGHT © 2014 JOHN WILEY & SONS Review New technologies and drugs in the management of diabetic retinopathy References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Michaelson IC. 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