The Importance of Ocular, Systemic and Psychosocial Factors in the Management of the Diabetic Macular Oedema Patient with Antivascular Endothelial Growth Factor Therapy

European Ophthalmic Review, 2016;10(2):117–24 DOI: https://doi.org/10.17925/EOR.2016.10.02.117

Abstract:

A comprehensive list of patient features that influence the management of patients with diabetic macular oedema (DMO) is discussed. These features are grouped into three overarching themes: ocular, systemic and psychosocial. Consensus statements about the relative importance of these features, supported by the literature, were formed by a panel of retinal experts. The major drivers influencing the management of DMO with anti-vascular endothelial growth factor (anti-VEGF) therapy are undoubtedly ocular specific, in particular visual acuity and optical coherence tomography (OCT) central retinal thickness. Systemic factors, such as control of glycated haemoglobin (HbA1c), blood pressure and serum lipid estimations, have limited direct influence on DMO management although they remain important considerations to communicate to the primary diabetic physician. A greater understanding is required on how many other factors, in particular psychosocial factors, influence the care of the DMO patient.
Keywords: Diabetic macular oedema (DMO); management recommendations; anti-vascular endothelial growth factor; visual acuity; OCT
Disclosure: Richard Gale has worked as a consultant for Novartis and Bayer. Julie de Zaeytijd has participated in advisory boards and/or consultancy for Allergan, Bayer, Novartis and Abbott, and lectured for Novartis. João Figueira has participated in advisory boards of Bayer, Allergan, Novartis, Alcon and Alimera. Nicolas Leveziel has participated in advisory boards of Bayer, Allergan and Novartis. Jose M Ruiz-Moreno has participated in advisory boards of Bayer, Allergan and Novartis.
Acknowledgments: Medical writing assistance was provided by Catherine Amey and James Gilbart, Touch Medical Media UK, funded by Bayer.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Received: November 02, 2016 Accepted December 06, 2016
Correspondence: Richard Gale, York Teaching Hospital NHS Foundation Trust, York, YO31 8HE, UK. E: richard.gale@york.nhs.uk
Support: The publication of this article was supported by Bayer. The views and opinions expressed are those of the author and do not necessarily reflect those of Bayer.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.



Diabetic macular oedema (DMO) is one of the leading causes of visual impairment in working adults.1 The implications of blinding due to DMO, including the loss of productivity and reduced quality of life (QoL), lead to a considerable socioeconomic burden on communities.2–5 Intravitreal treatment options, particularly with anti-vascular endothelial growth factor (anti-VEGF) agents, have shown the potential to reduce visual loss far beyond that achieved with laser therapy alone.6–10 Applying principles learnt from key clinical trials to the real world setting requires an understanding of the many patient-related factors that determine when and how treatment is started and continued. It is important for clinicians to not only understand such factors but also the evidence base for such.

The aim of this article is to bring clarity to the available data on the key patient-related factors that influence the treatment of DMO, by reviewing the literature, forming consensus statements and providing recommendations. Discussions are based around the optimum scenario in an ideal world where certain barriers were removed, for example, costing, reimbursement and resource capacity. Due to the broad nature of this topic and because anti-VEGF therapy is the commonest intravitreal intervention for DMO, the scope of the discussion is largely limited to treatment with anti-VEGF therapy.

Methods
A panel of 15 retinal experts (see Table 1) met on 14–15 November 2014 in Zurich, Switzerland, where the need for clarity of the factors that influence DMO management was initially discussed. The panel met again on 10–11 April 2015 in Berlin, Germany, and on 6–7 November 2015 in Paris, France, to take the work forward. Based on a Delphi-style methodology,11 a range of factors in the management of a patient with DMO were identified and the evidence for, and relative importance of each, was discussed. A literature search complemented this process. PubMed/Medline and EMBASE searches from 1 January 2005 to 22 June 2016 were carried out using these factors as exploded mesh terms that occurred in the publication title (i.e., the term itself and a series of similar terms and subtopic terms within a particular category as used to classify each record by the database providers). Animal studies and non-English language papers were excluded. Owing to the paucity of material identified through the searches on occupation/profession, co-morbidities, compliance and family history, it was decided to broaden the searches to papers where the specified factor was not used as a major term. After removing duplicates, the search results were screened for relevance by a single retinal expert (Richard Gale). Recommendations were formed and agreed by the panel.

Results
Factors were categorised into three overarching themes: ocular-specific, systemic influences and psychosocial factors (see Tables 2 and 3). Database searching identified 547 records and a further 140 records were provided from expert opinion (687 in total). Removing duplicates left 665 results, of which 606 were excluded by expert screening. In total, therefore, 59 full text articles were accessed and relevant articles discussed.

Ocular-specific factors that influence the management of diabetic macular oedema with anti-vascular endothelial growth factor therapy
(Recommendation 1)

Many overlapping definitions of DMO are currently used, for example, clinically significant macular oedema (CSMO), centre involving vision affecting (CIVA) oedema and focal or diffuse oedema.12,13 Using the correct definition is central to aligning treatment with the key clinical trials.

In 1985, the Early Treatment Diabetic Retinopathy Study (ETDRS) group defined CSMO,12 based on clinical examination alone: presence of any retinal thickening at or within 500 μm of the foveal centre, lipid exudates at or within 500 μm of the foveal centre with adjacent thickening or an area of retinal thickening at one or more Macular Photocoagulation Study DA (1 disk area ≅ 1.767 mm2) within one disk diameter (1.5 mm) of the foveal centre. This definition remains useful in patients undergoing macular laser therapy; however, it is not the driver when anti-VEGF therapy is used. The inclusion criteria for the majority of the pivotal trials uses a form of ‘centre involving, vision affecting’ criteria to initiate treatment. Tables 4 and 5 demonstrate that inclusion criteria for the RISE /RIDE, Protocol I and T, DA VINCI and VISTA/VIVID studies required a combination of vision loss and documented retinal thickening.6,7,10,12,14,15 It is worth noting, however, the inclusion criteria for the RESTORE study did not require a specific CRT measurement but a clinical diagnosis of diffuse or focal thickening.9 Focal DMO was defined as more than 67% of leakage originated from leaking microaneurysms (MAs) in the whole
oedema area or 30–67% leakage from MAs in the whole oedema area, but >67% of the leakage originated from MAs in the central subfield.9 Diffuse DMO was defined as <33% of leakage from MAs, the rest from diffuse leaking capillaries in the whole oedema area or 30–67% leakage from MAs, but <33% of the leakage originated from MAs in the central subfield. This definition is somewhat convoluted and is not clinically important as a sub-analysis of the RESTORE data demonstrated neither group performed better than the other.9

Optical coherence tomography findings
(Recommendation 2)
Optical coherence tomography (OCT) is the most widely used tool to diagnose and manage DMO. The central 1 mm subfield is the most useful parameter in determining initiation and retreatment. Patients were recruited into the DRCR.net Protocol I who had DMO involving the fovea that, amongst other criteria, required a mean OCT central subfield thickness on OCT >250 μm on time-domain OCT.16 Inclusion for participation in DRCR.net Protocol T included: central subfield thickness on OCT ≥250 μm on Zeiss Stratus; ≥320 if male or ≥305 if female on Heidelberg Spectralis; ≥305 if male or ≥290 if female on Zeiss Cirrus and definite retinal thickening on clinical exam due to DMO involving the centre of the macula.6 In the RISE and RIDE trials, eligible participants required macular oedema with a central subfield thickness ≥275 μm on time-domain OCT.14 In the DA VINCI study, clinically significant DMO with centre involvement of the fovea was defined as a central subfield measurement of ≥250 μm on time-domain OCT.7 Central DMO involvement was defined as retinal thickening involving 1 mm central (OCT) subfield thickness (CST) in the VISTA and VIVID trials.15

Structural OCT does not provide dynamic information about macular perfusion. OCT angiography (OCT-A) is a developing technology and, as yet, its role in the routine assessment of the DMO patient is still to be fully defined OCT. Used in parallel with spectral domain (SD OCT), OCT-A presents the opportunity to learn more about the disease.17,18

References:
1. Klein R, Knudtson MD, Lee KE, et al., The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: the twentyfive- year incidence of macular edema in persons with type 1 diabetes, Ophthalmology, 2009;116:497–503.
2. Brook RA, Kleinman NL, Patel S, et al., United States comparative costs and absenteeism of diabetic ophthalmic conditions, Postgrad Me, 2015;127:455–62.
3. Chen E, Looman M, Laouri M, et al., Burden of illness of diabetic macular edema: literature review, Curr Med Res Opin, 2010;26:1587–97.
4. Gonder JR, Walker VM, Barbeau M, et al., Costs and Quality of Life in Diabetic Macular Edema: Canadian Burden of Diabetic Macular Edema Observational Study (C-REALITY), J Ophthalmol, 2014;2014:939315.
5. Minassian DC, Owens DR, Reidy A, Prevalence of diabetic macular oedema and related health and social care resource use in England, Br J Ophthalmol, 2012;96:345–9.
6. van’t Veer LJ, Dai H, van de Vijver MJ, et al., Gene expression profiling predicts clinical outcome of breast cancer, Nature, 2002;415:530–6.
7. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al., The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema, Ophthalmology, 2011;118:1819–26.
8. Elman MJ, Qin H, Aiello LP, et al., Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results, Ophthalmology, 2012;119:2312–8.
9. Mitchell P, Bandello F, Schmidt-Erfurth U, et al., The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema, Ophthalmology, 2011;118:615–25.
10. Wells JA, Glassman AR, Ayala AR, et al., Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema, New Engl J Med, 2015;372:1193–203.
11. Brown BB, Delphi Process: A Methodology Used for the Elicitation of Opinions of Experts 1968. Available at: https:// www.rand.org/content/dam/rand/pubs/papers/2006/P3925.pdf (accessed 12 December 2016).
12. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group, Arch Ophthalmol, 1985;103:1796–806.
13. Bandello F, Midena E, Menchini U, Lanzetta P, Recommendations for the appropriate management of diabetic macular edema: Light on DME survey and consensus document by an expert panel, Eur J Ophthalmol, 2016;26:252–61.
14. Nguyen QD, Brown DM, Marcus DM, et al., Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE, Ophthalmology, 2012;119:789–801.
15. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al., Intravitreal aflibercept for diabetic macular edema, Ophthalmology, 2014;121:2247–54.
16. Elman MJ, Aiello LP, Beck RW, et al., Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema, Ophthalmology, 2010;117:1064–77.e35.
17. Coscas GJ, Lupidi M, Coscas F, et al., Optical coherence tomography angiography versus traditional multimodal imaging in assessing the activity of exudative age-related macular degeneration: A new diagnostic challenge, Retina, 2015;35:2219–28.
18. Jia Y, Bailey ST, Hwang TS, et al., Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye,Proc Natl Acad Sci U S A, 2015;112:E2395–402.
19. Do DV, Nguyen QD, Boyer D, et al., One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema, Ophthalmology, 2012;119:1658–65.
20. Bansal AS, Khurana RN, Wieland MR, et al., Influence of glycosylated hemoglobin on the efficacy of ranibizumab for diabetic macular edema: A post hoc analysis of the RIDE/RISE trials, Ophthalmology, 2015;122:1573–9.
21. Matsuda S, Tam T, Singh RP, et al., The impact of metabolic parameters on clinical response to VEGF inhibitors for diabetic macular edema, J Diabetes Complications, 2014;28:166–70.
22. Anon. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial, Diabetes, 1995;44:968–83.
23. Anon. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group, Lancet, 1998;352:837–53.
24. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group, N Engl J Med, 1993;329:977–86.
25. National Institute for Health and Care Excellence (NICE) guidelines [ng28] Type 2 diabetes in adults: management. Blood glucose and target levels 2015. Available at: https://www.nice. org.uk/guidance/ng28/ifp/chapter/blood-glucose-and-targetlevel (accessed 7 December 2016).
26. National Institute for Health and Care Excellence (NICE) guidelines [NG17] Type 1 diabetes in adults: diagnosis and management. Reccommendations 2015. Available at: www.nice.org.uk/guidance/ng17/chapter/1-recommendations (accessed 7 December 2016).
27. Klaassen I, Van Noorden CJ, Schlingemann RO, Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions, Prog Retin Eye Res, 2013;34:19–48.
28. Matthews DR, Stratton IM, Aldington SJ, et al., Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69, Arch Ophthalmol, 2004;122:1631–40.
29. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group, BMJ, 1998;317:703–13.
30. Gallego PH, Craig ME, Hing S, Donaghue KC, Role of blood pressure in development of early retinopathy in adolescents with type 1 diabetes: prospective cohort study, BMJ, 2008;337:a918.
31. Lyons TJ, Jenkins AJ, Zheng D, et al., Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort, Investigative Ophthalmology & Visual Science, 2004;45:910–8.
32. Lopes-Virella MF, Baker NL, Hunt KJ, et al., High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes, Diabetes Care, 2012;35:1333BP40.
33. Tapp RJ, Shaw JE, Harper CA, et al., The prevalence of and factors associated with diabetic retinopathy in the Australian population, Diabetes Care, 2003;26:1731BP7.
34. Wong TY, Klein R, Islam FM, et al., Diabetic retinopathy in a multi-ethnic cohort in the United States, Am J Ophthalmol, 2006;141:446BP55.
35. Cetin EN, Bulgu Y, Ozdemir S, et al., Association of serum lipid levels with diabetic retinopathy, Int J Ophthalmol, 2013;6:346BP9.
36. Chew EY, Klein ML, Ferris FL, 3rd, et al., Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22, Arch Ophthalmol, 1996;114:1079BP84.
37. Chew EY, Davis MD, Danis RP, et al., The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study, Ophthalmology, 2014;121:2443BP51.
38. Keech AC, Mitchell P, Summanen PA, et al., Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial, Lancet, 2007;370:1687BP97.
39. Das R, Kerr R, Chakravarthy U, Hogg RE, Dyslipidemia and diabetic macular edema: A systematic review and metaanalysis, Ophthalmology, 2015;122:1820BP7.
40. Landfeldt E, Lindgren P, Bell CF, et al., The burden of Duchenne muscular dystrophy: An international, cross-sectional study, Neurology, 2014;83:529-36.
41. Mendell JR, Shilling C, Leslie ND, et al., Evidence-based path to newborn screening for Duchenne muscular dystrophy, Ann Neurol, 2012;71:304BP13.
42. Ryan EH, Jr., Han DP, Ramsay RC, et al., Diabetic macular edema associated with glitazone use, Retina, 2006;26:562BP70.
43. Kaštelan S, Tomic M, Gverovic Antunica A, et al., Body mass index: a risk factor for retinopathy in type 2 diabetic patients, Mediators Inflamm, 2013;2013:436329.
44. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group, Lancet, 1998;352:854BP65.
45. Dirani M, Xie J, Fenwick E, et al., Are obesity and anthropometry risk factors for diabetic retinopathy? The diabetes management project, Investigative Ophthalmology & Visual Science, 2011;52:4416BP21.
46. Li X, Wang Z, Prevalence and incidence of retinopathy in elderly diabetic patients receiving early diagnosis and treatment, Exp Ther Med, 2013;5:1393BP6.
47. Klein R, Klein BE, Moss SE, Visual impairment in diabetes, Ophthalmology, 1984;91:1BP9.
48. Klein R, Klein BE, Moss SE, Is obesity related to microvascular and macrovascular complications in diabetes? The Wisconsin Epidemiologic Study of Diabetic Retinopathy, Arch Int Med, 1997;157:650BP6.
49. Obesity: identification, assessment and management BP NICE guidelines [cg189]. 2014.
50. Reduce your diabetes risk. 2015.
51. Polizzi S, Mahajan VB, Intravitreal anti-VEGF injections in pregnancy: Case series and review of literature, J Ocul Pharmacol Ther, 2015;31:605BP10.
52. Polizzi S, Ferrara G, Restaino S, et al., Inadvertent use of bevacizumab in pregnant women with diabetes mellitus type 1, J Basic Clin Physiol Pharmacol, 2015;26:161BP3.
53. Sullivan L, Kelly SP, Glenn A, et al., Intravitreal bevacizumab injection in unrecognised early pregnancy, Eye, 2014;28:492BP4.
54. Wu Z, Huang J, Sadda S, Inadvertent use of bevacizumab to treat choroidal neovascularisation during pregnancy: a case report, Ann Acad Med Singapore, 2010;39:143BP5.
55. Elman MJ, Ayala A, Bressler NM, et al., Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt versus Deferred Laser Treatment: 5BPYear Randomized Trial Results, Ophthalmology, 2015;122:375BP81.
56. The economic impact of diabetic macular oedema in Australia. 2015.
57. Lee LJ, Yu AP, Cahill KE, et al., Direct and indirect costs among employees with diabetic retinopathy in the United States, Curr Med Res Opin, 2008;24:1549BP59.
58. MojonB, Pazzi SM, Sousa-Poza A, Mojon DS, Impact of low vision on employment, Ophthalmologica, 2010;224:381BP8.
59. Fenwick E, Rees G, Pesudovs K, et al., Social and emotional impact of diabetic retinopathy: a review, Clin Exp Ophthalmol, 2012;40:27BP38.
60. Bressler SB, Glassman AR, Almukhtar T, et al., Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema, Am J Ophthalmol, 2016;164:57–68.
Keywords: Diabetic macular oedema (DMO); management recommendations; anti-vascular endothelial growth factor; visual acuity; OCT