Cost Effectiveness of Treatments for Diabetic Retinopathy: A Systematic Literature Review

  • Nikolaos Maniadakis
  • Evgenia KonstantakopoulouEmail author
Systematic Review



Diabetic retinopathy (DR) affects approximately one-third of people diagnosed with diabetes, can be sight-threatening, and generates significant human and economic burden. Over the last 2 decades, newer therapies have emerged, offering significant clinical benefits, however at a cost. Given the scarcity of available budgets, the cost effectiveness of these newer treatments is of vital importance to policy makers.


A systematic review was conducted in the PubMed, EMBASE, Cochrane, HEED and CRD databases to find and evaluate economic evaluations assessing the cost effectiveness of alterative DR treatments. Studies were assessed for their eligibility, findings and quality, and are presented in this systematic review.


Of the 5254 studies retrieved from the literature search, 17 were included in this review. For patients with proliferative DR, when early pars plana vitrectomy was compared with pan-retinal laser photocoagulation, similar cost per quality-adjusted life-year (QALY) was observed between the two. Treatment with either intravitreal ranibizumab (IVR) or intravitreal bevacizumab (IVB) falls within acceptable cost-effectiveness thresholds in the diabetic macular oedema (DMO) population; however, in the non-DMO population, the marginal benefit of IVR or IVB in relation to the marginal cost relative to laser does not justify their use. Among the anti-vascular endothelial growth factor (VEGF) therapies, IVB appears more attractive from an economic point of view due to its lower cost. For patients with DMO, studies indicate that a combination therapy of IVR or IVB with laser and, to a lesser degree, as monotherapy, are cost effective relative to laser monotherapy; IVR plus laser is cost effective relative to laser plus triamcinolone; and laser combined with triamcinolone injections is reportedly more cost effective over IVR for pseudophakic eyes only. Moreover, fluocinolone implants appear cost effective compared with sham implants, or when treating refractory DMO. IVR administered either pro re nata (PRN) or as ‘treat and extend’ dominated intravitreal aflibercept (IVA) in a few studies. On the other hand, IVR monotherapy or with laser (as well as IVA) does not compare favourably relative to IVB monotherapy or with laser.


Interpretation of cost-effectiveness data should be treated with caution in this case; details of the therapeutic regimen, such as dosage and frequency, and clinical efficacy of the treatments should be considered in relation to policy-making decisions. Given the scarcity of resources, the ever-increasing significance of health technology assessment, and the substantial differences in the methodologies of the studies presented in this review, there is a pressing need for more advanced and standardised approaches to assessing the effectiveness and cost effectiveness of the emerging anti-VEGF pharmacotherapies for the treatment of DMO.



The authors are grateful to Mr. Alexander Charonis, MD, for his valuable advice while preparing this manuscript.

Author Contributions

EK conducted the literature search and data assembly and collection, and wrote the first draft. NM reviewed and supervised all activities related to this systematic review. Both authors contributed materially to the research and manuscript preparation.


No funding was received for the preparation of this article.

Compliance with ethical standards

Conflict of interest

Professor Maniadakis and Dr Konstantakopoulou have no conflicts of interest directly relevant to the content of this article.

Supplementary material

40273_2019_800_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 kb)
40273_2019_800_MOESM2_ESM.docx (20 kb)
Supplementary material 2 (DOCX 19 kb)


  1. 1.
    Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556–64.CrossRefGoogle Scholar
  2. 2.
    Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124–36.CrossRefGoogle Scholar
  3. 3.
    Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17.CrossRefGoogle Scholar
  4. 4.
    Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin epidemiologic study of diabetic retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology. 2008;115(11):1859–68.CrossRefGoogle Scholar
  5. 5.
    Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 Suppl):766–85.Google Scholar
  6. 6.
    Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS report number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology. 1981;88(7):583–600.Google Scholar
  7. 7.
    Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122(10):2044–52.CrossRefGoogle Scholar
  8. 8.
    Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. A prospective randomised trial of IVB or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010;117(6):1078–86.CrossRefGoogle Scholar
  9. 9.
    Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615–25.CrossRefGoogle Scholar
  10. 10.
    Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, et al. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) study. Ophthalmology. 2009;116(11):2175–81.CrossRefGoogle Scholar
  11. 11.
    Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609–14.CrossRefGoogle Scholar
  12. 12.
    Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014;121(5):1045–53.CrossRefGoogle Scholar
  13. 13.
    Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8):972–9.CrossRefGoogle Scholar
  14. 14.
    Regnier S, Malcolm W, Allen F, Wright J, Bezlyak V. Efficacy of anti-VEGF and laser photocoagulation in the treatment of visual impairment due to diabetic macular edema: a systematic review and network meta-analysis. PloS One. 2014;9(7):e102309.CrossRefGoogle Scholar
  15. 15.
    Shea AM, Curtis LH, Hammill BG, Kowalski JW, Ravelo A, Lee PP, et al. Resource use and costs associated with diabetic macular edema in elderly persons. Arch Ophthalmol. 2008;126(12):1748–54.CrossRefGoogle Scholar
  16. 16.
    Wallick CJ, Hansen RN, Campbell J, Kiss S, Kowalski JW, Sullivan SD. Comorbidity and health care resource use among commercially insured non-elderly patients with diabetic macular edema. Ophthalmic Surg Lasers Imaging Retina. 2015;46(7):744–51.CrossRefGoogle Scholar
  17. 17.
    Elman MJ, Ayala A, Bressler NM, Browning D, Flaxel CJ, Glassman AR, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375–81.CrossRefGoogle Scholar
  18. 18.
    Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, Ferris FL 3rd, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312–8.CrossRefGoogle Scholar
  19. 19.
    Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006;113(9):1533–8.CrossRefGoogle Scholar
  20. 20.
    Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9):1447–9 (1449.e1–10).Google Scholar
  21. 21.
    Kim JE, Pollack JS, Miller DG, Mittra RA, Spaide RF, Isis Study Group. ISIS-DME: a prospective, randomized, dose-escalation intravitreal steroid injection study for refractory diabetic macular edema. Retina. 2008;28(5):735–40.CrossRefGoogle Scholar
  22. 22.
    Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109(5):920–7.CrossRefGoogle Scholar
  23. 23.
    Haller JA, Kuppermann BD, Blumenkranz MS, Williams GA, Weinberg DV, Chou C, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128(3):289–96.CrossRefGoogle Scholar
  24. 24.
    Gillies MC, Lim LL, Campain A, Quin GJ, Salem W, Li J, et al. A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study. Ophthalmology. 2014;121(12):2473–81.CrossRefGoogle Scholar
  25. 25.
    Ramu J, Yang Y, Menon G, Bailey C, Narendran N, Bunce C, et al. A randomized clinical trial comparing fixed vs pro-re-nata dosing of Ozurdex in refractory diabetic macular oedema (OZDRY study). Eye (Lond). 2015;29(12):1603–12.CrossRefGoogle Scholar
  26. 26.
    Callanan DG, Gupta S, Boyer DS, Ciulla TA, Singer MA, Kuppermann BD, et al. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology. 2013;120(9):1843–51.CrossRefGoogle Scholar
  27. 27.
    National Institute for Health and Care Excellence. Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy. Technology appraisal guidance TA3012013, 25 Aug 2018.Google Scholar
  28. 28.
    Pearson PA, Comstock TL, Ip M, Callanan D, Morse LS, Ashton P, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011;118(8):1580–7.CrossRefGoogle Scholar
  29. 29.
    Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4–14.CrossRefGoogle Scholar
  30. 30.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.CrossRefGoogle Scholar
  31. 31.
    Scanlon PH, Aldington SJ, Stratton IM. Epidemiological issues in diabetic retinopathy. Middle East Afr J Ophthalmol. 2013;20(4):293–300.CrossRefGoogle Scholar
  32. 32.
    Bagust A, Hopkinson PK, Maslove L, Currie CJ. The projected healthcare burden of Type 2 diabetes in the UK from 2000 to 2060. Diabet Med. 2002;19(Suppl 4):1–5.CrossRefGoogle Scholar
  33. 33.
    Hex N, Bartlett C, Wright D, Taylor M, Varley D. Estimating the current and future costs of Type 1 and Type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet Med. 2012;29(7):855–62.CrossRefGoogle Scholar
  34. 34.
    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9 (W64).CrossRefGoogle Scholar
  35. 35.
    Ofman JJ, Sullivan SD, Neumann PJ, Chiou CF, Henning JM, Wade SW, et al. Examining the value and quality of health economic analyses: implications of utilizing the QHES. J Manag Care Pharm. 2003;9(1):53–61.Google Scholar
  36. 36.
    Stein JD, Newman-Casey PA, Kim DD, Nwanyanwu KH, Johnson MW, Hutton DW. Cost-effectiveness of various interventions for newly diagnosed diabetic macular edema. Ophthalmology. 2013;120(9):1835–42.CrossRefGoogle Scholar
  37. 37.
    Sharma S, Hollands H, Brown GC, Brown MM, Shah GK, Sharma SM. The cost-effectiveness of early vitrectomy for the treatment of vitreous hemorrhage in diabetic retinopathy. Curr Opin Ophthalmol. 2001;12(3):230–4.CrossRefGoogle Scholar
  38. 38.
    Sharma S, Brown GC, Brown MM, Hollands H, Shah GK. The cost-effectiveness of grid laser photocoagulation for the treatment of diabetic macular edema: results of a patient-based cost-utility analysis. Curr Opin Ophthalmol. 2000;11(3):175–9.CrossRefGoogle Scholar
  39. 39.
    Regnier SA, Malcolm W, Haig J, Xue W. Cost-effectiveness of ranibizumab versus aflibercept in the treatment of visual impairment due to diabetic macular edema: a UK healthcare perspective. ClinicoEcon Outcomes Res. 2015;7:235–47.CrossRefGoogle Scholar
  40. 40.
    Pershing S, Enns EA, Matesic B, Owens DK, Goldhaber-Fiebert JD. Cost-effectiveness of treatment of diabetic macular edema. Ann Intern Med. 2014;160(1):18–29.CrossRefGoogle Scholar
  41. 41.
    Mitchell P, Annemans L, Gallagher M, Hasan R, Thomas S, Gairy K, et al. Cost-effectiveness of ranibizumab in treatment of diabetic macular oedema (DME) causing visual impairment: evidence from the RESTORE trial. Br J Ophthalmol. 2012;96(5):688–93.CrossRefGoogle Scholar
  42. 42.
    Lin J, Chang JS, Smiddy WE. Cost evaluation of panretinal photocoagulation versus intravitreal ranibizumab for proliferative diabetic retinopathy. Ophthalmology. 2016;123(9):1912–8.CrossRefGoogle Scholar
  43. 43.
    Haig J, Barbeau M, Ferreira A. Cost-effectiveness of ranibizumab in the treatment of visual impairment due to diabetic macular edema. J Med Econ. 2016;19(7):663–71.CrossRefGoogle Scholar
  44. 44.
    Dewan V, Lambert D, Edler J, Kymes S, Apte RS. Cost-effectiveness analysis of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2012;119(8):1679–84.CrossRefGoogle Scholar
  45. 45.
    D’Amico Ricci G, Bouzios D, Boscia F, Lupino M, Pinna A. Cost-effectiveness of intravitreal therapy with both anti-VEGF and dexamethasone implant in patients with diabetic macular edema. In: Acta Ophthalmologica conference: 22nd European Association for Vision and Eye Research conference, EVER. Acta Ophthalmologica 2017;95 (suppl 259).Google Scholar
  46. 46.
    Cutino A, Green K, Kendall R, Moore PT, Zachary C. Economic evaluation of a fluocinolone acetonide intravitreal implant for patients with DME based on the FAME study. Am J Manag Care. 2015;21(4 Suppl):S63–72.Google Scholar
  47. 47.
    Ch’ng SW, Brent AJ, Empeslidis T, Konidaris V, Banerjee S. Real-world cost savings demonstrated by switching patients with refractory diabetic macular edema to intravitreal fluocinolone acetonide (iluvien): a retrospective cost analysis study. Ophthalmol Ther. 2018;7(1):75–82.CrossRefGoogle Scholar
  48. 48.
    Chalk D, Pitt M, Stein K. Cost-effectiveness of bevacizumab for diabetic macular oedema. Br J Healthc Manag. 2014;20(12):585–93.CrossRefGoogle Scholar
  49. 49.
    Brown GC, Brown MM, Turpcu A, Rajput Y. The cost-effectiveness of ranibizumab for the treatment of diabetic macular edema. Ophthalmology. 2015;122(7):1416–25.CrossRefGoogle Scholar
  50. 50.
    Ross EL, Hutton DW, Stein JD, Bressler NM, Jampol LM, Glassman AR. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the diabetic retinopathy clinical research network comparative effectiveness trial. JAMA Ophthalmol. 2016;134(8):888–96.CrossRefGoogle Scholar
  51. 51.
    Hutton DW, Stein JD, Bressler NM, Jampol LM, Browning D, Glassman AR. Cost-effectiveness of intravitreous ranibizumab compared with panretinal photocoagulation for proliferative diabetic retinopathy: secondary analysis from a diabetic retinopathy clinical research network randomized clinical trial. JAMA Ophthalmol. 2017;135(6):576–84.CrossRefGoogle Scholar
  52. 52.
    Kourlaba G, Relakis J, Mahon R, Kalogeropoulou M, Pantelopoulou G, Kousidou O, et al. Cost-utility of ranibizumab versus aflibercept for treating visual impairment due to diabetic macular edema in Greece. Value Health. 2015;18(7):A423.Google Scholar
  53. 53.
    Lin J, Chang JS, Yannuzzi NA, Smiddy WE. Cost evaluation of early vitrectomy versus panretinal photocoagulation and intravitreal ranibizumab for proliferative diabetic retinopathy. Ophthalmology. 2018;125(9):1393–400.CrossRefGoogle Scholar
  54. 54.
    Kavanos P, van der Aardweg S, Schurer W. Diabetes expenditure, burden of disease and management in 5 EU countries. London : LSE Health, London School of Economics; 2012.Google Scholar
  55. 55.
    Romero-Aroca P, de la Riva-Fernandez S, Valls-Mateu A, Sagarra-Alamo R, Moreno-Ribas A, Soler N, et al. Cost of diabetic retinopathy and macular oedema in a population, an eight year follow up. BMC Ophthalmol. 2016;16:136.CrossRefGoogle Scholar
  56. 56.
    Clarke P, Gray A, Legood R, Briggs A, Holman R. The impact of diabetes-related complications on healthcare costs: results from the United Kingdom Prospective Diabetes Study (UKPDS Study No. 65). Diabet Med. 2003;20(6):442–50.CrossRefGoogle Scholar
  57. 57.
    Javitt JC, Aiello LP, Chiang Y, Ferris FL 3rd, Canner JK, Greenfield S. Preventive eye care in people with diabetes is cost-saving to the federal government. Implications for health-care reform. Diabetes Care. 1994;17(8):909–17.CrossRefGoogle Scholar
  58. 58.
    Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351–9.CrossRefGoogle Scholar
  59. 59.
    Parikh R, Ross JS, Sangaralingham LR, Adelman RA, Shah ND, Barkmeier AJ. Trends of anti-vascular endothelial growth factor use in ophthalmology among privately insured and medicare advantage patients. Ophthalmology. 2017;124(3):352–8.CrossRefGoogle Scholar
  60. 60.
    Cohen D. CCGs win right to offer patients Avastin for wet AMD. BMJ. 2018;362:k4035.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Health Services OrganizationNational School of Public HealthAthensGreece
  2. 2.NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation TrustLondonUK
  3. 3.Institute of OphthalmologyUniversity College LondonLondonUK
  4. 4.Division of Optics and Optometry, Department of Biomedical SciencesUniversity of West AtticaAthensGreece

Personalised recommendations