Download PDF
Klin Monbl Augenheilkd 2010; 227(9): 701-711
DOI: 10.1055/s-0029-1245718
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Die Rolle der Anti-VEGF-Therapie in der Behandlung des diabetischen Makulaödems

Anti-VEGF Inhibitors and Their Role in the Treatment of Diabetic Macular OedemaV. Kakkassery1 , S. Winterhalter1 , A. M. Joussen1
  • 1Klinik für Augenheilkunde, Charité Universitätsmedizin Berlin
Further Information

Publication History

Eingegangen: 9.7.2010

Angenommen: 24.8.2010

Publication Date:
15 September 2010 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Das diabetische Makulaödem (DME) und die diabetische Retinopathie sind die häufigsten Erblindungsursachen des mittleren Erwachsenenalters. Goldstandard der Therapie war bisher die parazentrale Laserkoagulation. Therapierefraktäre Verläufe, das fehlende Ansprechen bei einer ischämischen Makulopathie und Komplikationen limitieren das Verfahren. Die Suche nach nicht destruktiven Verfahren führte zu Untersuchungen von Vascular-Endothelial-Growth-Factor(VEGF)-Inhibitoren, die die Gefäßleckage und damit die Ödembildung reduzieren sollen. Therapeutische Antikörper-Fragmente gegen VEGF sind in der Behandlung der altersassoziierten Makuladegeneration (AMD) in verschiedenen Ländern zugelassen und haben sich bewährt. Zurzeit sind einige Anti-VEGF-Medikamente in Zulassungsverfahren. Erste Daten der Zulassungsstudien deuten auf eine Überlegenheit der Anti-VEGF-Therapie gegenüber der Laserkoagulation hin. Ziel dieser Übersichtsarbeit ist die Darstellung der vorliegenden Daten im Hinblick auf Dosierung, Injektionsschemata und eine praktikable klinische Anwendung.

Abstract

Diabetic macular edema (DME) and proliferative retinopathy are common causes for blindness in middle-aged patients. The gold standard for treatment has been laser coagulation. Limitations of this therapy are refractive DME, ischaemic diabetic maculopathy and complications after laser application. The need for a non-destructive and effective strategy has led to investigations regarding vascular endothelial growth factor (VEGF) inhibitors for reduction of vessel leakage and oedema formation. VEGF antibody fragments have been approved for age-associated macular degeneration (AMD) in different countries and have proved to be safe and effective. Trials for different anti-VEGF compounds are nearing completion or are completed. Published data show a superiority of anti-VEGF therapy compared to laser coagulation. In the present article, data regarding dose, injection scheme and practicable application form are reviewed.

Schlüsselwörter

Retina - diabetisches Makulaödem - Anti-VEGF-Therapie

Key words

retina - diabetic macular oedema - anti-VEGF therapy

Literatur

  • 1 Wild S, Roglic G, Green A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.  Diabetes Care. 2004;  27 1047-1053
    Google Scholar
  • 2 Moss S E, Klein R, Klein B E. Ten-year incidence of visual loss in a diabetic population.  Ophthalmology. 1994;  101 1061-1070
    Google Scholar
  • 3 Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings.  Ophthalmology. 1978;  85 82-106
    Google Scholar
  • 4 Beetham W P, Aiello L M, Balodimos M C et al. Ruby laser photocoagulation of early diabetic neovascular retinopathy. Preliminary report of a long-term controlled study.  Arch Ophthalmol. 1970;  83 261-272
    Google Scholar
  • 5 Lang G E. New developments in the treatment of diabetic macular oedema.  Klin Monbl Augenheilkd. 2003;  220 519
    Google Scholar
  • 6 Bresnick G H. Diabetic macular edema. A review.  Ophthalmology. 1986;  93 989-997
    Google Scholar
  • 7 Kinyoun J, Barton F, Fisher M et al. Detection of diabetic macular edema. Ophthalmoscopy versus photography – Early Treatment Diabetic Retinopathy Study Report Number 5. The ETDRS Research Group.  Ophthalmology. 1989;  96 746-750 discussion 750 – 741
    Google Scholar
  • 8 Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group.  Ophthalmology. 1987;  94 761-774
    Google Scholar
  • 9 Wilkinson C P, Ferris 3rd F L, Klein R E et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales.  Ophthalmology. 2003;  110 1677-1682
    Google Scholar
  • 10 Patz A, Finkelstein D, Fine S L et al. The role of fluorescein angiography in national collaborative studies.  Ophthalmology. 1986;  93 1466-1470
    Google Scholar
  • 11 Browning D J, Altaweel M M, Bressler N M et al. Diabetic macular edema: what is focal and what is diffuse?.  Am J Ophthalmol. 2008;  146 649-655
    Google Scholar
  • 12 A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema.  Ophthalmology. 2008;  115 1447-1449
    Google Scholar
  • 13 Beck R W, Edwards A R, Aiello L P et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema.  Arch Ophthalmol. 2009;  127 245-251
    Google Scholar
  • 14 Gragoudas E S, Adamis A P, Cunningham E T et al. Pegaptanib for neovascular age-related macular degeneration.  N Engl J Med. 2004;  351 2805-2816
    Google Scholar
  • 15 D’Amico D J, Masonson H N, Patel Jr M et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials.  Ophthalmology. 2006;  113 992-1001, e1006
    Google Scholar
  • 16 Heier J S, Antoszyk A N, Pavan P R et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study.  Ophthalmology. 2006;  113 633, e631-e634
    Google Scholar
  • 17 Rosenfeld P J, Schwartz S D, Blumenkranz M S et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration.  Ophthalmology. 2005;  112 1048-1053
    Google Scholar
  • 18 Presta L G, Chen H, O’Connor S J et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.  Cancer Res. 1997;  57 4593-4599
    Google Scholar
  • 19 Scott I U, Edwards A R, Beck R W et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema.  Ophthalmology. 2007;  114 1860-1867
    Google Scholar
  • 20 Nguyen Q D, Shah S M, Heier J S et al. Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study.  Ophthalmology. 2009;  116 2175-2181, e2171
    Google Scholar
  • 21 Cunningham E T, Adamis A P, Altaweel Jr M et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.  Ophthalmology. 2005;  112 1747-1757
    Google Scholar
  • 22 Do D V, Nguyen Q D, Shah S M et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema.  Br J Ophthalmol. 2009;  93 144-149
    Google Scholar
  • 23 Duke-Elder S, Dobree J H. The formation of avascular connective-tissue bands in proliferative diabetic retinopathy.  Bibl Ophthalmol. 1968;  76 133-138
    Google Scholar
  • 24 Behzadian M A, Windsor L J, Ghaly N et al. VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor.  Faseb J. 2003;  17 752-754
    Google Scholar
  • 25 Deissler H, Deissler H, Lang G K et al. Generation and characterization of iBREC: novel hTERT-immortalized bovine retinal endothelial cells.  Int J Mol Med. 2005;  16 65-70
    Google Scholar
  • 26 Deissler H, Deissler H, Lang S et al. VEGF-induced effects on proliferation, migration and tight junctions are restored by ranibizumab (Lucentis) in microvascular retinal endothelial cells.  Br J Ophthalmol. 2008;  92 839-843
    Google Scholar
  • 27 Tolentino M J, Miller J W, Gragoudas E S et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate.  Ophthalmology. 1996;  103 1820-1828
    Google Scholar
  • 28 Tolentino M J, McLeod D S, Taomoto M et al. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate.  Am J Ophthalmol. 2002;  133 373-385
    Google Scholar
  • 29 Qaum T, Xu Q, Joussen A M et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes.  Invest Ophthalmol Vis Sci. 2001;  42 2408-2413
    Google Scholar
  • 30 Aiello L P, Avery R L, Arrigg P G et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.  N Engl J Med. 1994;  331 1480-1487
    Google Scholar
  • 31 Boulton M, Foreman D, Williams G et al. VEGF localisation in diabetic retinopathy.  Br J Ophthalmol. 1998;  82 561-568
    Google Scholar
  • 32 Smith G, McLeod D, Foreman D et al. Immunolocalisation of the VEGF receptors FLT-1, KDR, and FLT-4 in diabetic retinopathy.  Br J Ophthalmol. 1999;  83 486-494
    Google Scholar
  • 33 Campochiaro P A, Choy D F, Do D V et al. Monitoring ocular drug therapy by analysis of aqueous samples.  Ophthalmology. 2009;  116 2158-2164
    Google Scholar
  • 34 Kumar A, Sinha S. Intravitreal bevacizumab (Avastin) treatment of diffuse diabetic macular edema in an Indian population.  Indian J Ophthalmol. 2007;  55 451-455
    Google Scholar
  • 35 Ahmadieh H, Ramezani A, Shoeibi N et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema, a placebo-controlled, randomized clinical trial.  Graefes Arch Clin Exp Ophthalmol. 2008;  246 483-489
    Google Scholar
  • 36 Faghihi H, Roohipoor R, Mohammadi S F et al. Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema.  Eur J Ophthalmol. 2008;  18 941-948
    Google Scholar
  • 37 Kook D, Wolf A, Kreutzer T et al. Long-term effect of intravitreal bevacizumab (avastin) in patients with chronic diffuse diabetic macular edema.  Retina. 2008;  28 1053-1060
    Google Scholar
  • 38 Paccola L, Costa R A, Folgosa M S et al. Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study).  Br J Ophthalmol. 2008;  92 76-80
    Google Scholar
  • 39 Fang X, Sakaguchi H, Gomi F et al. Efficacy and safety of one intravitreal injection of bevacizumab in diabetic macular oedema.  Acta Ophthalmol. 2008;  86 800-805
    Google Scholar
  • 40 Shimura M, Nakazawa T, Yasuda K et al. Comparative therapy evaluation of intravitreal bevacizumab and triamcinolone acetonide on persistent diffuse diabetic macular edema.  Am J Ophthalmol. 2008;  145 854-861
    Google Scholar
  • 41 Bonini-Filho M, Costa R A, Calucci D et al. Intravitreal bevacizumab for diabetic macular edema associated with severe capillary loss: one-year results of a pilot study.  Am J Ophthalmol. 2009;  147 1022-1030
    Google Scholar
  • 42 Lam D S, Lai T Y, Lee V Y et al. Efficacy of 1.25 MG versus 2.5 MG intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized controlled trial.  Retina. 2009;  29 292-299
    Google Scholar
  • 43 Seo J W, Park I W. Intravitreal bevacizumab for treatment of diabetic macular edema.  Korean J Ophthalmol. 2009;  23 17-22
    Google Scholar
  • 44 Soheilian M, Ramezani A, Obudi A et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema.  Ophthalmology. 2009;  116 1142-1150
    Google Scholar
  • 45 Soheilian M, Ramezani A, Bijanzadeh B et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema.  Retina. 2007;  27 1187-1195
    Google Scholar
  • 46 Velez-Montoya R, Fromow-Guerra J, Burgos O et al. The effect of unilateral intravitreal bevacizumab (avastin), in the treatment of diffuse bilateral diabetic macular edema: a pilot study.  Retina. 2009;  29 20-26
    Google Scholar
  • 47 Forte R, Cennamo G L, Finelli M et al. Intravitreal bevacizumab vs intravitreal triamcinolone combined with macular laser grid for diffuse diabetic macular oedema.  Eye. 2010;  24 (8) 1325-1330
    Google Scholar
  • 48 Kreutzer T C, Al Saeidi R, Kook D et al. Comparison of Intravitreal Bevacizumab versus Triamcinolone for the Treatment of Diffuse Diabetic Macular Edema.  Ophthalmologica. 2010;  224 258-264
    Google Scholar
  • 49 Haritoglou C, Kook D, Neubauer A et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema.  Retina. 2006;  26 999-1005
    Google Scholar
  • 50 Arevalo J F, Sanchez J G, Fromow-Guerra J et al. Comparison of two doses of primary intravitreal bevacizumab (Avastin) for diffuse diabetic macular edema: results from the Pan-American Collaborative Retina Study Group (PACORES) at 12-month follow-up.  Graefes Arch Clin Exp Ophthalmol. 2009;  247 735-743
    Google Scholar
  • 51 Arevalo J F, Sanchez J G, Wu L et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months.  Ophthalmology. 2009;  116 1488-1497
    Google Scholar
  • 52 Michaelides M, Kaines A, Hamilton R D et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2.  Ophthalmology. 2010;  117 1078-1086
    Google Scholar
  • 53 Michaelides M, Fraser-Bell S, Hamilton R et al. Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (Bolt Study).  Retina. 2010;  30 781-786
    Google Scholar
  • 54 Adamis A P, Altaweel M, Bressler N M et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.  Ophthalmology. 2006;  113 23-28
    Google Scholar
  • 55 Querques G, Bux A V, Martinelli D et al. Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema.  Acta Ophthalmol. 2009;  87 623-630
    Google Scholar
  • 56 Chun D W, Heier J S, Topping T M et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema.  Ophthalmology. 2006;  113 1706-1712
    Google Scholar
  • 57 Nguyen Q D, Tatlipinar S, Shah S M et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema.  Am J Ophthalmol. 2006;  142 961-969
    Google Scholar
  • 58 Elman M J, Aiello L P, Beck R W et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2010;  117 1064-1077 e1035
    Google Scholar
  • 59 Schmucker C, Ehlken C, Hansen L L et al. Intravitreal bevacizumab (Avastin) vs. ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a systematic review.  Curr Opin Ophthalmol. 2010;  21 218-226
    Google Scholar
  • 60 Querques G, Bux A V, Martinelli D et al. Short-term fluctuation of diabetic macular edema after intravitreal ranibizumab injection.  Retina. 2009;  29 1274-1281
    Google Scholar

Dr. Vinodh Kakkassery

Klinik für Augenheilkunde, Charité Universitätsmedizin Berlin

Augustenburger Platz 1

1353 Berlin

Phone: ++ 49/30/4 50 55 42 02

Fax: ++ 49/30/4 50 55 49 00

Email: Vinodh.Kakkassery@charite.de