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1 대한내과학회지 : 제 89 권제 3 호 특집 (Special Review) - 당뇨병성만성합병증의최신지견 당뇨망막병증최신지견 성균관대학교의과대학강북삼성병원안과 계효정 송수정 New Modalities for the Diagnosis and Treatment of Diabetic Retinopathy Hyo Jung Gye and Su Jeong Song Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea Over the past decade, significant advances have been made in both the diagnosis and treatment of diabetic retinopathy. Ultrawide field fundus photography and spectral domain optical coherence tomography have allowed more accurate, convenient, and early diagnosis of diabetic retinopathy. Numerous randomized clinical trials have demonstrated the effectiveness of anti-vascular endothelial growth factor agents for the treatment of diabetic retinopathy, although more work is necessary in terms of long-term clinical outcomes and socioeconomic costs associated with these treatments. (Korean J Med 2015;89: ) Keywords: Diabetic retinopathy; Epidemiology; Diagnosis; Treatment 서 론 본 론 당뇨망막병증은당뇨병성만성합병증중하나로전세계적으로중요실명원인중하나이다 [1,2]. 최근당뇨망막병증의진단분야에서는무산동광각안저촬영 (nonmydriatic ultra wide field fundus photography) 과스펙트럼영역빛간섭단층촬영 (spectral domain optical coherence tomography) 이보편화되고, 치료에서여러가지항혈관내피세포성장인자들 (vascular endothelial growth factor) 의유리체강내주사가광범위하게사용되고있다. 또한역학에서도제5기국민건강영양역학조사결과가발표되면서당뇨망막병증의역학에대한최신결과들이발표되었다 [3]. 이에당뇨망막병증의역학, 진단, 그리고치료에대한최신자료들을소개하고자한다. 역학의사와환자들모두에서당뇨병성만성합병증에대한인식이호전되고당뇨병의치료제가다양해지고향상됨에따라제1형당뇨병의경우는물론제2형당뇨병환자들에서도심한형태의당뇨망막병증의빈도가감소하였다는보고들이있다 [4-9]. 하지만그에반해당뇨황반부종의빈도는상대적으로증가하여이에대한진단과치료에대한중요성이부각되고있다 [4-9]. 한국인에서최신당뇨망막병증역학연구결과들에따르면당뇨병으로진단받은환자들에서당뇨망막병증의유병률은약 11-19% 까지보고되고있으며, 그중당뇨황반부종이나증식당뇨망막병증등심한당뇨망막병증의유 Correspondence to Su Jeong Song, M.D. Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea Tel: , 2251, Fax: , eye-su@hanmail.net Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

- The Korean Journal of Medicine: Vol. 89, No. 3, 2015 - 병률은약 5% 로보고되었다 [3,10,11]. 그리고이와연관된위험인자들로는당뇨병유병기간과혈중당화혈색소수치가있는것으로보고되었다 [3,10,11]. 당화혈색소수치가 8.

그외에도이두가지위험인자들은당뇨망막병증의발생과더불어이미당뇨망막병증을진단받은환자들에서심한형태의당뇨망막병증으로의진행에도관여하는것으로보고되어당뇨망막병증의발생과진행에혈당관리가가장중요함을재차확인할수있다. 또한당뇨병유병기간이 10년이상이된경우약반수이상에서당뇨망막병증을가지고있어고위험군들에대한당뇨망막병증검진의강조가필요하다.

산동을하게되면몇시간동안독서나운전등일상생활에지장이있고극히드문경우이나폐쇄각녹내장이악화될가능성이있어당뇨병환자들에서산동검사가힘든경우가종종있어왔다. 최근무산동광각안저촬영기술이개발되어임상에서사용되기시작하면서당뇨망막병증의진단에도움을주고있다 [18-20].

하지만아직은상대적으로낮은황반부해상도, 망막외병변들의간섭이나인공물 (artifact) 등의문제점들이있어무산동안저촬영과검사만으로당뇨망막병증을진단하기에는무리가있다 [18-20]. 앞으로무산동광각안저촬영이당뇨망막병증의진단에보편적으로사용되기위해서는이에대한보완이필요하다.

2 - The Korean Journal of Medicine: Vol. 89, No. 3, 병률은약 5% 로보고되었다 [3,10,11]. 그리고이와연관된위험인자들로는당뇨병유병기간과혈중당화혈색소수치가있는것으로보고되었다 [3,10,11]. 당화혈색소수치가 8.1% 이상인경우정상군에비해약 3배정도로당뇨망막병증이생길확률이높으며당뇨병유병기간이 11년이상인경우약 15배정도당뇨망막병증이생길확률이처음진단받은사람들에비해높은것으로발표되었다 [3,10,11]. 그외에도이두가지위험인자들은당뇨망막병증의발생과더불어이미당뇨망막병증을진단받은환자들에서심한형태의당뇨망막병증으로의진행에도관여하는것으로보고되어당뇨망막병증의발생과진행에혈당관리가가장중요함을재차확인할수있다. 또한당뇨병유병기간이 10년이상이된경우약반수이상에서당뇨망막병증을가지고있어고위험군들에대한당뇨망막병증검진의강조가필요하다. 최근외국의여러코호트연구들에서는당화혈색소수치와같은기존의위험인자외에도혈압, 지질대사이상, 임신, 신증, 유전, 비만, 영양상태등도위험인자들로거론되고있다. 한국인에서이런인자들이어떤영향을주는지에대한추가연구들이필요하다 [12-17]. 진단당뇨망막병증의진단에가장중요한검사는안저검사이며망막주변부까지관찰을해야하기에환자들의동공산 동은필수적이다. 산동을하게되면몇시간동안독서나운전등일상생활에지장이있고극히드문경우이나폐쇄각녹내장이악화될가능성이있어당뇨병환자들에서산동검사가힘든경우가종종있어왔다. 최근무산동광각안저촬영기술이개발되어임상에서사용되기시작하면서당뇨망막병증의진단에도움을주고있다 [18-20]. 무산동광각안저촬영은환자들산동이필요없으며, 기존의안저촬영에비해넓은부위를관찰할수있다는장점들이있어, 당뇨망막병증의진단을위한환자들의순응도와검사의민감도를향상시킬수있다는장점들이있다 [18-20]. 특히당뇨망막병증환자들에서놓치기쉬웠던주변부허혈변화나신생혈관들의진단에있어기존검사에비해민감도가많게는 4배이상좋은것으로보고되었다 (Fig. 1) [18-20]. 하지만아직은상대적으로낮은황반부해상도, 망막외병변들의간섭이나인공물 (artifact) 등의문제점들이있어무산동안저촬영과검사만으로당뇨망막병증을진단하기에는무리가있다 [18-20]. 앞으로무산동광각안저촬영이당뇨망막병증의진단에보편적으로사용되기위해서는이에대한보완이필요하다. 빛간섭단층촬영은안과진단분야에서 21세기최대의발명이라해도과언이아닐정도로, 망막은물론모든안과영역에서진단과치료에광범위하게사용되고있다. 빛간섭단층촬영은몇초라는짧은시간내에검사가가능하며, 비침습적이며, 황반상태를실시간, 정량적으로측정할수있다는 A B C D Figure 1. (A) Standard fundus photography: normal. (B) Standard fundus photography: diabetic retinopathy with multiple retinal hemorrhage and exudates. (C) Ultrawide field fundus photography: normal. (D) Ultrawide field fundus photography: diabetic retinopathy with multiple retinal hemorrhage and exudates

특히스펙트럼영역빛간섭단층촬영 (spectral domain optical coherence tomography) 이개발되어해상도가월등히좋아지면서여러망막질환에있어서진단이나추적관찰에필수검사로사용되고있다 [21-23].

3 - Hyo Jung Gye, et al. Update in diabetic retinopathy - A B Figure 2. (A) Spectral domain optical coherence tomography: normal fovea. (B) Spectral domain optical coherence tomography: diabetic macular edema with cystic space and disruption of retinal layers. 장점들이있다. 특히스펙트럼영역빛간섭단층촬영 (spectral domain optical coherence tomography) 이개발되어해상도가월등히좋아지면서여러망막질환에있어서진단이나추적관찰에필수검사로사용되고있다 [21-23]. 최근연구에따르면무증상의당뇨황반부종을찾아내는데있어높은민감도와특이도를보여주고있으며, 레이저광응고술이나유리체강내주사치료전후에있어서진단에필수적인검사가되었다 (Fig. 2) [21-23]. 또한당뇨황반부종환자에서중심망막두께는물론망막내외층의특징적인소견들을분석하여시력예후를예측하고자하는연구결과들이발표되고있다 [21-23]. 치료현재까지당뇨망막병증의치료에있어서가장중요한것은혈당관리이다. 하지만최근당뇨망막병증을치료하기위해많은새로운약이나기구들이개발되어왔다. 그중임상연구들을거쳐현재임상에서보편적으로사용되고있는새로운약제들을소개하고자한다. 스테로이드유리체강내주사당뇨망막병증의발생이나진행에있어가장중요한역할을하는것은혈관내피세포성장인자이다 [24]. 레이저치료는증식당뇨망막병증을가진눈에서허혈부위를감소시키고신생혈관의발생이나출혈을억제시키는것으로고위험당뇨망막병증환자에서급격한시력상실을막는데현재까지보편적으로사용되어온치료이다 [25]. 하지만당뇨황반부종이있는경우국소레이저 (focal laser) 치료후시력호전이어렵고황반부종의재발과레이저적응증이제한되어있어이를보완하기위한다른치료방법들이집중적으로연구되 어왔다. 스테로이드유리체강내주사는혈관내피세포성장인자들을억제하면서당뇨망막병증환자의망막에서만성적인염증상태를호전시키기위해널리사용되고있다 [26,27]. 최근안구내주사용으로보존제없는덱사메타손약이개발되고한번주사후장기간효과를나타내는덱사메타손유리체강내삽입물 (dexamethasone intravitreal implant) 이임상에서사용되기시작하여한번의시술로장기간의황반부종감소효과를기대할수있게되었다 [28,29]. 하지만안압상승이나백내장등스테로이드약자체에따른부작용에대한치료나이에대한보완이필요하다 [30]. 항혈관내피세포성장인자유리체강내주사당뇨황반부종환자에서유리체강내스테로이드주사는기존의레이저치료와더불어또는단독으로사용되어시력호전이나시력유지를얻을수있다는많은결과들이발표되어당뇨황반부종환자들에서치료에큰도움이되었다. 하지만스테로이드유리체강내주입후안압상승과백내장진행등스테로이드의부작용때문에다른혈관내피성장인자억제제들의도입이필요해졌는데현재까지사용되는대표적인약들로는 bevacizumab, ranibizumab, aflibercept 등이있다 [31-39]. 이중 ranibizumab (lucentis, Genentech, Inc., South San Francisco, CA, USA) 은안과영역에서처음으로개발된혈관내피성장인자억제제로혈관내피세포성장인자 A를억제하는단일클론항체 (monoclonal antibody) 이다 [31-35]. 많은임상연구결과들에서 ranibizumab 은혈관내피세포성장인자를억제하여신생혈관억제와황반부종을감소시켜시력향상이나유지에효과적인것으로발표되었다 [31-35]. 그러나주사후황반부종재발이흔해반복주사에따른비용이나

4 - 대한내과학회지 : 제 89 권제 3 호통권제 661 호 감염등여러가지제한점이있어앞으로이에대한보완이필요하다. Bevacizumab (avastin, Genentech, Inc., San Francisco, CA, USA) 은비록안과영역에서개발된약은아니나다른혈관내피세포성장인자억제제들과비교하여황반부종의감소나신생혈관들의억제에있어거의동등한효과를나타내면서비용이낮아현재임상에서많이사용되고있다 [36]. 하지만이역시문제점이있는데안구내투여후드물게발생하는전신부작용가능성에대한우려가있으나다른약제와비교해서통계적으로차이가있다고하기는힘들다 [37]. Aflibercept (Eylea ; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA, and Bayer AG, Berlin, Germany) 는가장최근에개발되어임상에서사용되기시작한혈관내피세포성장인자억제제로혈관내피세포성장인자수용체에결합하는재조합융합단백질 (recombinant fusion protein) 이다 [38,39]. 황반부종의감소에있어다른혈관내피세포성장인자억제제들과동등한결과를나타내면서작용기간이상대적으로길다는장점이있으나이에대해서는장기간의임상결과들의확인이필요하겠다 [38,39]. 소절개무봉합유리체절제술최근모든수술분야에서소절개수술이각광을받고있는데안과영역에서도예외는아니어서기존의 20게이지절개창을이용하는유리체절제술에비해수술후봉합이필요없는 23게이지나 25게이지무봉합유리체절제술이널리시행되고있다 [40-42]. 기존의유리체절제술에비해수술후시력회복이빠르고수술시간도단축될수있다는장점들이있다. 하지만수술후무봉합절개창의누출로인한감염이나저안압이발생할수있어이에대한주의가필요하다 [40-42]. 결론최근 10년동안당뇨망막병증의진단이나치료에있어서획기적인발전들이있어왔다. 하지만아직도완벽한진단방법이나예방보다더만족스러운치료방법은없다. 앞으로당뇨망막병증의치료에서는단순히당뇨망막병증을치료하는것보다는당뇨망막병증환자들의시력향상과더불어삶의질까지고려해야할것이다. 중심단어 : 당뇨망막병증 ; 역학 ; 진단 ; 치료 REFERENCES 1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010;376: Yau JW, Rogers SL, Kawasaki R, et al.; Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35: Yang JY, Kim NK, Lee YJ, et al. Prevalence and factors associated with diabetic retinopathy in a Korean adult population: the Korea National Health and Nutrition Examination Survey. Diabetes Res Clin Pract 2013;102: Hovind P, Tarnow L, Rossing K, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care 2003;26: Klein R, Klein BE. Is the prevalence of visual impairment rising or falling in the people with diabetes mellitus? It depends on who you study. JAMA Ophthalmol 2013;131: 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: Nordwall M, Bojestig M, Arnqvist HJ, Ludvigsson J; Linkoping Diabetes Complications Study. Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of type 1 diabetes-the Linkoping Diabetes Complications Study. Diabetologia 2004;47: Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology 2009;116: Klein R, Klein BE. Are individuals with diabetes seeing better?: a long-term epidemiological perspective. Diabetes 2010; 59: Park CY, Park SE, Bae JC, et al. Prevalence of and risk factors for diabetic retinopathy in Koreans with type II diabetes: baseline characteristics of Seoul Metropolitan City- Diabetes Prevention Program (SMC-DPP) participants. Br J Ophthalmol 2012;96: Kim YJ, Kim JG, Lee JY, et al. Development and progression of diabetic retinopathy and associated risk factors in Korean patients with type 2 diabetes: the experience of a tertiary center. J Korean Med Sci 2014;29: Huang YC, Lin JM, Lin HJ, et al. Genome-wide association study of diabetic retinopathy in a Taiwanese population

5 - 계효정외 1 인. 당뇨망막병증의최신지견 - Ophthalmology 2011;118: Sheu WH, Kuo JZ, Lee IT, et al. Genome-wide association study in a Chinese population with diabetic retinopathy. Hum Mol Genet 2013;22: Dirani M, Xie J, Fenwick E, et al. Are obesity and anthropometry risk factors for diabetic retinopathy? The diabetes management project. Invest Ophthalmol Vis Sci 2011;52: Klein R, Klein BE, Moss SE. Is obesity related to microvascular and macrovascular complications in diabetes? The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch Intern Med 1997;157: Tanaka S, Yoshimura Y, Kawasaki R, et al.; Japan Diabetes Complications Study Group. Fruit intake and incident diabetic retinopathy with type 2 diabetes. Epidemiology 2013; 24: Djuric Z, Ren J, Mekhovich O, Venkatranamoorthy R, Heilbrun LK. Effects of high fruit-vegetable and/or low-fat intervention on plasma micronutrient levels. J Am Coll Nutr 2006;25: Manivannan A, Plskova J, Farrow A, McKay S, Sharp PF, Forrester JV. Ultra-wide-field fluorescein angiography of the ocular fundus. Am J Ophthalmol 2005;140: Wessel MM, Aaker GD, Parlitsis G, Cho M, D Amico DJ, Kiss S. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina 2012;32: Wessel MM, Nair N, Aaker GD, Ehrlich JR, D'Amico DJ, Kiss S. Peripheral retinal ischaemia, as evaluated by ultrawidefield fluorescein angiography, is associated with diabetic macular oedema. Br J Ophthalmol 2012;96: Lim JI, Zelkha R, Niec M, Setlur V, Shahidi M. Inner and outer retinal thickness mapping of nonproliferative diabetic retinopathy by spectral-domain optical coherence tomography. Ophthalmic Surg Lasers Imaging Retina 2015;46: Boynton GE, Stem MS, Kwark L, Jackson GR, Farsiu S, Gardner TW. Multimodal characterization of proliferative diabetic retinopathy reveals alterations in outer retinal function and structure. Ophthalmology 2015;122: Bonnin S, Tadayoni R, Erginay A, Massin P, Dupas B. Correlation between ganglion cell layer thinning and poor visual function after resolution of diabetic macular edema. Invest Ophthalmol Vis Sci 2015;56: Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 2008;27: Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103: Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115: Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117: e Boyer DS, Yoon YH, Belfort R Jr, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121: Callanan DG, Gupta S, Boyer DS, et al.; Ozurdex PLACID Study Group. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 2013;120: Lauer AK, Bressler NM, Edwards AR; Diabetic Retinopathy Clinical Research Network. Frequency of intraocular pressure increase within days after intravitreal triamcinolone injections in the diabetic retinopathy clinical research network. Arch Ophthalmol 2011;129: Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015;372: Nguyen QD, Brown DM, Marcus DM, et al.; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119: Brown DM, Nguyen QD, Marcus DM, et al.; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;120: Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 2010;33: Mitchell P, Bandello F, Schmidt-Erfurth U, et al.; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118: Michaelides M, Kaines A, Hamilton RD, 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: e Moja L, Lucenteforte E, Kwag KH, et al. Systemic safety of

6 - The Korean Journal of Medicine: Vol. 89, No. 3, bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014;9: CD 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: Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014; 121: Farouk MM, Naito T, Sayed KM, et al. Outcomes of 25-gauge vitrectomy for proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2011;249: Park DH, Shin JP, Kim SY. Comparison of clinical outcomes between 23-gauge and 20-gauge vitrectomy in patients with proliferative diabetic retinopathy. Retina 2010;30: Ozone D, Hirano Y, Ueda J, Yasukawa T, Yoshida M, Ogura Y. Outcomes and complications of 25-gauge transconjunctival sutureless vitrectomy for proliferative diabetic retinopathy. Ophthalmologica 2011;226:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R