今日の臨床サポート

糖尿病網膜症

著者: 善本三和子1) 東京逓信病院眼科

著者: 加藤 聡2) 元東京大学大学院眼科

監修: 沖波聡 倉敷中央病院眼科

著者校正/監修レビュー済:2022/08/03
参考ガイドライン:
  1. 日本糖尿病学会:糖尿病診療ガイドライン2019
  1. 日本糖尿病眼学会:糖尿病網膜症診療ガイドライン(第1版)2020
  1. 日本糖尿病・生活習慣病ヒューマンデータ学会:糖尿病標準診療マニュアル2021 一般診療所・クリニック向け:(2021)
患者向け説明資料

概要・推奨   

  1. 糖尿病網膜症とは、糖尿病に起因した特徴的眼底所見を呈する病態であり、基本的には網膜における最小血管障害に起因する種々の変化が生じる疾患である。診断は眼底所見に加えて種々の検査を組み合わせ、総合的に行う必要がある。
  1. 世界における糖尿病患者における糖尿病網膜症の有病率は35.4%である[1]
  1. 日本人2型糖尿病患者における糖尿病網膜症発症率は3.98%といわれている(約8年追跡)。
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  1. 糖尿病罹病期間が長いほど、糖尿病網膜症の有病率と重症度はともに上昇するため、早期からの血糖管理が重要である(推奨度1)。糖尿病罹病期間が5年以上経過すると糖尿病網膜症の発症のリスクが高くなること[2]や、発症年齢が若いほうが糖尿病網膜症が重症化しやすい。
  1. 2型糖尿病患者では発症時期を決定することは困難であるが、約30%の患者が診断時にすでに糖尿病網膜症を発症している[3]。また、推定罹病期間5年未満で28.8%(増殖網膜症は2.0%)、15年以上で77.8%(増殖網膜症は15.5%)が網膜症を有している[4][5][6]
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  1. 妊娠患者は非妊娠患者に比して1.60-2.48倍の糖尿病網膜症進展リスクがある[7]。妊娠の可能性のある糖尿病患者では、妊娠前からの眼科定期検査のうえに妊娠が明らかとなった場合には、ただちに眼科受診が必要である(推奨度1)
  1. 糖尿病網膜症が存在する場合には糖尿病網膜症の重症度に応じて診察間隔を決定し、病状に応じて治療を行う[7][8][9]が、出産後も網膜症が増悪するリスクが高いため、眼科受診の継続が必要である(推奨度2)
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
善本三和子 : 特に申告事項無し[2022年]
加藤 聡 : 特に申告事項無し[2022年]
監修:沖波聡 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 糖尿病網膜症診療ガイドライン第1版に基づき、内容を変更した。

病態・疫学・診察

疾患情報  
病態:
  1. 糖尿病網膜症は、神経障害、腎症と並び、糖尿病患者に発生する3大最小血管合併症の一つであり、基本的には網膜における最小血管障害に起因する種々の変化が生じる疾患である。糖尿病網膜症は、診断時点の糖尿病の有無にかかわらず過去の糖尿病の既往によっても発生し得る。
 
疫学:
  1. 【海外の報告】米国、オーストラリア、ヨーロッパ、アジア各国から集めたメタ解析研究では、糖尿病患者における糖尿病網膜症の有病率は35.4%であるが [1]、日本を含むアジア地域では何らかの糖尿病網膜症の有病率は19.9%、増殖糖尿病網膜症1.5%、糖尿病黄斑浮腫5.0%、視力をおびやかす可能性のある糖尿病網膜症5.3%とされている。
  1. 【日本の報告】日本における疫学研究では、糖尿病網膜症の有病率は、福岡県久山町研究によると40歳以上の糖尿病患者で15.0%(2007年)、山形県舟形町研究では、35歳以上の糖尿病患者で23.0%(2008年)であった。また、日本人2型糖尿病患者を約8年追跡した研究では、糖尿病網膜症の発症率は3.83-3.93%であった[10][2]
 
診断:
  1. 特徴的眼底所見に加えて種々の検査を組み合わせ、総合的に行う必要がある[11]
 
妊娠に関連する事項(J):
  1. 糖尿病合併妊娠(pregestational diabetes)
  1. 妊娠患者は非妊娠患者に比較し、1.60~2.48倍の糖尿病網膜症進展リスクがある[7]
  1. 増殖・増殖前網膜症は妊娠中および産褥期に悪化しやすい。
  1. 挙児希望のある糖尿病患者は、妊娠前に眼科受診を行う必要がある。
  1. 妊娠確定後は、早期に眼科受診をし、網膜所見なしならば1回/6~12カ月、軽症または中等症非増殖糖尿病網膜症ならば1回/3~6カ月、重症非増殖糖尿病網膜症以上ならば1回/1~3カ月程度の眼科診察が推奨される(推奨度2)
  1. 増殖糖尿病網膜症は進行性であるため、妊娠中であっても網膜光凝固や硝子体手術の適応があれば行う(推奨度1)
  1. 糖尿病黄斑浮腫に対する抗血管内皮増殖因子(VEGF)療法は、安全性が確立されていない。
 
  1. 妊娠中に発見された糖代謝異常
  1. 妊娠糖尿病(gestational diabetes mellitus:GDM)
  1. 将来2型糖尿病を発症するリスクが正常耐糖能妊婦の7.43倍と効率である[12]
  1. 妊娠前に糖尿病合併が疑われる症例では眼底検査が必要である(推奨度2)
  1. 妊娠中の明らかな糖尿病(overt diabetes in pregnancy)
  1. 糖尿病診断時に眼科受診が必要である[13]。いずれの場合も、出産後も糖尿病網膜症が進行することがあるため、出産後も1年間は慎重に眼底検査を受けることが推奨され、その後の診察間隔は網膜症の重症度による(推奨度2)
 
いずれの場合も、出産後も糖尿病網膜症が進行することがあるため、出産後も1年間は慎重に眼底検査を受けることが推奨され、その後の診察間隔は網膜症の重症度による(推奨度2)
 
問診・診察のポイント  
  1. 糖尿病の有無、既往の有無を確認する。

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文献 

Joanne W Y Yau, Sophie L Rogers, Ryo Kawasaki, Ecosse L Lamoureux, Jonathan W Kowalski, Toke Bek, Shih-Jen Chen, Jacqueline M Dekker, Astrid Fletcher, Jakob Grauslund, Steven Haffner, Richard F Hamman, M Kamran Ikram, Takamasa Kayama, Barbara E K Klein, Ronald Klein, Sannapaneni Krishnaiah, Korapat Mayurasakorn, Joseph P O'Hare, Trevor J Orchard, Massimo Porta, Mohan Rema, Monique S Roy, Tarun Sharma, Jonathan Shaw, Hugh Taylor, James M Tielsch, Rohit Varma, Jie Jin Wang, Ningli Wang, Sheila West, Liang Xu, Miho Yasuda, Xinzhi Zhang, Paul Mitchell, Tien Y Wong, Meta-Analysis for Eye Disease (META-EYE) Study Group
Global prevalence and major risk factors of diabetic retinopathy.
Diabetes Care. 2012 Mar;35(3):556-64. doi: 10.2337/dc11-1909. Epub 2012 Feb 1.
Abstract/Text OBJECTIVE: To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes.
RESEARCH DESIGN AND METHODS: A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20-79 years.
RESULTS: A total of 35 studies (1980-2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5-34.8) for any DR, 6.96% (6.87-7.04) for proliferative DR, 6.81% (6.74-6.89) for diabetic macular edema, and 10.2% (10.1-10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A(1c), and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes.
CONCLUSIONS: There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

PMID 22301125
R Kawasaki, S Tanaka, S Tanaka, T Yamamoto, H Sone, Y Ohashi, Y Akanuma, N Yamada, H Yamashita, Japan Diabetes Complications Study Group
Incidence and progression of diabetic retinopathy in Japanese adults with type 2 diabetes: 8 year follow-up study of the Japan Diabetes Complications Study (JDCS).
Diabetologia. 2011 Sep;54(9):2288-94. doi: 10.1007/s00125-011-2199-0. Epub 2011 Jun 1.
Abstract/Text AIMS/HYPOTHESIS: The aim of this study was to determine the incidence and progression rates of diabetic retinopathy and their associations in Japanese individuals with type 2 diabetes.
METHODS: This is a part of the Japan Diabetic Complications Study (JDCS), a multi-centred randomised trial of type 2 diabetes patients aged 40-70 years with an 8 year follow-up. There were 1,221 patients without diabetic retinopathy at baseline; incidence of diabetic retinopathy was defined as the development of any diabetic retinopathy. There were 410 patients with mild non-proliferative diabetic retinopathy at baseline; progression of diabetic retinopathy was defined as the development of severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy. We used multivariate proportional Cox hazard models, and generalised additive models were also applied to identify potential threshold effect.
RESULTS: The incidence and progression rate of diabetic retinopathy was 38.3/1,000 person-years and 21.1/1,000 person-years, respectively. Higher HbA(1c) (adjusted HR [aHR] per 1% [10.9 mmol/mol] 1.36 [95% CI 1.28-1.45]), longer duration of diabetes (aHR per 5 year period 1.26 [95% CI 1.17-1.35]), higher systolic blood pressure (aHR per +10 mmHg 1.01 [95% CI 1.00-1.02]) and higher body mass index (aHR per 1 kg/m(2) 1.05 [95% CI 1.00-1.09]) were associated with incident diabetic retinopathy. The association between HbA(1c) and incident diabetic retinopathy was linear; the association with duration of diabetes increased rapidly between 5 and 10 years. Higher HbA(1c) was also associated with progression of diabetic retinopathy (aHR per 1% [10.9 mmol/mol] 1.66 [95% CI 1.41-1.96]).
CONCLUSIONS: Observed incidence and progression rates of diabetic retinopathy seemed lower than that in western populations. HbA(1c) was the only factor associated with both incidence and progression of diabetic retinopathy. The strength of the association between duration of diabetes and incidence of diabetic retinopathy increased rapidly during a period of 5 to 10 years duration of diabetes.
TRIAL REGISTRATION: C000000222 ( www.umin.ac.jp )
FUNDING: This study is supported by the Ministry of Health, Labour and Welfare, Japan.

PMID 21630126
Gregg T Lueder, Janet Silverstein, American Academy of Pediatrics Section on Ophthalmology and Section on Endocrinology
Screening for retinopathy in the pediatric patient with type 1 diabetes mellitus.
Pediatrics. 2005 Jul;116(1):270-3. doi: 10.1542/peds.2005-0875.
Abstract/Text Diabetic retinopathy (DR) is the leading cause of blindness in young adults in the United States. Early identification and treatment of DR can decrease the risk of vision loss in affected patients. This clinical report reviews the risk factors for the development of DR and screening guidance for pediatric patients with type 1 diabetes mellitus.

PMID 15995070
Abstract/Text In a population-based study in southern Wisconsin, 1,370 patients given diagnoses of diabetes at age 30 years or older were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 28.8% in persons who had diabetes for less than five years to 77.8% in persons who had diabetes for 15 or more years. The rate of proliferative diabetic retinopathy varied from 2.0% in persons who had diabetes for less than five years to 15.5% in persons who had diabetes for 15 or more years. By using the Cox regression model, the severity of retinopathy was found to be related to longer duration of diabetes, younger age at diagnosis, higher glycosylated hemoglobin levels, higher systolic BP, use of insulin, presence of proteinuria, and small body mass.

PMID 6367725
R Klein, B E Klein, S E Moss
Epidemiology of proliferative diabetic retinopathy.
Diabetes Care. 1992 Dec;15(12):1875-91. doi: 10.2337/diacare.15.12.1875.
Abstract/Text OBJECTIVE: This review examines recent epidemiological data about the prevalence and incidence of and risk factors for proliferative diabetic retinopathy. In addition, the relation of proliferative retinopathy to other systemic complications associated with diabetes is reviewed.
RESEARCH DESIGN AND METHODS: The data come mostly from the baseline and 4-yr follow-up examinations of a large population-based study, the WESDR, which involved 996 younger-onset insulin-dependent people whose diabetes was diagnosed at < 30 yr of age and 1370 older-onset people whose diabetes was diagnosed at > or = 30 yr of age, and who were taking or not taking insulin.
RESULTS: The major finding is that proliferative retinopathy is a prevalent complication (23% in the WESDR younger-onset group, 10% in the WESDR older-onset group that takes insulin, and 3% in the group that does not take insulin). Hyperglycemia, longer duration of diabetes, and more severe retinopathy at baseline were associated with an increased 4-yr risk of developing proliferative retinopathy. However, higher blood pressure at baseline was associated only with the development of proliferative retinopathy in the younger-onset group. The presence of proliferative diabetic retinopathy was associated with an increased 4-yr risk of loss of vision, cardiovascular disease, diabetic nephropathy, and mortality. In the WESDR, a significant number of diabetic people with proliferative retinopathy at risk for vision loss were not under the care of an ophthalmologist or had not undergone panretinal photocoagulation.
CONCLUSIONS: These data suggest that hyperglycemia and, possibly, high blood pressure are related to proliferative retinopathy. They also suggest that once proliferative diabetic retinopathy is detected, people should have a medical evaluation, because it is a strong indicator for the presence and development of systemic disease. These data also indicate that diabetic patients and their physicians should be aware of the need for routine ophthalmological examinations to detect and treat proliferative retinopathy.

PMID 1464243
Diabetes Prevention Program Research Group
The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program.
Diabet Med. 2007 Feb;24(2):137-44. doi: 10.1111/j.1464-5491.2007.02043.x.
Abstract/Text AIMS: Retinopathy is considered the complication most closely associated with and characteristic of diabetes mellitus. Hyperglycaemia below levels diagnostic of diabetes, so called pre-diabetes, is associated with a low prevalence of 'diabetic' retinopathy. However, few longitudinal studies of non-diabetic populations have performed repeated measures of glycaemia and screened for retinopathy to determine its occurrence in the non-diabetic population and the onset of retinopathy in new-onset diabetic patients. We determined the prevalence of retinopathy characteristically seen in diabetes in persons with impaired glucose tolerance and in patients with new-onset diabetes of known duration in the Diabetes Prevention Program (DPP) cohort.
METHODS: The DPP recruited persons with elevated fasting glucose (5.3-6.9 mmol/l) and impaired glucose tolerance, and no history of diagnosed diabetes, other than gestational diabetes not persisting after pregnancy. Seven-field, stereoscopic fundus photography was completed a mean of 3.1 years after the development of diabetes in 594 of 878 participants who had developed diabetes during the DPP, and in a random sample of 302 participants who remained non-diabetic.
RESULTS: Retinopathy consistent with diabetic retinopathy was detected in 12.6 and 7.9% of the diabetic and non-diabetic participants, respectively (P = 0.03, comparing prevalence in the two groups). Systolic blood pressure and HbA(1c) were higher at baseline in the diabetic participants who had retinopathy compared with the diabetic participants without retinopathy.
CONCLUSIONS: Retinopathy characteristic of diabetes is present in persons with elevated fasting glucose and impaired glucose tolerance and no known history of diabetes. The prevalence of retinopathy is significantly higher in persons who develop diabetes, even within 3 years of diagnosis.

PMID 17257275
Abstract/Text OBJECTIVE: To assess the effect of pregnancy on the development and progression of retinopathy and microalbuminuria in type 1 diabetes.
RESEARCH DESIGN AND METHODS: We conducted longitudinal analyses of the Diabetes Control and Complications Trial (DCCT), a multicenter controlled clinical trial that compared intensive treatment with conventional diabetes therapy and studied 180 women who had 270 pregnancies and 500 women who did not become pregnant during an average of 6.5 years of follow-up. Women assigned to the conventional treatment group were changed to intensive therapy if they were planning pregnancy or as soon as possible after conception. Fundus photography was performed every 6 months, and the urinary albumin excretion rate (AER) was measured annually.
RESULTS: Compared with nonpregnant women, pregnant women had a 1.63-fold greater risk of any worsening of retinopathy from before to during pregnancy (P < 0.05) in the intensive treatment group; the risk was 2.48-fold greater for pregnant vs. not pregnant women in the conventional group (P < 0.001). In the conventional group, the odds of > or =3-step progression from the baseline retinopathy level was >2.9-fold among pregnant vs. not pregnant women (P = 0.003). The odds ratio (OR) peaked during the second trimester (OR = 4.26, P = 0.001) and persisted as long as 12 months postpregnancy (OR = 2.87, P = 0.005). The level of AER during pregnancy in the intensive group, but not in the conventional group, was significantly elevated from the level at baseline, albeit in the normal range. Although individual patients had transient worsening of retinopathy during pregnancy, even to the proliferative level, at the end of the DCCT, mean levels of retinopathy and albuminuria in subjects who had become pregnant were similar to those in subjects who had not become pregnant within each treatment group.
CONCLUSIONS: Pregnancy in type 1 diabetes induces a transient increase in the risk of retinopathy; increased ophthalmologic surveillance is needed during pregnancy and the first year postpartum. The long-term risk of progression of early retinopathy and albumin excretion, however, does not appear to be increased by pregnancy.

PMID 10937502
B E Klein, S E Moss, R Klein
Effect of pregnancy on progression of diabetic retinopathy.
Diabetes Care. 1990 Jan;13(1):34-40. doi: 10.2337/diacare.13.1.34.
Abstract/Text A prospective study was undertaken to determine the effect of pregnancy on diabetic retinopathy. Insulin-taking diabetic women were enrolled; one group was comprised of pregnant women, the other group was comprised of women who were not pregnant. Women were evaluated on referral and again in the postpartum period. The severity of diabetic retinopathy was based on grading of fundus photographs of seven standard photographic fields. The glycosylated hemoglobin, duration of diabetes, current age, diastolic blood pressure, number of past pregnancies, and current pregnancy status were evaluated as risk factors for progression of diabetic retinopathy. After adjusting for glycosylated hemoglobin, current pregnancy was significantly associated with progression (P less than 0.005, adjusted odds ratio 2.3). Diastolic blood pressure had a lesser effect on the probability of progression. The findings from this study indicate that pregnancy and level of glycemia are associated with progression of diabetic retinopathy.

PMID 2404715
E Y Chew, J L Mills, B E Metzger, N A Remaley, L Jovanovic-Peterson, R H Knopp, M Conley, L Rand, J L Simpson, L B Holmes
Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study.
Diabetes Care. 1995 May;18(5):631-7.
Abstract/Text OBJECTIVE: To evaluate the role of metabolic control in the progression of diabetic retinopathy during pregnancy.
RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of 155 diabetic women in the Diabetes in Early Pregnancy Study followed from the periconceptional period to 1 month postpartum. Fundus photographs were obtained shortly after conception (95% within 5 weeks of conception) and within 1 month postpartum. Glycosylated hemoglobin was measured weekly during the 1st trimester and monthly thereafter.
RESULTS: In the 140 patients who did not have proliferative retinopathy at baseline, progression of retinopathy was seen in 10.3, 21.1, 18.8, and 54.8% of patients with no retinopathy, microaneurysms only, mild nonproliferative retinopathy, and moderate-to-severe nonproliferative retinopathy at baseline, respectively. Proliferative retinopathy developed in 6.3% with mild and 29% with moderate-to-severe baseline retinopathy. Elevated glycosylated hemoglobin at baseline and the magnitude of improvement of glucose control through week 14 were associated with a higher risk of progression of retinopathy (adjusted odds ratio for progression in those with glycohemoglobin > or = 6 SD above the control mean versus those within 2 SD was 2.7; 95% confidence interval was 1.1-7.2; P = 0.039).
CONCLUSIONS: The risk for progression of diabetic retinopathy was increased by initial glycosylated hemoglobin elevations as low as 6 SD above the control mean. This increased risk may be due to suboptimal control itself or to the rapid improvement in metabolic control that occurred in early pregnancy. Excellent metabolic control before conception may be required to avoid this increase in risk. Those with moderate-to-severe retinopathy at conception need more careful ophthalmic monitoring, particularly if their diabetes was suboptimally controlled at conception.

PMID 8586000
A Sasaki, N Horiuchi, K Hasewgawa, M Uehara
Development of diabetic retinopathy and its associated risk factors in type 2 diabetic patients in Osaka district, Japan: a long-term prospective study.
Diabetes Res Clin Pract. 1990 Nov-Dec;10(3):257-63. doi: 10.1016/0168-8227(90)90069-6.
Abstract/Text Incidence rates of diabetic retinopathy and its associated risk factors were studied in a long-term prospective study involving 976 type 2 (non-insulin dependent) diabetic patients that showed no retinopathy at entry to the study. 322 of the patients (one-third of the subjects studied) developed diabetic retinopathy during the observation period (average length 8.3 years). The incidence rate per 1000 person-years was 39.8. The rate was significantly related to age at onset of diabetes, to fasting plasma glucose (FPG) level at entry, and to type of treatment. The incidence rate was also related to the duration of the disease. Glycemic control clearly played a role in the occurrence of retinopathy. Patients with FPG greater than or equal to 200 mg/dl had the highest incidence rate, while patients with FPG less than 140 mg/dl showed the lowest incidence rate throughout the observation period. Furthermore, a longer period between onset of diabetes and development of retinopathy was observed in patients with FPG less than 140 mg/dl compared to patients with FPG greater than or equal to 200 mg/dl. The findings suggest that strict glycemic control may be of particular value to reduce the incidence of retinopathy and to delay its appearance in type 2 diabetic patients.

PMID 2073873
R Green, G Giebisch
Ionic requirements of proximal tubular sodium transport. II. Hydrogen ion.
Am J Physiol. 1975 Nov;229(5):1216-26. doi: 10.1152/ajplegacy.1975.229.5.1216.
Abstract/Text Simultaneous perfusion to proximal convoluted tubules and peritubular capillaries was used to study the effects of different perfusion fluids on sodium reabsorption and hydrogen secretion, which was calculated as bicarbonate reabsorption and titratable acid. Results show that sodium reabsorption was not tightly coupled to hydrogen secretion. Bicarbonate stimulates both sodium reabsorption and hydrogen secretion, but Tris stimulates only sodium reabsorption. Imposing an adverse chloride gradient across the proximal tubule (C1- peritubular greater than C1- luminal) decreased sodium reabsorption but did not diminish hydrogen secretion. Diamox inhibited both net sodium and hydrogen transport. It is concluded that there is not firm linkage between sodium reabsorption and hydrogen secretion and that bicarbonate probably stimulates sodium transport by a number of mechanisms, including an effect on the sodium transport unrelated to its ability to increase hydrogen ion secretion.

PMID 909
Leanne Bellamy, Juan-Pablo Casas, Aroon D Hingorani, David Williams
Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis.
Lancet. 2009 May 23;373(9677):1773-9. doi: 10.1016/S0140-6736(09)60731-5.
Abstract/Text BACKGROUND: Women with gestational diabetes are at increased risk of developing type 2 diabetes, but the risk and time of onset have not been fully quantified. We therefore did a comprehensive systematic review and meta-analysis to assess the strength of association between these conditions and the effect of factors that might modify the risk.
METHODS: We identified cohort studies in which women who had developed type 2 diabetes after gestational diabetes were followed up between Jan 1, 1960, and Jan 31, 2009, from Embase and Medline. 205 relevant reports were hand searched. We selected 20 studies that included 675 455 women and 10 859 type 2 diabetic events. We calculated and pooled unadjusted relative risks (RRs) with 95% CIs for each study using a random-effects model. Subgroups analysed were the number of cases of type 2 diabetes, ethnic origin, duration of follow-up, maternal age, body-mass index, and diagnostic criteria.
FINDINGS: Women with gestational diabetes had an increased risk of developing type 2 diabetes compared with those who had a normoglycaemic pregnancy (RR 7.43, 95% CI 4.79-11.51). Although the largest study (659 164 women; 9502 cases of type 2 diabetes) had the largest RR (12.6, 95% CI 12.15-13.19), RRs were generally consistent among the subgroups assessed.
INTERPRETATION: Increased awareness of the magnitude and timing of the risk of type 2 diabetes after gestational diabetes among patients and clinicians could provide an opportunity to test and use dietary, lifestyle, and pharmacological interventions that might prevent or delay the onset of type 2 diabetes in affected women.
FUNDING: None.

PMID 19465232
T Sugiyama, M Saito, H Nishigori, S Nagase, N Yaegashi, N Sagawa, R Kawano, K Ichihara, M Sanaka, S Akazawa, S Anazawa, M Waguri, H Sameshima, Y Hiramatsu, N Toyoda, Japan Diabetes and Pregnancy Study Group
Comparison of pregnancy outcomes between women with gestational diabetes and overt diabetes first diagnosed in pregnancy: a retrospective multi-institutional study in Japan.
Diabetes Res Clin Pract. 2014 Jan;103(1):20-5. doi: 10.1016/j.diabres.2013.10.020. Epub 2013 Nov 8.
Abstract/Text AIMS: To determine differences in pregnancy outcomes including diabetic complications, maternal and perinatal complications between gestational diabetes mellitus and overt diabetes in pregnancy in Japan.
METHODS: A multi-institutional retrospective study compared pregnancy outcomes between gestational diabetes mellitus and overt diabetes in pregnancy. We examined pregnant women who met the former criteria for gestational diabetes mellitus and received dietary intervention with self-monitoring of blood glucose with or without insulin. Overt diabetes in pregnancy was defined as ≥2 abnormal values on 75-g oral glucose tolerance test, fasting glucose ≥126 mg/dl (7.0 mmol/l) and 2-h postprandial glucose ≥200 mg/dl (11.1 mmol/l), or glycated hemoglobin levels ≥6.5% (48 mmol/mol).
RESULTS: Data were collected on 1267 women with gestational diabetes and 348 with overt diabetes in pregnancy. Pregestational body mass index was higher (26.2 ± 6.1 vs. 24.9 ± 5.7 kg, P<0.05) and gestational age at delivery was earlier (37.8 ± 2.5 weeks vs. 38.1 ± 2.1 weeks, P<0.05) in overt diabetes than in gestational diabetes. Glycated hemoglobin (6.8 ± 1.1% [51 mmol/mol] vs. 5.8 ± 0.5% [40 mmol/mol], P<0.05) and glucose on 75-g oral glucose tolerance test and prevalence of retinopathy (1.2% vs. 0%, P<0.05) and pregnancy-induced hypertension (10.1% vs. 6.1%, P<0.05) were higher in overt diabetes than in gestational diabetes. Pregnancy-induced hypertension was associated with pregestational body mass index, gestational weight gain, chronic hypertension, and nulliparity but not with 75-g oral glucose tolerance test.
CONCLUSIONS: Overt diabetes in pregnancy is significantly associated with maternal complications such as retinopathy and pregnancy-induced hypertension.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
PMID 24405981
Abstract/Text In a population-based study in southern Wisconsin, 996 insulin-taking, younger-onset diabetic persons were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 17% to 97.5% in persons with diabetes for less than five years and 15 or more years, respectively. Proliferative retinopathy varied from 1.2% to 67% in persons with diabetes for less than ten years and 35 or more years, respectively. For persons with diabetes of 10 years' duration or less, the Cox regression model relates the severity or retinopathy to longer duration, older age at examination, and higher levels of glycosylated hemoglobin. After ten years of diabetes, severity of retinopathy was related to longer duration, high levels of glycosylated hemoglobin, presence of proteinuria, higher diastolic BP, and male sex.

PMID 6367724
Abstract/Text Data from the Early Treatment Diabetic Retinopathy Study (ETDRS) show that focal photocoagulation of "clinically significant" diabetic macular edema substantially reduces the risk of visual loss. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. In this randomized clinical trial, which was supported by the National Eye Institute, 754 eyes that had macular edema and mild to moderate diabetic retinopathy were randomly assigned to focal argon laser photocoagulation, while 1,490 such eyes were randomly assigned to deferral of photocoagulation. The beneficial effects of treatment demonstrated in this trial suggest that all eyes with clinically significant diabetic macular edema should be considered for focal photocoagulation. Clinically significant macular edema is defined as retinal thickening that involves or threatens the center of the macula (even if visual acuity is not yet reduced) and is assessed by stereo contact lens biomicroscopy or stereo photography. Follow-up of all ETDRS patients continues without other modifications in the study protocol.

PMID 2866759
David J Browning, Michael M Altaweel, Neil M Bressler, Susan B Bressler, Ingrid U Scott, Diabetic Retinopathy Clinical Research Network
Diabetic macular edema: what is focal and what is diffuse?
Am J Ophthalmol. 2008 Nov;146(5):649-55, 655.e1-6. doi: 10.1016/j.ajo.2008.07.013. Epub 2008 Sep 5.
Abstract/Text PURPOSE: To review the available information on classification of diabetic macular edema (DME) as focal or diffuse.
DESIGN: Interpretive essay.
METHODS: Literature review and interpretation.
RESULTS: The terms focal diabetic macular edema and diffuse diabetic macular edema frequently are used without clear definitions. Published definitions often use different examination methods and often are inconsistent. Evaluating published information on the prevalence of focal and diffuse DME, the responses of focal and diffuse DME to treatments, and the importance of focal and diffuse DME in assessing prognosis is hindered because the terms are used inconsistently. A newer vocabulary may be more constructive, one that describes discrete components of the concepts such as extent and location of macular thickening, involvement of the center of the macula, quantity and pattern of lipid exudates, source of fluorescein leakage, and regional variation in macular thickening and that distinguishes these terms from the use of the term focal when describing one type of photocoagulation technique. Developing methods for assessing component variables that can be used in clinical practice and establishing reproducibility of the methods are important tasks.
CONCLUSIONS: Little evidence exists that characteristics of DME described by the terms focal and diffuse help to explain variation in visual acuity or response to treatment. It is unresolved whether a concept of focal and diffuse DME will prove clinically useful despite frequent use of the terms when describing management of DME. Further studies to address the issues are needed.

PMID 18774122
Y Ohkubo, H Kishikawa, E Araki, T Miyata, S Isami, S Motoyoshi, Y Kojima, N Furuyoshi, M Shichiri
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
Diabetes Res Clin Pract. 1995 May;28(2):103-17.
Abstract/Text To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows; HbA1c < 6.5%, FBG < 110 mg/dl, and 2-h post-prandial blood glucose concentration < 180 mg/dl.

PMID 7587918
日本糖尿病学会:糖尿病診療ガイドライン2019.
Abstract/Text BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.
METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.
FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).
INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)

PMID 9742976
Rury R Holman, Sanjoy K Paul, M Angelyn Bethel, David R Matthews, H Andrew W Neil
10-year follow-up of intensive glucose control in type 2 diabetes.
N Engl J Med. 2008 Oct 9;359(15):1577-89. doi: 10.1056/NEJMoa0806470. Epub 2008 Sep 10.
Abstract/Text BACKGROUND: During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.
METHODS: Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.
RESULTS: Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).
CONCLUSIONS: Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)

2008 Massachusetts Medical Society
PMID 18784090
Abstract/Text BACKGROUND: Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS: A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS: In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

PMID 8366922
Abstract/Text BACKGROUND: Among patients with type 1 diabetes mellitus, intensive therapy (with the aim of achieving near-normal blood glucose and glycosylated hemoglobin concentrations [hemoglobin A1c]) markedly reduces the risk of microvascular complications as compared with conventional therapy. To assess whether these benefits persist, we compared the effects of former and intensive conventional therapy on the recurrence and severity of retinopathy and nephropathy for four years after the end of the Diabetes Control and Complications Trial (DCCT).
METHODS: At the end of the DCCT, the patients in the conventional-therapy group were offered intensive therapy, and the care of all patients was transferred to their own physicians. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1208 patients during the fourth year after the DCCT ended, and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year, approximately half of whom were from each treatment group.
RESULTS: The difference in the median glycosylated hemoglobin values between the conventional-therapy and intensive-therapy groups during the 6.5 years of the DCCT (average, 9.1 percent and 7.2 percent, respectively) narrowed during follow-up (median during 4 years, 8.2 percent and 7.9 percent, respectively, P<0.001). Nevertheless, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular edema, and the need for laser therapy, was lower in the intensive-therapy group than in the conventional-therapy group (odds reduction, 72 percent to 87 percent, P<0.001). The proportion of patients with an increase in urinary albumin excretion was significantly lower in the intensive-therapy group.
CONCLUSIONS: The reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persists for at least four years, despite increasing hyperglycemia.

PMID 10666428
David M Nathan, Patricia A Cleary, Jye-Yu C Backlund, Saul M Genuth, John M Lachin, Trevor J Orchard, Philip Raskin, Bernard Zinman, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group
Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
N Engl J Med. 2005 Dec 22;353(25):2643-53. doi: 10.1056/NEJMoa052187.
Abstract/Text BACKGROUND: Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease.
METHODS: The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and 1993. Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee.
RESULTS: During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P< or =0.05) after adjusting for these factors.
CONCLUSIONS: Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.

Copyright 2005 Massachusetts Medical Society.
PMID 16371630
Neil H White, Wanjie Sun, Patricia A Cleary, Ronald P Danis, Matthew D Davis, Dean P Hainsworth, Larry D Hubbard, John M Lachin, David M Nathan
Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial.
Arch Ophthalmol. 2008 Dec;126(12):1707-15. doi: 10.1001/archopht.126.12.1707.
Abstract/Text OBJECTIVE: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.
METHODS: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.
RESULTS: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT.
CONCLUSION: The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.
TRIAL REGISTRATION: (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

PMID 19064853
Abstract/Text OBJECTIVES: To document the frequency, importance of, and risk factors for "early worsening" of diabetic retinopathy in the Diabetes Control and Complications Trial (DCCT).
METHODS: The DCCT was a multicenter, randomized clinical trial comparing intensive vs conventional treatment in insulin-dependent diabetic patients who had no to moderate nonproliferative retinopathy. Retinopathy severity was assessed in 7-field stereoscopic fundus photographs taken at baseline and every 6 months. For this study, worsening was defined as progression of 3 steps or more on the Early Treatment Diabetic Retinopathy Study final scale, as the development of soft exudates and/or intraretinal microvascular abnormalities, as the development of clinically important retinopathy, or as any of the above, and was considered "early" if it occurred between baseline and 12-month follow-up visits.
RESULTS: Early worsening was observed at the 6- and/or 12-month visit in 13.1% of 711 patients assigned to intensive treatment and in 7.6% of 728 patients assigned to conventional treatment (odds ratio, 2.06; P < .001); recovery had occurred at the 18-month visit in 51% and 55% of these groups, respectively (P = .39). The risk of 3-step or greater progression from the retinopathy level present 18 months after entry into the trial was greater in patients who previously had had early worsening than in those who had not. However, the large long-term risk reduction with intensive treatment was such that outcomes in intensively treated patients who had early worsening were similar to or more favorable than outcomes in conventionally treated patients who had not. The most important risk factors for early worsening were higher hemoglobin A1c level at screening and reduction of this level during the first 6 months after randomization. We found no evidence to suggest that more gradual reduction of glycemia might be associated with less risk of early worsening. Early worsening led to high-risk proliferative retinopathy in 2 patients and to clinically significant macular edema in 3; all responded well to treatment.
CONCLUSIONS: In the DCCT, the long-term benefits of intensive insulin treatment greatly outweighed the risks of early worsening. Although no case of early worsening was associated with serious visual loss, our results are consistent with previous reports of sight-threatening worsening when intensive treatment is initiated in patients with long-standing poor glycemic control, particularly if retinopathy is at or past the moderate nonproliferative stage. Ophthalmologic monitoring before initiation of intensive treatment and at 3-month intervals for 6 to 12 months thereafter seems appropriate for such patients. In patients whose retinopathy is already approaching the high-risk stage, it may be prudent to delay the initiation of intensive treatment until photocoagulation can be completed, particularly if hemoglobin A1c is high.

PMID 9682700
Masahiko Yamamoto, Kazuya Fujihara, Masahiro Ishizawa, Taeko Osawa, Masanori Kaneko, Hajime Ishiguro, Yasuhiro Matsubayashi, Hiroyasu Seida, Nauta Yamanaka, Shiro Tanaka, Satoru Kodama, Hiruma Hasebe, Hirohito Sone
Pulse Pressure is a Stronger Predictor Than Systolic Blood Pressure for Severe Eye Diseases in Diabetes Mellitus.
J Am Heart Assoc. 2019 Apr 16;8(8):e010627. doi: 10.1161/JAHA.118.010627.
Abstract/Text Background Evidence of the role of systolic blood pressure ( SBP ) in development of severe diabetic retinopathy is not strong, although the adverse effect of low diastolic blood pressure has been a partial explanation. We assessed the predictive ability of incident severe diabetic retinopathy between pulse pressure ( PP ) which considers both SBP and diastolic blood pressure, compared with SBP . Methods and Results Eligible patients (12 242, 83% men) aged 19 to 72 years from a nationwide claims database were analyzed for a median observational 4.8-year period. Severe diabetic retinopathy was defined as vision-threatening treatment-required diabetic eye diseases. Multivariate Cox regression analysis revealed that hazard ratios (95% CI ) of treatment-required diabetic eye diseases for 1 increment of standard deviation and the top tertile compared with the bottom tertile were 1.39 (1.21-1.60) and 1.72 (1.17-2.51), respectively, for PP and 1.22 (1.05-1.41) and 1.43 (0.97-2.11), respectively, for SBP adjusted for age, sex, body mass index, hemoglobin A1c, fasting plasma glucose, lipids, and smoking status. In a model with SBP and PP simultaneously as covariates, the hazard ratios of only PP (hazard ratios [95% CI ], 1.57 [1.26-1.96]) but not SBP (0.85 [0.68-1.07]) were statistically significant. Delong test revealed a significant difference in the area under the receiver operating characteristic curve between PP and SBP (area under the receiver operating characteristic curve [95% CI ], 0.58 [0.54-0.63] versus 0.54 [0.50-0.59]; P=0.03). The strongest predictor remained as hemoglobin A1c (area under the receiver operating characteristic curve [95% CI ], 0.80 [0.77-0.84]). Conclusions After excluding the significant impact of glycemic control, PP in comparison with SBP is a better predictor of severe diabetic retinopathy, suggesting a role of diastolic blood pressure and arterial stiffness in pathology.

PMID 30971163
A C Keech, P Mitchell, P A Summanen, J O'Day, T M E Davis, M S Moffitt, M-R Taskinen, R J Simes, D Tse, E Williamson, A Merrifield, L T Laatikainen, M C d'Emden, D C Crimet, R L O'Connell, P G Colman, FIELD study investigators
Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.
Lancet. 2007 Nov 17;370(9600):1687-97. doi: 10.1016/S0140-6736(07)61607-9. Epub 2007 Nov 7.
Abstract/Text BACKGROUND: Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus.
METHODS: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481.
FINDINGS: Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022).
INTERPRETATION: Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.

PMID 17988728
ACCORD Study Group, ACCORD Eye Study Group, Emily Y Chew, Walter T Ambrosius, Matthew D Davis, Ronald P Danis, Sapna Gangaputra, Craig M Greven, Larry Hubbard, Barbara A Esser, James F Lovato, Letitia H Perdue, David C Goff, William C Cushman, Henry N Ginsberg, Marshall B Elam, Saul Genuth, Hertzel C Gerstein, Ulrich Schubart, Lawrence J Fine
Effects of medical therapies on retinopathy progression in type 2 diabetes.
N Engl J Med. 2010 Jul 15;363(3):233-44. doi: 10.1056/NEJMoa1001288. Epub 2010 Jun 29.
Abstract/Text BACKGROUND: We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy.
METHODS: In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.
RESULTS: At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29).
CONCLUSIONS: Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

2010 Massachusetts Medical Society
PMID 20587587
Sune F Nielsen, Børge G Nordestgaard
Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study.
Lancet Diabetes Endocrinol. 2014 Nov;2(11):894-900. doi: 10.1016/S2213-8587(14)70173-1. Epub 2014 Sep 9.
Abstract/Text BACKGROUND: The role of statins in the development of microvascular disease in patients with diabetes is unknown. We tested the hypothesis that statin use increases the risk of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and gangrene of the foot in individuals with diabetes.
METHODS: We identified all patients living in Denmark who were aged 40 years or older and were diagnosed with incident diabetes between Jan 1, 1996, and Dec 31, 2009. We obtained patients' data from the Danish Patient Registry and information on drug use from the Danish Registry of Medicinal Product Statistics. We randomly selected 15,679 individuals from the database who had used statins regularly until their diagnosis of diabetes (statin users) and matched them in a 1:3 ratio with 47,037 individuals who had never used statins before diagnosis (non-statin users). Our primary outcome was to compare the cumulative incidence of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or gangrene of the foot in statin users versus non-statin users. We analysed data with Cox regression models, adjusted for covariates including sex, age at diabetes diagnosis, and method of diabetes diagnosis. To address potential biases between statin users and non-statin users, we made adjustments to our analysis with a propensity score and with other factors. Median follow-up was 2·7 years (range 0-13).
FINDINGS: During 215,725 person-years of follow-up, 2866 patients developed diabetic retinopathy, 1406 developed diabetic neuropathy, 1248 developed diabetic nephropathy, and 2392 developed gangrene of the foot. Compared with non-statin users, statin users had a lower cumulative incidence of diabetic retinopathy (hazard ratio 0·60, 95% CI 0·54-0·66; p<0·0001), diabetic neuropathy (0·66, 0·57-0·75; p<0·0001), and gangrene of the foot (0·88, 0·80-0·97; p=0·010), but not diabetic nephropathy (0·97, 0·85-1·10; p=0·62). These results were similar after adjusting for the competing risk of death, after matching for a propensity score, after adjusting for visits to a family doctor, and by stratification on covariates. The corresponding multivariable adjusted hazard ratio for risk of diabetes in the total population was 1·17 (95% CI 1·14-1·21; p<0·0001).
INTERPRETATION: Use of statins before diagnosis of incident diabetes was not associated with an increased risk of microvascular disease. Whether statins are protective against some forms of microvascular disease-a possibility raised by these data-will need to be addressed in other studies similar to ours, in mendelian randomisation studies, and preferably in randomised controlled trials.
FUNDING: Herlev Hospital, Copenhagen University Hospital.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25217178
Haibing Chen, Zhi Zheng, Yan Huang, Kaifeng Guo, Junxi Lu, Lei Zhang, Haoyong Yu, Yuqian Bao, Weiping Jia
A microalbuminuria threshold to predict the risk for the development of diabetic retinopathy in type 2 diabetes mellitus patients.
PLoS One. 2012;7(5):e36718. doi: 10.1371/journal.pone.0036718. Epub 2012 May 10.
Abstract/Text OBJECTIVE: To test the hypothesis that a microalbuminuria (MA) threshold can help predict the risk for the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM)_ patients.
DESIGN: We conducted a cross-sectional study of 4739 subjects with T2DM and a prospective study of 297 subjects with T2DM in China respectively.
METHODS: Clinical and laboratory data were collected and biologic risk factors associated with any DR were analysed.
RESULTS: In the cross-sectional study, we found that MA was an independent risk factor for DR development; further, when the patients were divided into MA deciles, odds ratio (ORs) of DR for the patients in the sixth MA decile (10.7 mg/24 h) was 1.579-fold (1.161-2.147) compared to that for patients in the first MA decile. Furthermore, the OR of DR increased with a gradual increase in MA levels. Similarly, in the prospective study, during a mean follow-up of 4.5 years, we found that 51 patients (29.0%) of the 176 subjects with high MA level (10.7-30 mg/24 h) developed DR, while 17 patients (14.1%) of the 121 subjects with lower MA (<10.7 mg/24 h) developed DR, and the relative risk ratio of the development of DR is 2.13(95% CI, 1.58-3.62, P<0.001).
CONCLUSION: These data suggest that an MA threshold can predict the risk for the development of DR in type 2 diabetes mellitus, although it is still within the traditionally established normal range.

PMID 22590593
Ryan Eyn Kidd Man, Muhammad Bayu Sasongko, Jie Jin Wang, Richard MacIsaac, Tien Yin Wong, Charumathi Sabanayagam, Ecosse L Lamoureux
The Association of Estimated Glomerular Filtration Rate With Diabetic Retinopathy and Macular Edema.
Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4810-6. doi: 10.1167/iovs.15-16987.
Abstract/Text PURPOSE: Albuminuria, a marker of diabetic kidney disease, is closely associated with diabetic retinopathy (DR) and diabetic macular edema (DME). However, the relationship between estimated glomerular filtration rate (eGFR) with DR and DME remains unclear, particularly in type 2 diabetes. We investigated the association of eGFR with DR and DME in a sample of patients with type 2 diabetes.
METHODS: We included 263 Caucasian patients with type 2 diabetes aged ≥ 18 years who participated in a clinic-based cross-sectional study in Melbourne, Australia. Diabetic retinopathy (n = 140) and DME (n = 61) were assessed from retinal photographs graded using the modified Airlie House classification and further confirmed with optical coherence tomography. Estimated glomerular filtration rate, assessed using the CKD-EPI formula, was analyzed continuously (per SD change) and categorically (normal renal function ≥ 90; impaired renal function, 60-89, and chronic kidney disease [CKD] < 60 mL/min/1.73 m2).
RESULTS: When eGFR was analyzed categorically, impaired renal function and CKD were associated with the presence of DR when compared to normal renal function in multivariable models (odds ratio [OR] with 95% confidence interval [CI] of 2.97 [1.12-7.87] and 3.77 [1.28-11.10]), respectively. In DR severity analyses, CKD showed significant associations with moderate (5.83 [1.44-23.5], P-trend = 0.02) and severe DR (4.91 [1.26-19.0], P-trend = 0.04). These associations persisted when eGFR was analyzed continuously (P = 0.04). No significant associations were found between eGFR and DME.
CONCLUSIONS: Our results suggest that lower levels of eGFR were associated with the presence and severity of DR, but not with DME.

PMID 26218909
Yoshihiro Takamura, Takehiro Matsumura, Kishiko Ohkoshi, Tatsuhiko Takei, Kunihiro Ishikawa, Masahiko Shimura, Tetsuo Ueda, Masahiko Sugimoto, Takao Hirano, Kei Takayama, Makoto Gozawa, Yutaka Yamada, Masakazu Morioka, Masayuki Iwano, Masaru Inatani
Functional and anatomical changes in diabetic macular edema after hemodialysis initiation: One-year follow-up multicenter study.
Sci Rep. 2020 May 8;10(1):7788. doi: 10.1038/s41598-020-64798-4. Epub 2020 May 8.
Abstract/Text Diabetic nephropathy and retinopathy (DR) including diabetic macular edema (DME) are representative microvascular complications of diabetes. We conducted a retrospective multicenter study analyzing records from patients with DR (132 eyes in 70 patients) and end-stage renal diseases (ESRD) who underwent hemodialysis for the first time. We demonstrated that the central retinal thickness (CRT) values were significantly decreased (p < 0.0001), and the best-corrected visual acuity (BCVA) values were improved (p < 0.05) at 1, 3, 6, 9, and 12 months after hemodialysis initiation, in spite of a lack of specific ocular treatments for DME in 93.2% of eyes. We found a significant positive correlation in the rates of CRT changes between right and left eyes. The CRT reductions were greater in eyes with DME type subretinal detachment than in those with spongelike swelling and cystoid macular edema. The visual outcome gain was associated with the CRT reduction at 12 months in the eyes with good initial BCVA (≧20/50). Hemodialysis induction contributed to functional and anatomical improvements after 1 year, independently of initial laboratory values before the hemodialysis.

PMID 32385333
Diabetic Retinopathy Clinical Research Network, Michael J Elman, Lloyd Paul Aiello, Roy W Beck, Neil M Bressler, Susan B Bressler, Allison R Edwards, Frederick L Ferris, Scott M Friedman, Adam R Glassman, Kellee M Miller, Ingrid U Scott, Cynthia R Stockdale, Jennifer K Sun
Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.
Ophthalmology. 2010 Jun;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031. Epub 2010 Apr 28.
Abstract/Text OBJECTIVE: Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
METHODS: Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at 1 year.
RESULTS: The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
CONCLUSIONS: Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.

Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PMID 20427088
Quan Dong Nguyen, Syed Mahmood Shah, Afsheen A Khwaja, Roomasa Channa, Elham Hatef, Diana V Do, David Boyer, Jeffery S Heier, Prema Abraham, Allen B Thach, Eugene S Lit, Bradley S Foster, Erik Kruger, Pravin Dugel, Thomas Chang, Arup Das, Thomas A Ciulla, John S Pollack, Jennifer I Lim, Dean Eliott, Dean Eliot, Peter A Campochiaro, READ-2 Study Group
Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study.
Ophthalmology. 2010 Nov;117(11):2146-51. doi: 10.1016/j.ophtha.2010.08.016. Epub 2010 Sep 19.
Abstract/Text OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME).
DESIGN: Prospective, randomized, interventional, multicenter clinical trial.
PARTICIPANTS: One hundred twenty-six patients with DME.
METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ.
MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24.
RESULTS: After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively.
CONCLUSIONS: Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PMID 20855114
Paul Mitchell, Francesco Bandello, Ursula Schmidt-Erfurth, Gabriele E Lang, Pascale Massin, Reinier O Schlingemann, Florian Sutter, Christian Simader, Gabriela Burian, Ortrud Gerstner, Andreas Weichselberger, RESTORE study group
The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema.
Ophthalmology. 2011 Apr;118(4):615-25. doi: 10.1016/j.ophtha.2011.01.031.
Abstract/Text OBJECTIVE: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).
DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
PARTICIPANTS: We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
METHODS: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
MAIN OUTCOME MEASURES: Mean average change in BCVA from baseline to month 1 through 12 and safety.
RESULTS: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
CONCLUSIONS: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.

Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PMID 21459215
Jean-François Korobelnik, Diana V Do, Ursula Schmidt-Erfurth, David S Boyer, Frank G Holz, Jeffrey S Heier, Edoardo Midena, Peter K Kaiser, Hiroko Terasaki, Dennis M Marcus, Quan D Nguyen, Glenn J Jaffe, Jason S Slakter, Christian Simader, Yuhwen Soo, Thomas Schmelter, George D Yancopoulos, Neil Stahl, Robert Vitti, Alyson J Berliner, Oliver Zeitz, Carola Metzig, David M Brown
Intravitreal aflibercept for diabetic macular edema.
Ophthalmology. 2014 Nov;121(11):2247-54. doi: 10.1016/j.ophtha.2014.05.006. Epub 2014 Jul 8.
Abstract/Text PURPOSE: A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME).
DESIGN: Two similarly designed, double-masked, randomized, phase 3 trials, VISTA(DME) and VIVID(DME).
PARTICIPANTS: We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement.
METHODS: Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation.
MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography.
RESULTS: Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 μm (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 μm (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups.
CONCLUSIONS: At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated.

Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PMID 25012934
Quan Dong Nguyen, David M Brown, Dennis M Marcus, David S Boyer, Sunil Patel, Leonard Feiner, Andrea Gibson, Judy Sy, Amy Chen Rundle, J Jill Hopkins, Roman G Rubio, Jason S Ehrlich, RISE and RIDE Research Group
Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE.
Ophthalmology. 2012 Apr;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11.
Abstract/Text PURPOSE: To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients.
DESIGN: Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies.
PARTICIPANTS: Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT).
INTERVENTION: Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria.
MAIN OUTCOME MEASURES: Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months.
RESULTS: In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8-34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7-31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8-42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3-0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients.
CONCLUSIONS: Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.

Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PMID 22330964
Christian Prünte, Franck Fajnkuchen, Sajjad Mahmood, Federico Ricci, Katja Hatz, Jan Studnička, Vladimir Bezlyak, Soumil Parikh, William John Stubbings, Andreas Wenzel, João Figueira, RETAIN Study Group
Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study.
Br J Ophthalmol. 2016 Jun;100(6):787-95. doi: 10.1136/bjophthalmol-2015-307249. Epub 2015 Oct 9.
Abstract/Text AIMS: To demonstrate non-inferiority of ranibizumab treat-and-extend (T&E) with/without laser to ranibizumab pro re nata (PRN) for best-corrected visual acuity (BCVA) in patients with diabetic macular oedema (DMO).
METHODS: A 24-month single-masked study with patients randomised 1:1:1 to T&E+laser (n=121), T&E (n=128) or PRN (control; n=123). All patients received monthly injections until BCVA stabilisation. The investigator decided on re-treatment in the PRN and treatment-interval adaptations in the T&E groups based on loss of BCVA stability due to DMO activity. Likewise, laser treatment was at investigator's discretion. Collectively, these features reflect a real-life scenario. Endpoints included mean average change in BCVA from baseline to months 1-12 (primary), mean BCVA change from baseline to months 12 and 24, treatment exposure and safety profile.
RESULTS: Both T&E regimens were non-inferior to PRN based on mean average BCVA change from baseline to months 1-12 (T&E+laser: +5.9 and T&E: +6.1 vs PRN: +6.2 letters; both p<0.0001). Mean BCVA change at month 24 was similar across groups (+8.3, +6.5 and +8.1 letters, respectively). The mean number of injections was 12.4 and 12.8 in the T&E+laser and T&E groups and 10.7 in the PRN group. The T&E regimens showed 46% reduction in the number of clinic visits. Over 70% of patients maintained their BCVA, with treatment intervals of ≥2 months over 24 months. Safety profile was consistent with that described in the product information.
CONCLUSIONS: T&E is a feasible treatment option for patients with DMO, with a potential to reduce treatment burden. Slightly more injections were required versus PRN, likely due to the specifics of the T&E regimen applied here.
TRIAL REGISTRATION NUMBER: NCT01171976.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
PMID 26453639
H Lewis, G W Abrams, M S Blumenkranz, R V Campo
Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction.
Ophthalmology. 1992 May;99(5):753-9. doi: 10.1016/s0161-6420(92)31901-3.
Abstract/Text Pars plana vitrectomy with separation of the posterior hyaloid was performed in 10 eyes with diabetic macular edema and traction associated with a thickened and taut premacular posterior hyaloid. Nine of the 10 eyes had previous macular photocoagulation. Preoperative fluorescein angiography showed a deep and diffuse pattern of leakage in the macula. Intraoperatively, the attached and thickened posterior hyaloid was lifted and separated from the retina. Postoperatively, vision improved in nine eyes. The macular traction and edema resolved in eight eyes and decreased in two. Complications included a vitreous hemorrhage, a rhegmatogenous retinal detachment, cataract formation, and a mild epimacular membrane, each occurring in one eye. Vitreous surgery can improve the visual prognosis of some eyes with diabetic macular traction and edema associated with a thickened and taut posterior hyaloid.

PMID 1594222
N Tachi, N Ogino
Vitrectomy for diffuse macular edema in cases of diabetic retinopathy.
Am J Ophthalmol. 1996 Aug;122(2):258-60. doi: 10.1016/s0002-9394(14)72018-5.
Abstract/Text PURPOSE: To ascertain the effects of posterior vitreous detachment for diffuse diabetic macular edema.
METHODS: We performed vitrectomy on 58 eyes of 41 consecutive patients with diabetic macular edema without posterior vitreous detachment. Follow-up was done at 12 months postoperatively.
RESULTS: In 57 of 58 eyes after vitrectomy and posterior vitreous detachment, macular edema resolved, and diffuse fluorescein leakage disappeared in 35 of 36 eyes examined at the 12th month. Visual improvement was statistically significant (P < .0001, paired t test).
CONCLUSION: In eyes with diffuse diabetic macular edema and without posterior vitreous detachment, vitrectomy with posterior vitreous detachment may be effective.

PMID 8694095
Teiko Yamamoto, Koichiro Hitani, Itsuro Tsukahara, Shuichi Yamamoto, Ryo Kawasaki, Hidetoshi Yamashita, Shinobu Takeuchi
Early postoperative retinal thickness changes and complications after vitrectomy for diabetic macular edema.
Am J Ophthalmol. 2003 Jan;135(1):14-9. doi: 10.1016/s0002-9394(02)01819-6.
Abstract/Text PURPOSE: To determine the early postoperative changes in retinal thickness and complications after pars plana vitrectomy for diabetic macular edema.
DESIGN: Consecutive interventional case series.
METHODS: Studied retrospectively, pars plana vitrectomy was performed on 65 consecutive eyes of 63 patients with diabetic macular edema. The follow-up interval ranged from 6 to 36 months (12.6 +/- 7.4 months [mean +/- standard deviation (SD)]). The indications of pars plana vitrectomy in this study were (1) diffuse diabetic macular edema, (2) preoperative visual acuity less than 20/40, and (3) noneffective macular photocoagulation therapy. Preoperative and postoperative examinations by stereoscopic biomicroscopy, color fundus photography of the macula and optical coherence tomography (OCT) were performed on all eyes. Preoperatively, direct photocoagulation to microaneurysms in the macula had been performed in 48 eyes, and focal/grid photocoagulation had been performed in five eyes. Preoperative examination showed that epiretinal membranes were observed in 20 eyes, cystoid macular edema in 40 eyes, and 23 eyes had a complete posterior vitreous detachment (PVD). Epimacular membranes, removed during surgery, were examined histopathologically.
RESULTS: The postoperative mean best-corrected visual acuity (logarithm of the minimum angle of resolution [logMAR] = 0.696 +/- 0.491 [mean +/- SD]) was significantly better than the preoperative mean best-corrected visual acuity (0.827 +/- 0.361; P <.0001; Wilcoxon signed-rank test). The final visual acuity improved by 2 or more lines in 32 of 65 eyes (45%), remained unchanged in 32 of 65 eyes (49%), and exacerbated after the surgery in 4 of 65 eyes (6%) due to neovascular glaucoma (2 eyes) and residual cystoid macular edema (2 eyes). The postoperative foveal retinal thickness (224.9 +/- 116.9 microm) at the last visit was significantly thinner than the preoperative foveal retinal thickness (463.7 +/- 177.3 microm; P <.0001; Wilcoxon signed-rank test). The foveal retinal thickness did not decrease linearly but fluctuated: The mean postoperative retinal thickness had decreased significantly 7 days after surgery, then remained unchanged for approximately 1 month, and thereafter gradually decreased until 4 months. The intraoperative and postoperative complications included peripheral retinal tear in 3 of 65 (4.6%) eyes, postoperative rhegmatogenous retinal detachment in 1 of 65 (1.5%) eyes, neovascular glaucoma in 3 of 65 (5%) eyes, recurrent vitreous hemorrhage in 1 of 65 (1.5%) eyes, hard exudates in the center of the macula in 3 of 56 (4.6%) eyes, postoperative epiretinal membrane formation in 9 of 65 (13.8%) eyes, and a lamellar macular hole in 1 of 65 (1.5%) eyes.
CONCLUSIONS: Vitrectomy for diabetic macular edema is an effective procedure for reducing the edema and improving visual acuity. Because the postoperative reduction in retinal thickness is not complete until 4 months, the assessment of vitrectomy on foveal thickness should not be made until this time. In addition, there are severe complications from vitrectomy for diabetic macular edema, and careful preoperative and postoperative examinations and surgical methods are required.

PMID 12504691
Abstract/Text The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3711 patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy in both eyes. One eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation. Follow-up examinations were scheduled at least every 4 months and photocoagulation was initiated in eyes assigned to deferral as soon as high-risk proliferative retinopathy was detected. Eyes selected for early photocoagulation received one of four different combinations of scatter (panretinal) and focal treatment. This early treatment, compared with deferral of photocoagulation, was associated with a small reduction in the incidence of severe visual loss (visual acuity less than 5/200 at two consecutive visits), but 5-year rates were low in both the early treatment and deferral groups (2.6% and 3.7%, respectively). Adverse effects of scatter photocoagulation on visual acuity and visual field also were observed. These adverse effects were most evident in the months immediately following treatment and were less in eyes assigned to less extensive scatter photocoagulation. Provided careful follow-up can be maintained, scatter photocoagulation is not recommended for eyes with mild or moderate nonproliferative diabetic retinopathy. When retinopathy is more severe, scatter photocoagulation should be considered and usually should not be delayed if the eye has reached the high-risk proliferative stage. The ETDRS results demonstrate that, for eyes with macular edema, focal photocoagulation is effective in reducing the risk of moderate visual loss but that scatter photocoagulation is not. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. Focal treatment should be considered for eyes with macular edema that involves or threatens the center of the macula.

PMID 2062512
Japanese Society of Ophthalmic Diabetology, Subcommittee on the Study of Diabetic Retinopathy Treatment, Yukihiro Sato, Noriko Kojimahara, Shigehiko Kitano, Satoshi Kato, Noburo Ando, Naohito Yamaguchi, Sadao Hori
Multicenter randomized clinical trial of retinal photocoagulation for preproliferative diabetic retinopathy.
Jpn J Ophthalmol. 2012 Jan;56(1):52-9. doi: 10.1007/s10384-011-0095-2. Epub 2011 Oct 19.
Abstract/Text PURPOSE: To evaluate the effectiveness of selective photocoagulation (S-PC) for nonperfusion areas (NPA) in preproliferative diabetic retinopathy (PPDR).
SUBJECTS AND METHODS: A multicenter randomized controlled clinical trial of 69 patients with PPDR showing NPA comparable to or larger than those on reference photographs. The patients were assigned to 2 groups; one was treated with S-PC (PC group: 32 patients), while the other did not receive S-PS (non-PC group: 37 patients). In the non-PC group, panretinal photocoagulation (PRP) was performed whenever proliferative diabetic retinopathy (PDR) developed. In the PC group, S-PC of the NPA was performed followed by additional coagulation whenever the NPA extended, and PRP was performed whenever PDR developed. The primary outcome was the development of PDR.
RESULTS: During the entire course, PDR developed in 18 (26%) of the 69 patients. The incidence was significantly higher in the non-PC group than in the PC group. Comparison of the visual acuity at the time of registration and after 36 months showed no significant differences between the two groups.
CONCLUSIONS: S-PC for NPA in PPDR is effective at preventing PDR development.

PMID 22009219
Writing Committee for the Diabetic Retinopathy Clinical Research Network, Jeffrey G Gross, Adam R Glassman, Lee M Jampol, Seidu Inusah, Lloyd Paul Aiello, Andrew N Antoszyk, Carl W Baker, Brian B Berger, Neil M Bressler, David Browning, Michael J Elman, Frederick L Ferris, Scott M Friedman, Dennis M Marcus, Michele Melia, Cynthia R Stockdale, Jennifer K Sun, Roy W Beck
Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.
JAMA. 2015 Nov 24;314(20):2137-2146. doi: 10.1001/jama.2015.15217.
Abstract/Text IMPORTANCE: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME).
OBJECTIVE: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy.
DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.
INTERVENTIONS: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME.
MAIN OUTCOMES AND MEASURES: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.
RESULTS: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified.
CONCLUSIONS AND RELEVANCE: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01489189.

PMID 26565927
Sobha Sivaprasad, A Toby Prevost, Joana C Vasconcelos, Amy Riddell, Caroline Murphy, Joanna Kelly, James Bainbridge, Rhiannon Tudor-Edwards, David Hopkins, Philip Hykin, CLARITY Study Group
Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial.
Lancet. 2017 Jun 3;389(10085):2193-2203. doi: 10.1016/S0140-6736(17)31193-5. Epub 2017 May 7.
Abstract/Text BACKGROUND: Proliferative diabetic retinopathy is the most common cause of severe sight impairment in people with diabetes. Proliferative diabetic retinopathy has been managed by panretinal laser photocoagulation (PRP) for the past 40 years. We report the 1 year safety and efficacy of intravitreal aflibercept.
METHODS: In this phase 2b, single-blind, non-inferiority trial (CLARITY), adults (aged ≥18 years) with type 1 or 2 diabetes and previously untreated or post-laser treated active proliferative diabetic retinopathy were recruited from 22 UK ophthalmic centres. Patients were randomly assigned (1:1) to repeated intravitreal aflibercept (2 mg/0·05 mL at baseline, 4 weeks, and 8 weeks, and from week 12 patients were reviewed every 4 weeks and aflibercept injections were given as needed) or PRP standard care (single spot or mutlispot laser at baseline, fractionated fortnightly thereafter, and from week 12 patients were assessed every 8 weeks and treated with PRP as needed) for 52 weeks. Randomisation was by minimisation with a web-based computer generated system. Primary outcome assessors were masked optometrists. The treating ophthalmologists and participants were not masked. The primary outcome was defined as a change in best-corrected visual acuity at 52 weeks with a linear mixed-effect model that estimated adjusted treatment effects at both 12 weeks and 52 weeks, having excluded fluctuations in best corrected visual acuity owing to vitreous haemorrhage. This modified intention-to-treat analysis was reapplied to the per protocol participants. The non-inferiority margin was prespecified as -5 Early Treatment Diabetic Retinopathy Study letters. Safety was assessed in all participants. This trial is registered with ISRCTN registry, number 32207582.
FINDINGS: We recruited 232 participants (116 per group) between Aug 22, 2014 and Nov 30, 2015. 221 participants (112 in aflibercept group, 109 in PRP group) contributed to the modified intention-to-treat model, and 210 participants (104 in aflibercept group and 106 in PRP group) within per protocol. Aflibercept was non-inferior and superior to PRP in both the modified intention-to-treat population (mean best corrected visual acuity difference 3·9 letters [95% CI 2·3-5·6], p<0·0001) and the per-protocol population (4·0 letters [2·4-5·7], p<0·0001). There were no safety concerns. The 95% CI adjusted difference between groups was more than the prespecified acceptable margin of -5 letters at both 12 weeks and 52 weeks.
INTERPRETATION: Patients with proliferative diabetic retinopathy who were treated with intravitreal aflibercept had an improved outcome at 1 year compared with those treated with PRP standard care.
FUNDING: The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28494920
Abstract/Text
PMID 2447027
Abstract/Text The Diabetic Retinopathy Study (DRS) Research Group has so far identified four retinopathy factors that increase the two-year risk of developing severe visual loss. The risk grows as the number of risk factors increases. Eyes with three or more risk factors (eyes with "high-risk characteristics") are at a much higher risk than eyes with two or fewer factors. The DRS protocol was changed in 1976 to require consideration of treatment for these "high-risk" eyes.

PMID 426679
Daniel Lavinsky, Jose A Cardillo, Yossi Mandel, Philip Huie, Luiz A Melo, Michel E Farah, Rubens Belfort, Daniel Palanker
Restoration of retinal morphology and residual scarring after photocoagulation.
Acta Ophthalmol. 2013 Jun;91(4):e315-23. doi: 10.1111/aos.12045. Epub 2013 Apr 5.
Abstract/Text PURPOSE: To study healing of retinal laser lesions in patients undergoing PRP using SD-OCT.
METHODS: Moderate, light and barely visible retinal burns were produced in patients with proliferative diabetic retinopathy scheduled for PRP using 100-, 20- and 10-ms pulses of 532-nm laser, with retinal spot sizes of 100, 200 and 400 μm. Lesions were measured with OCT at 1 hr, 1 week, 1, 2, 4, 6, 9 and 12 months. OCT imaging was correlated with histology in a separate study in rabbits.
RESULTS: Lesions produced by the standard 100-ms exposures exhibited steady scarring, with the damage zone stabilized after 2 months. For 400- and 200-μm spots and 100-ms pulses, the residual scar area at 12 months was approximately 50% of the initial lesion size for moderate, light and barely visible burns. In contrast, lesions produced by shorter exposures demonstrated enhanced restoration of the photoreceptor layer, especially in smaller burns. With 20-ms pulses, the damage zone decreased to 32%, 24% and 20% for moderate, light and barely visible burns of 400 μm, respectively, and down to 12% for barely visible burns of 200 μm. In the 100-μm spots, the residual scar area of the moderate 100-ms burns was 41% of the initial lesion, while barely visible 10-ms burns contracted to 6% of the initial size. Histological observations in rabbits were useful for proper interpretation of the damage zone boundaries in OCT.
CONCLUSIONS: Traditional photocoagulation parameters (400 μm, 100 ms and moderate burn) result in a stable scar similar in size to the beam diameter. Restoration of the damaged photoreceptor layer in lighter lesions produced by shorter pulses should allow reducing the common side-effects of photocoagulation such as scotomata and scarring.

© 2013 The Authors. Acta Ophthalmologica © 2013 Acta Ophthalmologica Scandinavica Foundation.
PMID 23557390
Aimee V Chappelow, Kevin Tan, Nadia K Waheed, Peter K Kaiser
Panretinal photocoagulation for proliferative diabetic retinopathy: pattern scan laser versus argon laser.
Am J Ophthalmol. 2012 Jan;153(1):137-42.e2. doi: 10.1016/j.ajo.2011.05.035. Epub 2011 Sep 19.
Abstract/Text PURPOSE: To evaluate the efficacy of the pattern scan laser (PASCAL) in treating newly diagnosed high-risk proliferative diabetic retinopathy (PDR).
DESIGN: Retrospective comparative case series.
METHODS:
SETTING: Institutional.
STUDY POPULATION: Eighty-two consecutive eyes of the same number of patients with newly diagnosed high-risk PDR treated with panretinal photocoagulation (PRP) using either argon green laser (41 eyes treated before February 2007) or PASCAL (41 eyes treated February 2007 or thereafter), then followed for at least 6 months.
PROCEDURE: Retrospective chart review with attention to main outcome measures, age, sex, race, follow-up interval, insulin dependence, hemoglobin A1c, and total number of lasers spots.
MAIN OUTCOME MEASURES: Persistence or recurrence of neovascularization, incidence of vitreous hemorrhage (VH), neovascularization of the iris (NVI), neovascular glaucoma (NVG), and need for vitrectomy.
RESULTS: Patients treated with the PASCAL and argon laser received a similar number of spots (1438 vs 1386; P = .59). Patients treated with the PASCAL were more likely to experience persistence or recurrence of neovascularization within 6 months of initial treatment (73% vs 34%; P < .0008). The study was not adequately powered to detect a significant difference in incidence of vitreous hemorrhage, NVI, NVG, or need for vitrectomy.
CONCLUSIONS: When using traditional laser settings, PRP performed with the PASCAL is less effective than that performed with traditional argon laser in effecting lasting regression of retinal neovascularization in the setting of previously untreated high-risk PDR. Physicians may need to change treatment parameters when using PASCAL pattern laser therapy for high-risk PDR.

Copyright © 2012 Elsevier Inc. All rights reserved.
PMID 21937017
María H Berrocal, Luis A Acaba, Alexandra Acaba
Surgery for Diabetic Eye Complications.
Curr Diab Rep. 2016 Oct;16(10):99. doi: 10.1007/s11892-016-0787-6.
Abstract/Text New modalities for the treatment of diabetic eye complications have emerged in the past decade. Nevertheless, many severe diabetic retinopathy complications can only be treated with vitreoretinal surgery. Technological advances in pars plana vitrectomy have expanded the gamut of pathologies that can be successfully treated with surgery. The most common pathologies managed surgically include vitreous opacities and traction retinal detachment. The indications, surgical objectives, adjunctive pharmacotherapy, microincisional surgical techniques, and outcomes of diabetic vitrectomy for proliferative diabetic retinopathy and diabetic tractional retinal detachment will be discussed. With the availability of new microincisional vitrectomy technology, wide angle microscope viewing systems, and pharmacologic agents, vitrectomy can improve visual acuity and achieve long-term anatomic stability in eyes with severe complications from proliferative diabetic retinopathy.

PMID 27612846
Anthony P Adamis, Michael Altaweel, Neil M Bressler, Emmett T Cunningham, Matthew D Davis, Mauro Goldbaum, Christine Gonzales, David R Guyer, Katz Barrett, Manju Patel, Macugen Diabetic Retinopathy Study Group
Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.
Ophthalmology. 2006 Jan;113(1):23-8. doi: 10.1016/j.ophtha.2005.10.012. Epub 2005 Dec 15.
Abstract/Text OBJECTIVE: To study effects of intravitreal pegaptanib (Macugen) on retinal neovascularization.
DESIGN: Retrospective analysis of a randomized clinical trial. PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURES: Individuals with retinal neovascularization identified from a multicenter, randomized, controlled trial evaluating pegaptanib for treatment of diabetic macular edema, with a best-corrected visual acuity letter score between 68 and 25 (approximate Snellen equivalent between 20/50 and 20/320) and receiving a sham injection or intravitreal pegaptanib (0.3 mg, 1 mg, 3 mg) administered at study entry, week 6, and week 12, with additional injections and/or focal photocoagulation as needed during the ensuing 18 weeks, up to a maximum of 6 pegaptanib/sham therapies, were evaluated. Scatter panretinal photocoagulation before study enrollment was permitted, but not within 6 months of randomization and study entry. Changes in retinal neovascularization were assessed on fundus photographs and fluorescein angiograms graded at a reading center in a masked fashion.
RESULTS: Of 172 participants, 19 had retinal neovascularization in the study eye at baseline. Excluding 1 who had scatter photocoagulation 13 days before randomization and 2 with no follow-up photographs, 1 of the remaining 16 subjects had panretinal photocoagulation during study follow-up. Of these 16 subjects, 8 of 13 (62%) in a pegaptanib treatment group (including the one receiving panretinal photocoagulation), 0 of 3 in the sham group, and 0 of 4 fellow (nonstudy) eyes showed either regression of neovascularization on fundus photographs or regression or absence of fluorescein leakage from neovascularization (or both) at 36 weeks. In 3 of 8 with regression, neovascularization progressed at week 52 after cessation of pegaptanib at week 30.
CONCLUSIONS: Most subjects with retinal neovascularization at baseline assigned to pegaptanib showed regression of neovascularization by week 36. These findings suggest a direct effect of pegaptanib upon retinal neovascularization in patients with diabetes mellitus.

PMID 16343627
Ri-ichiro Kohno, Yasuaki Hata, Yasutaka Mochizuki, Ryoichi Arita, Shuhei Kawahara, Takeshi Kita, Masanori Miyazaki, Toshio Hisatomi, Yasuhiro Ikeda, Lloyd Paul Aiello, Tatsuro Ishibashi
Histopathology of neovascular tissue from eyes with proliferative diabetic retinopathy after intravitreal bevacizumab injection.
Am J Ophthalmol. 2010 Aug;150(2):223-229.e1. doi: 10.1016/j.ajo.2010.03.016. Epub 2010 Jun 9.
Abstract/Text PURPOSE: To examine the histopathologic effect of a single intravitreal injection of bevacizumab on newly formed vessels in eyes with proliferative diabetic retinopathy (PDR).
DESIGN: Interventional case series and laboratory investigation.
METHODS: Two days after intravitreal injection of bevacizumab (1.25 mg/eye), pars plana vitrectomy or trabeculectomy was performed for the treatment of PDR or neovascular glaucoma (NVG) associated with PDR. Ten surgically removed preretinal proliferative tissues and 6 deep scleral flaps containing trabecular meshwork were fixed in 2% glutaraldehyde or 4% paraformaldehyde and were subjected to transmission electron microscopic analysis, immunohistochemical analysis, and terminal deoxyuridiine triphosphate (dUTP) nick-end labeling staining. Two surgically removed preretinal proliferative tissues and 2 deep scleral flaps from patients with PDR and NVG, but without preoperative intravitreal injection of bevacizumab (IVB), served as controls.
RESULTS: In control tissues, vascular endothelial cells possessed many fenestrations and were accompanied by pericytes. Apoptotic vascular endothelial cells frequently were observed in tissue after intravitreal injection of bevacizumab, whereas they were not observed in control tissues. Additionally, no apparent fenestration was observed in newly formed vessels from either proliferative tissue or trabecular meshwork after intravitreal injection of bevacizumab. In both PDR and NVG tissues after intravitreal injection of bevacizumab, overexpression of smooth muscle actin was observed in newly formed vessels, suggesting that the treatment may have increased pericytes on the vasculature as compared with control tissue.
CONCLUSIONS: Intravitreal injection of bevacizumab may induce changes in immature, newly formed vessels of PDR or NVG tissue, leading to endothelial apoptosis with vascular regression, while inducing normalization of premature vessels by increasing pericyte coverage and reducing vessel fenestration.

Copyright (c) 2010 Elsevier Inc. All rights reserved.
PMID 20542485
Ayman A Alkawas, Ezzat A Shahien, Atef M Hussein
Management of neovascular glaucoma with panretinal photocoagulation, intravitreal bevacizumab, and subsequent trabeculectomy with mitomycin C.
J Glaucoma. 2010 Dec;19(9):622-6. doi: 10.1097/IJG.0b013e3181ccb794.
Abstract/Text PURPOSE: The aim of this study was to evaluate the safety and efficacy of using intravitreal bevacizumab, panretinal photocoagulation, and trabeculectomy with mitomycin C in the management of neovascular glaucoma.
PATIENTS AND METHODS: The study included 17 eyes of 15 patients with neovascular glaucoma. Panretinal photocoagulation was performed combined with intravitreal bevacizumab injection (1.25 mg in 0.05 mL). A fornix-based conjunctival flap trabeculectomy with intraoperative mitomycin C (0.4mg/mL for 3min) was then performed.
RESULTS: The causes of neovascular glaucoma included: diabetic retinopathy (10 eyes), central retinal vein occlusion (5 eyes), and branch retinal vein occlusion (2 eyes). Complete regression of iris neovascularization after intravitreal bevacizumab injection and panretinal photocoagulation occurred in 14 eyes (82.4%). After trabeculectomy with mitomycin C, mean intraocular pressure was reduced from 42.9±4.2 mm Hg preoperatively to 15.1±2.2, 16.3±2.0, and 19.7±2.1 mm Hg at first week, first month, and sixth months postoperatively, respectively. This reduction was statistically significant (P<0.05). The mean number of antiglaucoma medications used before surgery was 2.8±0.4 (range: 2 to 3) that decreased to 0.8±0.6 (range: 0 to 3) after surgery. Postoperative hypotony (intraocular pressure 7 mm Hg) was observed in 17.6% (3 of 17 eyes), conjunctival dehiscence in 5.9%, shallow anterior chamber in 11.8%, hyphema in 23.5%, choroidal detachment in 11.8%, and epithelial corneal erosions related to applications of mitomycin C in 1 eye (5.9%).
CONCLUSIONS: Trabeculectomy with intraoperative mitomycin C after an adjunctive treatment with intravitreal bevacizumab and panretinal photocoagulation is a good treatment modality in the management of eyes with neovascular glaucoma.

PMID 20179624
Suleyman Ciftci, Yildirim Bayezit Sakalar, Kaan Unlu, Ugur Keklikci, Ihsan Caca, Eyup Dogan
Intravitreal bevacizumab combined with panretinal photocoagulation in the treatment of open angle neovascular glaucoma.
Eur J Ophthalmol. 2009 Nov-Dec;19(6):1028-33.
Abstract/Text PURPOSE: To evaluate the clinical efficacy of intravitreal bevacizumab (IVB) combined with panretinal photocoagulation in patients with open angle neovascular glaucoma (NVG).
METHODS: Nine patients (9 eyes) with NVG participated in this study. Patients received IVB (1.25 mg) as the initial treatment for NVG and were followed up for at least 4 months. IVB was offered as the first treatment of choice to patients with NVG. Panretinal photocoagulation was performed as soon as feasible after the second week and completed in all patients the fourth week after IVB. The main outcome measures are resolution of INV, inhibition of peripheral anterior synechia (PAS), and controllability of intraocular pressure (IOP).
RESULTS: The mean follow-up period was 5.6+/-1.4 months (range, 4-9 months). The mean IOP before treatment was 35.1+/-9.7 mmHg (range, 24-56) under medication before IVB treatment. After IVB and after combined treatment, the mean IOP was reduced to 22.8+/-8.1 mmHg (range, 9-33) and 13.0+/-4.0 mmHg (range, 7-20), respectively. The mean referral INV was 3.6+/-0.4 grade (range, 3-4) and reduced to 1.6+/-0.4 (range 1-2) grade after IVB and 0.6+/-0.8 (range 0-2) grade after combined therapy. By IVB, combined panretinal photocoagulation recurrence of INV was not observed.
CONCLUSIONS: In NVG, IVB treatment can reduce iris and angle neovascularization and inhibits further PAS formation temporarily. Panretinal photocoagulation inhibits neovascularization constantly. Therefore, management of open angle NVG is more feasible with bevacizumab combined with panretinal photocoagulation.

PMID 19882572
Julia Beutel, Swaantje Peters, Matthias Lüke, Sabin Aisenbrey, Peter Szurman, Martin S Spitzer, Efdal Yoeruek, Bevacizumab Study Group, Salvatore Grisanti
Bevacizumab as adjuvant for neovascular glaucoma.
Acta Ophthalmol. 2010 Feb;88(1):103-9. doi: 10.1111/j.1755-3768.2008.01355.x. Epub 2009 Sep 20.
Abstract/Text PURPOSE: We aimed to evaluate the longterm effects of intraocular bevacizumab (Avastin) injections as adjuvant treatment in patients with neovascular glaucoma.
METHODS: Twenty eyes of 18 consecutive patients with secondary neovascular glaucoma caused by proliferative diabetic retinopathy (n = 7), ischaemic central retinal vein occlusion (n = 7), ischaemic ophthalmopathy (n = 2) and retinal ischaemia resulting from persistent detachment (n = 2) were treated with intraocular bevacizumab injections (1.25 mg/0.05 ml) in addition to other treatments. The main outcome measure was the change in degree of iris rubeosis. Secondary outcomes included intraocular pressure (IOP), best corrected visual acuity (BCVA) and numbers of additional interventions or antiglaucoma medications administered after injection.
RESULTS: Mean (+/- standard deviation) follow-up was 67.7 +/- 13.8 weeks (range 50-93 weeks). At the last follow-up, complete regression of rubeosis was detectable in five (20%) eyes, incomplete regression in seven (35%), stabilization in six (30%), and an increase in two (10%) eyes. Mean IOP was 26.0 +/- 8.9 mmHg at baseline and significantly decreased to 14.75 +/- 5.3 mmHg at the last follow-up visit (p = 0.000005). Mean baseline BCVA (logMAR [logarithm of the minimum angle of resolution] 1.43 +/- 0.89) was stabilized during the follow-up period (logMAR 1.5 +/- 0.98). Patients received an average of 2.75 injections. Additional treatments were laser photocoagulation in 13 (65%) eyes, cyclodestructive procedure in 14 (70%), cryopexy in six (30%), drainage procedures in two (10%), and vitrectomy in five (25%) eyes.
CONCLUSIONS: Bevacizumab may be beneficial as adjuvant treatment in neovascular glaucoma because of its anti-angiogenic properties and its ability to prevent establishment or progression of angular obstruction. The causative disease inducing the angiogenic process requires treatment in all cases. Antiglaucoma treatment is needed in cases of persistent elevated IOP.

PMID 18811641
Yanrong Jiang, Xiaoying Liang, Xiaoxin Li, Yong Tao, Kai Wang
Analysis of the clinical efficacy of intravitreal bevacizumab in the treatment of iris neovascularization caused by proliferative diabetic retinopathy.
Acta Ophthalmol. 2009 Nov;87(7):736-40. doi: 10.1111/j.1755-3768.2008.01353.x. Epub 2008 Sep 18.
Abstract/Text PURPOSE:  To evaluate the therapeutic effect of intravitreal bevacizumab (Avastin) (IVB) in the treatment of iris neovascularization (INV) in proliferative diabetic retinopathy (PDR).
METHODS: A retrospective analysis on data collected from 28 eyes of 22 patients with PDR was performed. The analysis included grading of INV, visual acuity (VA) and intraocular pressure (IOP) prior to and after IVB treatment.
RESULTS: Significant regression was noted in 20 eyes (71.4%); six eyes (21.4%) showed partial regression; no change or worsening was observed in two eyes (7.2%). VA (measured with a Snellen acuity chart) improved in five eyes (17.9%) while the remaining 23 eyes (82.1%) had no improvement. In the 11 eyes with preoperative neovascular glaucoma, IOP decreased in 10 eyes (91%) and increased in one eye (9%) after treatment.
CONCLUSION: IVB treatment of INV in PDR patients shows a promising short-term result. Further studies are needed to evaluate long-term results.

PMID 18803622
Pascale Massin, Francesco Bandello, Justus G Garweg, Lutz L Hansen, Simon P Harding, Michael Larsen, Paul Mitchell, Dianne Sharp, U E K Wolf-Schnurrbusch, Margarita Gekkieva, Andreas Weichselberger, Sebastian Wolf
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 Nov;33(11):2399-405. doi: 10.2337/dc10-0493.
Abstract/Text OBJECTIVE: The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.
RESEARCH DESIGN AND METHODS: This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection).
RESULTS: At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 μm with ranibizumab and 48.4±153.4 μm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab.
CONCLUSIONS: Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

PMID 20980427
Diabetic Retinopathy Clinical Research Network, John A Wells, Adam R Glassman, Allison R Ayala, Lee M Jampol, Lloyd Paul Aiello, Andrew N Antoszyk, Bambi Arnold-Bush, Carl W Baker, Neil M Bressler, David J Browning, Michael J Elman, Frederick L Ferris, Scott M Friedman, Michele Melia, Dante J Pieramici, Jennifer K Sun, Roy W Beck
Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.
N Engl J Med. 2015 Mar 26;372(13):1193-203. doi: 10.1056/NEJMoa1414264. Epub 2015 Feb 18.
Abstract/Text BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown.
METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year.
RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56).
CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

PMID 25692915
Abstract/Text Additional follow-up confirms previous reports from the Diabetic Retinopathy Study (DRS) that photocoagulation, as used in the study, reduces the risk of severe visual loss by 50% or more. Decreases of visual acuity of one or more lines and constriction of peripheral visual field due to treatment were also observed in some eyes. These harmful effects were more frequent and more severe following the DRS xenon technique. The two-year risk of severe visual loss without treatment outweighs the risk of harmful treatment effects for two groups of eyes: (1) eyes with new vessels and preretinal or vitreous hemorrhage; and (2) eyes with new vessels on or within one disc diameter of the optic disc (NVD) equaling or exceeding 1/4 to 1/3 disc area in extent, (Fig 1), even in the absence of preretinal or vitreous hemorrhage. For eyes with these characteristics, prompt treatment is usually advisable. For eyes with less severe retinopathy, DRS findings do not provide a clear choice between prompt treatment or deferral unless progression to these more severe stages occurs.

PMID 7196564

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