Current Treatments and Innovations in Diabetic Retinopathy and Diabetic Macular Edema

Diabetic retinopathy (DR) is one of the leading causes of blindness worldwide. Multiple treatment options have been used over time to attempt to modify the natural progression of the disease in both proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). These two retinal complications are the result of microvascular occlusions and vascular hyperpermeability and are considered one of the leading causes of irreversible blindness in patients of working age. It is now well demonstrated that PDR and DME are associated with increased levels of inflammatory and pro-angiogenic factors in the ocular compartment. To date, laser photocoagulation, vascular endothelial growth factor (VEGF) inhibitors, and corticosteroids have demonstrated efficacy in their treatment in large randomized controlled trials and in real-life observational studies. This manuscript aims to provide a comprehensive review of current treatments, including the main drugs used in diabetic pathologic manifestations, as well as new therapeutic alternatives, such as extended-release intraocular devices.

[1]  M. Rahmanian,et al.  Silymarin reduces retinal microvascular damage in streptozotocin-induced diabetic rats , 2022, Scientific Reports.

[2]  L. Kodjikian,et al.  Intra-Ocular Pressure Response to Dexamethasone Implant Injections in Patients with a History of Filtering Surgery: The TRABEX Study , 2022, Pharmaceutics.

[3]  Jennifer K. Sun,et al.  Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. , 2022, The New England journal of medicine.

[4]  A. Mai,et al.  Biochemical Functions and Clinical Characterizations of the Sirtuins in Diabetes-Induced Retinal Pathologies , 2022, International journal of molecular sciences.

[5]  L. Kodjikian,et al.  Efficacy and Safety of Intravitreal Fluocinolone Acetonide Implant for Chronic Diabetic Macular Edema Previously Treated in Real-Life Practice: The REALFAc Study , 2022, Pharmaceutics.

[6]  T. Connor,et al.  Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders , 2022, International journal of molecular sciences.

[7]  F. Behar-Cohen,et al.  Fluocinolone acetonide implant in diabetic macular edema: International experts’ panel consensus guidelines and treatment algorithm , 2022, European journal of ophthalmology.

[8]  Arthur D. Fu,et al.  Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. , 2022, Lancet.

[9]  N. Ngah,et al.  KESTREL and KITE: 52-week results from two Phase III pivotal trials of brolucizumab for diabetic macular edema , 2022, American Journal of Ophthalmology.

[10]  K. Tsubota,et al.  Updates on the Current Treatments for Diabetic Retinopathy and Possibility of Future Oral Therapy , 2021, Journal of clinical medicine.

[11]  A. Sudhalkar,et al.  Treatment Algorithm in Proliferative Diabetic Retinopathy. From Protocols to the Real World , 2021, Diabetic Eye Disease - From Therapeutic Pipeline to the Real World [Working Title].

[12]  C. Wykoff,et al.  Evaluation of Intravitreal Aflibercept for the Treatment of Severe Nonproliferative Diabetic Retinopathy , 2021, JAMA ophthalmology.

[13]  L. Kodjikian,et al.  Real-World Experience with Brolucizumab in Wet Age-Related Macular Degeneration: The REBA Study , 2021, Journal of clinical medicine.

[14]  P. Kaiser,et al.  Intravitreal conbercept for diabetic macular oedema: 2-year results from a randomised controlled trial and open-label extension study , 2021, British Journal of Ophthalmology.

[15]  Jennifer K. Sun,et al.  Effect of Intravitreous Anti-Vascular Endothelial Growth Factor vs Sham Treatment for Prevention of Vision-Threatening Complications of Diabetic Retinopathy: The Protocol W Randomized Clinical Trial. , 2021, JAMA ophthalmology.

[16]  C. Creuzot-Garcher,et al.  Real-World Efficacy and Safety of Fluocinolone Acetonide Implant for Diabetic Macular Edema: A Systematic Review , 2021, Pharmaceutics.

[17]  Jennifer K. Sun,et al.  Effect of Intravitreous Aflibercept vs Vitrectomy With Panretinal Photocoagulation on Visual Acuity in Patients With Vitreous Hemorrhage From Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. , 2020, JAMA.

[18]  N. Voirin,et al.  LONG-TERM INCIDENCE AND RISK FACTORS OF OCULAR HYPERTENSION FOLLOWING DEXAMETHASONE-IMPLANT INJECTIONS , 2020, Retina.

[19]  Ivana K. Kim,et al.  Risk of inflammation, retinal vasculitis and retinal occlusion-related events with brolucizumab: post-hoc review of HAWK and HARRIER. , 2020, Ophthalmology.

[20]  Nitin Chitranshi,et al.  Recent advances in intraocular and novel drug delivery systems for the treatment of diabetic retinopathy , 2020, Expert opinion on drug delivery.

[21]  N. Voirin,et al.  Long-term follow-up of diabetic macular edema treated with dexamethasone implant: a real-life study , 2020, Acta Diabetologica.

[22]  K. Khunti,et al.  Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group , 2020, Eye.

[23]  Jennifer K. Sun,et al.  Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study). , 2020, Ophthalmology.

[24]  Yan Mei,et al.  Accumulation of advanced glycation end products potentiate human retinal capillary endothelial cells mediated diabetic retinopathy , 2019, Molecular medicine reports.

[25]  C. Wykoff,et al.  Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial. , 2019, Ophthalmology.

[26]  Christina Y. Weng,et al.  Treatment of Diabetic Macular Edema , 2019, Current Diabetes Reports.

[27]  J. Naor,et al.  Phase 1 first-in-human study of KSI-301: a novel anti-VEGF antibody biopolymer conjugate with extended durability , 2019 .

[28]  T. Ciulla,et al.  Innovative therapies for neovascular age-related macular degeneration , 2019, Expert opinion on pharmacotherapy.

[29]  A. Koh,et al.  First-line treatment algorithm and guidelines in center-involving diabetic macular edema , 2019, European journal of ophthalmology.

[30]  A. Loewenstein,et al.  TRActional DIabetic reTInal detachment surgery with co-adjuvant intravitreal dexamethasONe implant: the TRADITION STUDY , 2019, Acta Diabetologica.

[31]  A. Loewenstein,et al.  The Role of Steroids in the Management of Diabetic Macular Edema , 2019, Ophthalmic Research.

[32]  Hao-jie Liu,et al.  Fangchinoline Ameliorates Diabetic Retinopathy by Inhibiting Receptor for Advanced Glycation End-Products (RAGE)-Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) Pathway in Streptozotocin (STZ)-Induced Diabetic Rats , 2019, Medical science monitor : international medical journal of experimental and clinical research.

[33]  Horace Massa,et al.  Intravitreal fluocinolone acetonide implant (ILUVIEN®) for diabetic macular oedema: a literature review , 2018, The Journal of international medical research.

[34]  U. Schmidt-Erfurth,et al.  HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. , 2019, Ophthalmology.

[35]  M. Maia,et al.  Effectiveness and Safety of Intravitreal Dexamethasone Implant (Ozurdex) in Patients with Diabetic Macular Edema: A Real-World Experience , 2018, Ophthalmologica.

[36]  L. Kodjikian,et al.  Pharmacological Management of Diabetic Macular Edema in Real-Life Observational Studies , 2018, BioMed research international.

[37]  Dong Li,et al.  Conbercept for patients with age-related macular degeneration: a systematic review , 2018, BMC Ophthalmology.

[38]  Bo-jie Hu,et al.  A meta-analysis of the effect of a dexamethasone intravitreal implant versus intravitreal anti-vascular endothelial growth factor treatment for diabetic macular edema , 2018, BMC Ophthalmology.

[39]  A. Loewenstein,et al.  Progression of diabetic retinopathy severity after treatment with dexamethasone implant: a 24-month cohort study the ‘DR-Pro-DEX Study’ , 2018, Acta Diabetologica.

[40]  G. Karimi,et al.  The role of SIRT1 in diabetic retinopathy. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[41]  R. Avery,et al.  SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB , 2017, Retina.

[42]  C. Klein,et al.  Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases , 2017, EMBO molecular medicine.

[43]  K. Alitalo,et al.  Therapeutic targeting of the angiopoietin–TIE pathway , 2017, Nature Reviews Drug Discovery.

[44]  Bianca S. Gerendas,et al.  Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA) , 2017, Ophthalmologica.

[45]  D. Steel,et al.  Diabetic Macular Edema Outcomes in Eyes Treated with Fluocinolone Acetonide 0.2 µg/d Intravitreal Implant: Real-World UK Experience , 2017, European journal of ophthalmology.

[46]  B. Mushtaq,et al.  Report of 12-months efficacy and safety of intravitreal fluocinolone acetonide implant for the treatment of chronic diabetic macular oedema: a real-world result in the United Kingdom , 2017, Eye.

[47]  P. Kaiser,et al.  Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. , 2016, Ophthalmology.

[48]  N. Bressler,et al.  Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. , 2016, Ophthalmology.

[49]  T. Lim,et al.  Drug, delivery and devices for diabetic retinopathy (3Ds in DR) , 2016, Expert opinion on drug delivery.

[50]  David R Webb,et al.  Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective , 2015, Postgraduate Medical Journal.

[51]  Jennifer K. Sun,et al.  Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. , 2015, JAMA.

[52]  P. Kaiser,et al.  Intravitreal aflibercept for diabetic macular edema. , 2014, Ophthalmology.

[53]  P. Campochiaro,et al.  Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema. , 2014, Ophthalmology.

[54]  S. Whitcup,et al.  Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. , 2014, Ophthalmology.

[55]  W. Lee,et al.  EFFECT OF INTRAVITREAL TRIAMCINOLONE IN DIABETIC MACULAR EDEMA UNRESPONSIVE TO INTRAVITREAL BEVACIZUMAB , 2014, Retina.

[56]  R. Avery,et al.  Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD , 2014, British Journal of Ophthalmology.

[57]  R. Schlingemann,et al.  Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions , 2013, Progress in Retinal and Eye Research.

[58]  P. Kuebler,et al.  Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: a population approach. , 2013, Investigative ophthalmology & visual science.

[59]  Jian Huang,et al.  Structural Characterization of a Recombinant Fusion Protein by Instrumental Analysis and Molecular Modeling , 2013, PloS one.

[60]  M. Carducci,et al.  From Bevacizumab to Tasquinimod: Angiogenesis as a Therapeutic Target in Prostate Cancer , 2013, Cancer journal.

[61]  Shuqin Wei,et al.  Intravitreal Versus Subtenon Triamcinolone Acetonide Injection for Diabetic Macular Edema: A Systematic Review and Meta-analysis , 2012, Current eye research.

[62]  Ursula Schmidt-Erfurth,et al.  One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. , 2012, Ophthalmology.

[63]  T. Peto,et al.  A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. , 2012, Archives of ophthalmology.

[64]  F. Machibya,et al.  Effect of fangchinoline on root resorption during rat orthodontic tooth movement , 2012, Korean journal of orthodontics.

[65]  Quan Dong Nguyen,et al.  Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. , 2012, Ophthalmology.

[66]  T. Kern,et al.  Inflammation in diabetic retinopathy , 2011, Progress in Retinal and Eye Research.

[67]  M. B. Sultan,et al.  A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. , 2011, Ophthalmology.

[68]  T. Peto,et al.  A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. , 2010, Ophthalmology.

[69]  Lloyd Paul Aiello,et al.  Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema , 2010, Ophthalmology.

[70]  M. Blumenkranz,et al.  Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. , 2010, Ophthalmology.

[71]  T. Peto,et al.  Prospective Randomised Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT Study) - 12 Month Data , 2010 .

[72]  M. Subramanian,et al.  Meta-analysis and review on the effect of bevacizumab in diabetic macular edema , 2010, Graefe's Archive for Clinical and Experimental Ophthalmology.

[73]  坂本 泰二 糖尿病黄斑症の治療はレーザー光凝固かステロイドか? : Diabetic Retinopathy Clinical Research Network 報告について , 2009 .

[74]  N. Bressler,et al.  Observational study of the development of diabetic macular edema following panretinal (scatter) photocoagulation given in 1 or 4 sittings. , 2009, Archives of ophthalmology.

[75]  T. Mimura,et al.  Association of vitreous inflammatory factors with diabetic macular edema. , 2009, Ophthalmology.

[76]  N. Eter,et al.  Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. , 2008, American journal of ophthalmology.

[77]  A. Adamis,et al.  Vascular endothelial growth factor and the potential therapeutic use of pegaptanib (macugen) in diabetic retinopathy. , 2007, Developments in ophthalmology.

[78]  T. Ianchulev,et al.  Role of vascular endothelial growth factor in ocular angiogenesis. , 2006, Ophthalmology clinics of North America.

[79]  Manju Patel,et al.  A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. , 2005, Ophthalmology.

[80]  Martin Vanderlaan,et al.  Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro , 2004, Angiogenesis.

[81]  L. M. Aiello,et al.  Perspectives on diabetic retinopathy. , 2003, American journal of ophthalmology.

[82]  Uday B Kompella,et al.  Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. , 2003, Investigative ophthalmology & visual science.

[83]  G. Yancopoulos,et al.  VEGF-Trap: A VEGF blocker with potent antitumor effects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[84]  H. Yamashita,et al.  Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. , 2002, American journal of ophthalmology.

[85]  E. Dejana,et al.  Interendothelial Junctions and their Role in the Control of Angiogenesis, Vascular Permeability and Leukocyte Transmigration , 2001, Thrombosis and Haemostasis.

[86]  G. Karakiulakis,et al.  Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. , 1998, European journal of pharmacology.

[87]  Thomas N. Sato,et al.  Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation , 1995, Nature.

[88]  Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. , 1985, Archives of ophthalmology.