Paradigm Shift in the treatment of Diabetic Retinopathy. Haytham I. S. Salti, MD Associate Professor

Paradigm Shift in the treatment of Diabetic Retinopathy Haytham I. S. Salti, MD Associate Professor

Disclosure No financial interests related to the subject matter of this talk This presentation includes the off-label use of some medications such as Bevacizumab (Avastin ) and Triamcinolone (Kenacort )

Objectives DR epidemiology Review the recent developments in imaging and studying Diabetic Retinopathy. Review the treatment options for Diabetic Macular Edema (DME). Review the treatment options for Proliferative Diabetic Retinopathy (PDR). Take a look into the future.

The Diabetes Epidemic Significant increase in the incidence of diabetes during the last 20 years Increase across all regions, demographic groups, ages, genders, racial/ethnic groups and subpopulations 800,000 new cases/year in US

1921: Discovery of Insulin: DM became a disease you can live with

With the era of insulin, we moved from the era of diabetic coma to the era of diabetic complications. -- Elliott P. Joslin, 1931

Prevalence of Diabetes Persons over 20 Years of Age 25 20 Percent 15 10 5 0 20-44 45-64 65-74 75+ Age (years)

Vision Loss From Diabetic Retinopathy Vitreous Hemorrhage Traction Retinal Detachment Diabetic Macular Edema

Diabetic Macular Edema and Proliferative Diabetic Retinopathy Prevalence in Lebanon In a recent study, Diabetes Mellitus (DM) prevalence was reported to be around 15.8% in the greater Beirut area. DR reported to be present in 35% of the DM population. 9% having proliferative disease 8% having macular edema.

Diabetic Retinopathy Prevalence in Lebanon

Imaging of DR Stereo Fundus Images

Imaging Fluoresceine Angiography

Imaging Wide field fundus photography and fundus angiography

Imaging Optical Coherence Tomography

OCT angiography Imaging

Diabetic Retinopathy Clinical Research Network DRCR.net: Dedicated to multicenter clinical research of diabetic retinopathy, macular edema & associated disorders

DRCR Network Overview Funding: National Eye Institute-sponsored cooperative agreement initiated September 2002 Objective: The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions.

DRCR Network Sites DRCR.net >150 sites overall >90 communities >450 total PIs >1000 study personnel 40 States www.drcr.net

DRCR DME and PDR studies Randomized trial comparing intravitreal triamcinolone acetonide and laser photocoagulation for DME Evaluation of vitrectomy for DME Observational study of development of DME following scatter laser photocoagulation Subclinical DME study Avastin/ Lucentis / Eylea studies for DME Prompt Panretinal Photocoagulation versus Intravitreal Ranibizumab with Deferred Panretinal Photocoagulation for PDR Randomized Clinical Trial Evaluating Intravitreal Ranibizumab or Intravitreal Saline for Vitreous Hemorrhage from PDR Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study

Sheikh Zayed Road, 1990 Sheikh Zayed Road, 2005

Sheikh Zayed Road, 1990

One of the first randomized trials to establish the benefits of laser for DME Standard of care Focal/Grid laser for CSME Risk of moderate visual loss by 50% or more Improvement of VA by 3 lines was uncommon (<3%)

ETDRS Laser Treatment for CSME 1 year 50% reduction in visual loss 3 years 66% reduction in visual loss

Limitations of Laser Rx: ETDRS (1985) VA rarely improved to => 20/40 Only 3% of pts improved >3 lines of VA (36 months after Rx) Eyes with advanced retinopathy or diffuse ME responded less well No benefit was demonstrated in pts with non-csme

Ablative therapy Pharmacotherapy Zayed Rd 2003

Steroids Potent anti-inflammatory, anti-permeability and anti-angiogenesis effects Administer topically, peribulbar or into the vitreous cavity Triesence (Alcon) Trivaris (Allergan)

Peribulbar Triamcinolone With and Without Focal Laser for Mild DME No significant difference in VA and retinal thickness in all treatment arms at end Steroid caused elevated intra ocular pressure, lid ptosis DRCR Network. Randomized Trial of Peribulbar Triamcinolone Acetonide with and without Focal Photocoagulation for Mild Diabetic Macular Edema A Pilot Study. Ophthalmology. 2007 Jun;114(6): 1190-6

Intravitreal Triamcinolone (IVTA) Initial trials show significant improvement in DME and visual acuity Large trial 2 years 4mg IVTA vs. Sham Half the risk of further loss 56% gained 5 letters vs. 26% placebo Gillies, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2006; 113:1533 1538.

Intravitreal Triamcinolone (IVTA) However. Required repeat injections 68% had increase > 5mm Hg in IOP 55% needed cataract surgery One case of infectious endophthalmitis

Three-Year Follow-up of a Randomized Trial Comparing Focal/Grid Photocoagulation and Intreavitreal Triamcinolone for DME. DRCR Network (Arch Ophthalmol/vol127(No.3)Mar 2009) Objective: To Evaluate 1mg & 4mg doses of IVTA v/s Focal/Grid for DME Design: Prospective, randomized clinical trial Participants: A total of 306 eyes with DME

Focal/Grid Photocoagulation Vs IVTA DME visual loss VA 20/32-20/320 OCT =>250um CSF Laser Focal/Grid 1mg IVTA 4mg IVTA 4 month FU VA was the Primary outcome measure

Focal/Grid Photocoagulation Vs IVTA Laser Focal/Grid 1mg IVTA 4mg IVTA Change in VA letter score from baseline 3 yrs +5 0 0 Worsening VA =>10 letters from baseline 3 yrs 12% 26% 22%

Focal/Grid Photocoagulation Vs Intreavitreal Triamcinolone Conclusion: 1. No long-term benefit of IVTA vs focal/grid Lx in pts with DME 1. Initial response of steroid did not persist 2. Most eyes receiving 4 mg of TA as given in this study are likely to require cataract surgery

Summary: Steroids for DME 1. Modest role for DME 2. Extensive ocular side effects 1. May be of value in a specific subset of patients: 1. pseudophakic 2. poor responders to other therapy

Intravitreal Steroid Pre Post

Vascular Endothelial Growth Factor (VEGF) Elevated intraocular levels in diabetic retinopathy VEGF-A levels Elevated in eyes with DME Higher in eye with extensive leakage than minimal leakage Implicated in the breakdown of blood-retina barrier Increases vascular permeability

Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.

Macugen Intravitreal injection of pegaptanib for DME Gain in VA of 10 letters in 34% vs. 10% control Mean central retinal thickness decreased by 68µm with 0.3mg versus increase of 4µm with sham Decreased necessity for focal laser (25% vs. 48%) Cunningham, et al. A phase II randomized double-masked trial of pegaptanib for diabetic macular edema. Ophthalmology. 2005 Oct; 112(10): 1747 57.

Avastin Primary Treatment Studies suggest significant improvement in visual acuity and macular thickness

Avastin: DRCR net Phase II trial with intravitreal Bevacizumab (Avastin) and/or laser outcome at 24 weeks (short term study) 121 eyes 5 groups: Focal 1.25 mg Avastin once at baseline 1.25 mg avastin at base and 6 weeks 1.25 mg avastin at base and 6 weeks with focal at 3 weeks 2.5 mg avastin at base and 6 weeks DRCR Network. A Phase II Randomized Clinical Trial of Intravitreal Bevacizumab for Diabetic Macular Edema. Ophthalmology. 2007 Oct;114(10): 1860-7

Avastin: DRCR net Avastin groups did better than focal for VA and CMT Quicker response than laser No difference between 1.25mg vs. 2.5mg dose Adding focal to avastin did not appear to add much. DRCR Network. A Phase II Randomized Clinical Trial of Intravitreal Bevacizumab for Diabetic Macular Edema. Ophthalmology. 2007 Oct;114(10): 1860-7

Lucentis (Ranibizumab) READ Study (Ranibizumab for Edema of the macula in Diabetes)

Two-Year Outcomes of the Ranibizumab for Edema of the macula in Diabetes (READ-2) Study Ophthalmology 2010;117:2146 2151 Design: Prospective, randomized, interventional, multicenter clinical trial Participants: A total of 126 patients with DME

0.5 mg RBZ 0, 1, 3, & 5 mth (n=33) Focal/Grid Laser 0 & 3 mth (if needed) (n=34) 0.5 mg RBZ + Laser 0, 3 mth (n=34) Mean improvement in BCVA (letters) @ 6 mth 7.4 0.5 3.8 Mean improvement in BCVA (letters) @ 24 mth 7.7 5.1 6.8

0.5 mg RBZ 0, 1, 3, & 5 mth (n=33) Focal/Grid Laser 0 & 3 mth (if needed) (n=34) 0.5 mg RBZ + Laser 0, 3 mth (n=34) % pt who gained =>3 lines of BCVA @ 6 mths 21 0 6 % pt who gained =>3 lines of BCVA @ 24 mths 24 18 26

0.5 mg RBZ 0, 1, 3, & 5 mth (n=33) Focal/Grid laser 0 & 3 mth (=>250um) (n=34) 0.5 mg RBZ + Laser 0, 3 mth (n=34) Primary end point @ 6 mths Mean no. of injections needed during 18-month (6-24) 5.3 4.4 2.9

Conclusions: 1.IV RBZ provided benefit for pts with DME for at least 2 years 2. IV RBZ gives a quick and long lasting effect 3.when combined with focal/grid laser Tx: Residual edema (36 months data from ARVO) Frequency of injections

Lucentis cases X4 injections X4 injections X4 injections X4 injections

Eylea VIVID and VISTA studies 406 and 466 patients were enrolled respectively.

Eylea

Which is better?

Diabetic Retinopathy Clinical Research Network Aflibercept, Bevacizumab, or Ranibizumab for DME Supported through a cooperative agreement from the National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817

Study Design Randomized, multi-center clinical trial (89 Sites) Participants meeting all of the following criteria: At least 18 years old Type 1 or type 2 diabetes Study eye meeting all of the following criteria: ~Snellen equivalent visual acuity 20/32 or worse and 20/320 or better Central-involved DME on clinical exam Central subfield (CSF) thickness protocol-defined gender and optical coherence tomography (OCT) machine-specific thresholds No history of an anti-vegf treatment for DME in the past 12 months or any other DME treatment in the past 4 months

Mean Change in Visual Acuity Over 2 Years Full Cohort +13.3 +11.2 +9.7 +12.8 +12.3 +10.0 104-Week Treatment Group Comparison*: Aflibercept vs. Bevacizumab P = 0.02 Aflibercept vs. Ranibizumab P = 0.47 Ranibizumab vs. Bevacizumab P = 0.11 61 * P-values adjusted for baseline visual acuity and multiple comparisons

62 Mean Change in Visual Acuity Over 2 Years By Baseline Visual Acuity Subgroup

Pre-Specified Ocular Adverse Events through 2 Years (Non-Study Eyes Receiving Study Drug) % of eyes with at least 1 event Aflibercept (N = 144) Bevacizumab (N = 134) Ranibizumab (N = 132) No. of injections 1180 1316 1225 Endophthalmitis <1% 0 <1% Inflammation 2% <1% 2% Retinal detachment/tear 0 0 2% Vitreous hemorrhage 8% 9% 7% Injection related cataract 1% <1% 0 Intraocular pressure elevation 13% 11% 14% Includes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreal cells. Includes intraocular pressure increase 10mmHg from baseline at any visit, intraocular pressure 30 mmhg at any visit, or initiation of intraocular pressure-lowering medications not in use at baseline, or glaucoma surgery. 63

Pre-specified APTC* Adverse Events through 2 Years % of pts with at least one event Aflibercept (N = 224) Bevacizumab (N = 218) Ranibizumab (N = 218) Non-fatal MI 3% 1% 3% Non-fatal stroke <1% 3% 5% Global P-Value Vascular death 1% 4% 4% Any APTC Event 5% 8% 12% 0.047 Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P = 0.34, aflibercept-ranibizumab: P = 0.047, bevacizumab-ranibizumab: P = 0.20. Global P-value adjusting for gender, age at baseline, Hemoglobin A1c at baseline, diabetes type, diabetes duration at baseline, insulin use, prior coronary artery disease, prior myocardial infarction, prior stroke, prior transient ischemic attack, prior hypertension, smoking status: P = 0.09. * Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy--i: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. 64 Antiplatelet Trialists' Collaboration. BMJ 1994;308:81-106.

Summary: Anti-VEGF for DME 1. Important role in DME 2. Also all three showed that roughly 30% of cases develop regression of their DR stage 3. Good safety profile 4. Could be first line therapy

Steroid Implants

Dexamethazone Implants Ozurdex Injectable, biodegradable intravitreal dexamethasone extended release implant

MEAD study: Three-Year, Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Diabetic Macular Edema David S. Boyer, MD, Young Hee Yoon, MD, PhD, Rubens Belfort, MD, PhD, Francesco Bandello, MD, Raj K. Maturi, MD, Albert J. Augustin, MD, Xiao-Yan Li, MD, Harry Cui, MS, Yehia Hashad, MD, Scott M. Whitcup, MD Ophthalmology Volume 121, Issue 10, Pages 1904-1914 (October 2014) DOI: 10.1016/j.ophtha.2014.04.024 Copyright 2014 American Academy of Ophthalmology Terms and Conditions

Steroid Implants Retisert Intravitreal fluocinolone acetonide implant: lasts 3 years ($15-$18K) 58% implanted vs. 30% of control eyes had resolution of DME 100% cataract About 90% glaucoma 28% needed filtering procedure 5% explanted Pearson, et al. Flucinolone Acetonide Implant Study Group. Retisert to treat diabetic macular edema. Invest Ophthalmol Vis Sci 2006;47

Flucinolone acetonide Implant: (Illuvien): FAME Trial 0.5 mcg/d implant (n=393) 0.2 mcg/d implant (n=375) Sham injection (n=185) Mean improvement in BCVA (letters) @ 24 mth 5.4 4.4 1.7 Campochiaro PA et al. The FAME study. Ophthalmol 2011;118:626-635.

Flucinolone acetonide Implant: (Illuvien): FAME Trial 0.5 mcg/d implant (n=393) 0.2 mcg/d implant (n=375) Sham injection (n=185) Percent improvement of 15 or more letters in BCVA @ 24 mth 28.6 28.7 16.2 100% cataract 30-40% glaucoma Up to 7.6% required trabeculectomy Campochiaro PA et al. The FAME study. Ophthalmol 2011;118:626-635.

FAME A + B: Percentage of Patients With 15-Letter Improvement Over Baseline Primary Readout P =.002 28.7% 28.7% Patients (%) 28.6% 16.2% 27.8% 18.9% P =.018 Months

Diabetic Macular Edema: What is the Treatment Paradigm in 2016?

General Classification CS-DME Center involving (CMT>250microns) Non-center involving Anti-VEGF agents laser

Proposed Classification of DME CS-DME Focal leak Focal thick g Focal leak Diffuse thick g Diffuse non-defined leak Diffuse thickening Diffuse leak Focal thick g laser Laser+ Anti-VEGF agents Anti-VEGF agents laser Ischemic maculopathy Lipid maculopathy

Ablative therapy 25 yr experience Outcomes are durable?limitation ETDRS Pharmacotherapy Acknowledging substantial progress?? Long-term results?? to be answered DRCR net Read 2 study VIVID/ VISTA trials Exact RX and regimen will need to be tailored to individual patients

Panretinal Laser Photocoagulation Benefits: Suppression of severe visual loss 50% reduction in all patients 96% reduction in patients approaching high-risk stage 98% reduction when combined with vitrectomy and glycemic control Suppression of retinal leakage 40% reduction in moderate visual loss Noninvasive, outpatient

Panretinal Laser Photocoagulation Drawbacks: Destroys retina in an attempt to maintain vision Side Effects: Peripheral and night vision loss Changes in color vision Complications: Cornea, iris, lens, fovea burns; choroidal, vitreous hemorrhage, epiretinal membranes/traction

Potential Complications of Laser Photocoagulation PRP through the Macula Laser Burn to Fovea Laser-induced Bruchs Puncture PRP-induced Lenticular Burns

Ablative therapy Pharmacotherapy Zayed Rd 2003

The Diabetic Retinopathy Clinical Research Network Prompt PRP vs. Ranibizumab + Deferred PRP for PDR Study Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 84

10 Letter Score Improvement* N = 104 N = 110 85 *Baseline VA 20/32 or worse N = 81 N = 86

10 Letter Score Worsening P= # 86

15 Letter Score Worsening 2-Year Adjusted Difference: -2% 95% Confidence Interval: (-8%, +3%) 87 N = 191 N = 203 N = 160 N = 168

An ARVO 2011 presentation from NYU Compared 0.5 mg versus 1 mg lucentis for DME 3 initial monthly injections followed by PRN However, the PRN was at 2 monthly intervals The 1 mg group did best but the numbers were too small to conclude A 2 mg group was then added Increasing the dose to 2 mg did not improve the outcome Conclusion: the number of PRN injections may be reduced by studying a 1mg dose in trial settings

Oral Medications Ruboxistaurin Protein Kinase C (PKC) Beta inhibitor Reduces permeability of the blood-retinal barrier PKC-DME Trial No significant effect on progression to sightthreatening DME or need for focal laser Secondary analysis Reduced progression of DR vs. placebo (p=.054) PKC-DMES Study group. Effect of ruboxistaurin in patients with diabetic macular edema. Arch Ophthal 2007; 125:318-324

Anti-TNF Miscellaneous Infliximab is a chimeric IgG1 monoclonal antibody used to treat inflammatory conditions Launching Phase III trial of infliximab for DME Surgical removal of massive macular hard exudate combined with intravitreal triamcinolone in diabetic maculopathy Eye (2007) 21, 562 564 Intravitreal Microplasmin: inducing PVD to treat DME A Phase 2 Multicenter Study to Compare Multiple Doses of Intravitreal Microplasmin for Treatment of Patients With DME (ThromboGenics) Recently FDA approved Miropulse laser: subthreshold micropulsed diode laser burns (each laser application= 100-150 micropulses, 2ms apart) Promising data from clinical trials so far

Failed Oral Medications Aspirin No effect on diabetic retinopathy Ticlopidine Decreased MA s but adverse reactions Sorbinil No effect Astemizol (Antihistamine) No effect Fenofibrate/Clofibrate No effect on DME Octreotide Decreased DR and high-risk DR progression (Thyroxine replacement needed in all treated patients)

Conclusion Prompt Referral to an ophthalmologist for diagnosis and treatment of DME and PDR is important. Controlling systemic factors Treatment should be individually tailored according to patients.

Our secret weapons remain