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Diabetic retinopathy

Diabetic retinopathy. Juan G. Santiago, MD Valley Retina Institute, P.A. Introduction. Epidemiology Pathophysiology Classification Diabetic Retinopathy Diabetic Macular Edema Clinical Trials DRS ETDRS DCCT UKPDS Intro to Treatment. DM in America. 24 million (8%) Americans

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Diabetic retinopathy

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  1. Diabetic retinopathy Juan G. Santiago, MD Valley Retina Institute, P.A.

  2. Introduction • Epidemiology • Pathophysiology • Classification • Diabetic Retinopathy • Diabetic Macular Edema • Clinical Trials • DRS • ETDRS • DCCT • UKPDS • Intro to Treatment

  3. DM in America • 24 million (8%) Americans • ~18 million diagnosed • ~6 million undiagnosed • 5-10% with type 1 diabetes • 57 million with pre-diabetes • 25% > 60 yrs of age with DM *  National Diabetes Fact Sheet, 2007

  4. Prevalence of Diabetes

  5. The Diabetes Epidemic • Significant increase in the incidence of diabetes during the last decade • 1.6 million new cases (aged ≥20 yrs) per year • Increase across all regions, demographic groups, ages, genders, racial/ethnic groups and subpopulations

  6. Incidence of Diabetes

  7. Prevalence of Diabetes by Race/Ethnicity

  8. Diabetic Retinopathy Prevalence • WESDR • ~ 50.3% of DM patients have DR of any type • UKPDS (newly diagnosed Type 2 DM) • ~ 40% with DR at entrance into study

  9. Diabetic Retinopathy Leading cause of PREVENTABLE new-onset blindness in working-age population

  10. Systemic Risk Factors for Progression of DR • Poor glycemic control • Hypertension • Renal Disease • Dyslipidemia • Anemia • Abdominal Obesity • Eating Disorders • Gastroparesis • Pregnancy

  11. Vision Loss From Diabetes • Vitreous Hemorrhage • Tractional Retinal Detachment • Diabetic Macular Edema • Neovascular Glaucoma • Ischemic Maculopathy

  12. Pathophysiology of DR • Fundamental cause – Uncertain • Relative hypoxia • Biochemical changes / Glucose mediated microvascular changes (PKC, advanced glycation end products, VEGF) • Compromised neuroretinal function • Inflammation – “diabetic retinitis” • Glucose excess / insulin deficiency

  13. Pathophysiologic Processes of DR • Loss of pericytes associated with retinal capillaries • Thickening of the basement membrane • Changes in retinal blood flow • Outpouching of capillary walls to form MA’s • Closure of retinal capillaries and arterioles leading to retinal nonperfusion • Breakdown of the blood / retinal barrier with increased vascular permeability of retinal capillaries • Proliferation of new retinal and/or iris vessels • Development of fibrovascular tissue • Contraction of vitreous and fibrous proliferation with subsequent VH and/or RD as a result of traction

  14. Retinal Signs of Hypoxia • Cotton wool spots • 1/1 correlation with retinal ischemia • Venous caliber abnormalities • Change in course / dimention / direction of vessel • Venous beading • Venous tortuosity • Arteriolar abnormalities • IRMA • 70% of NV occurs in areas of IRMA • Featureless retina

  15. Featureless Retina • Lack of H/Ma and IRMA • Reduced small arteriole branches • “Pruning” of capillaries • Opaque retinal appearance

  16. PDR at 1-Year Visit, by severity of lesion ETDRS Report 12. Ophthalmology 1991

  17. Diabetic Changes in Macular Structure • Macular Edema • Nonperfusion • Traction • Intraretinal or Pre-retinal Hemorrhage • Lamellar or Full-Thickness Hole Formation • Combination of above

  18. Classification of Diabetic Retinopathy

  19. No Diabetic Retinopathy • No clinical signs of DR • Early biochemical changes and changes in retinal blood flow • Nondiabetic changes and complications may be present

  20. Mild Nonproliferative DR • At least one microaneurysm • Criteria not met for more severe levels of DR • H/Ma < 2A in all 4 quadrants Standard Photo 2A PDR (1 yr): 5% HR-PDR (5yr): 15%

  21. Moderate Nonproliferative DR • H/Ma ≥ standard photo 2A in 1-3 retinal quadrants or • Soft exudates, venous beading, or IRMA definitely present • Criteria not met for more severe levels o DR Standard Photo 2A PDR (1 yr): 12-27% HR-PDR (5yr): 33%

  22. Severe Nonproliferative DR The 4-2-1 Rule • H/Ma ≥ standard 2A in all 4 retinal quadrants or • Venous beading in 2 or more retinal quadrants or • IRMA ≥ standard 8A in a least quadrant • Criteria not met for more severe levels of DR Standard Photo 8A PDR (1 yr): 52% HR-PDR (5yr): 60%

  23. Very Severe Nonproliferative DR • Any 2 or more criteria of Severe NPDR • Criteria not met for more severe DR Standard Photo 6B PDR (1 yr): 75% HR-PDR (5yr): 75%

  24. High Risk Proliferative DR • NVD ≥ standard 10A (¼ - 1/3 DA) • NVD < standard 10A with fresh preretinal or vitreous hemorrhage • NVE ≥ ½ DA with fresh preretinal or vitreous hemorrhage Standard Photo 10A

  25. Rates of DR Progression

  26. Clinically Significant Macular Edema • Macular edema that involves or threatens the center of the macula • CSME can be present with any level of DR

  27. Clinically Significant Macular Edema • Retinal thickening at or within 500 um from the center of the macula • Hard exudates at or within 500 um from the center of the macula if accompanied by thickening of the adjacent retina • A zone of retinal thickening, 1 disc area or larger in size, located 1 disc diameter or less from the center of the macula

  28. International Clinical DR and DME Disease Severity Scales • No apparent DR No abnormalities • Mild NPDR Microaneurysm only • Moderate NPDR More than Ma only but less than severe NPDR • Severe NPDR Any of the following: >20 intraretinal hemorrhages, definite VB in ≥ 2 quadrants, prominent IRMA in ≥ 1 quadrant and no PDR • PDR One or more of: NV, VH, PRH Ophthalmology. September 2003

  29. International Clinical DR and DME Disease Severity Scales • DME apparently absent No apparent retinal thickening or HE in posterior pole • DME apparently present Some apparent retinal thickening or HE in posterior pole • Mild DME – some retinal thickening or HE in posterior pole but distant from center of the macula (ETDRS: DME but not CSME) • Moderate DME – retinal thickening or HE approaching the center of the macula but not involving the center (ETDRS: CSME) • Severe DME – retinal thickening or HE involving the center of the macula (ETDRS: CSME) Ophthalmology. September 2003

  30. Clinical Trials of Diabetic Retinopathy THE SCIENCE BEHIND THE CARE Diabetic Retinopathy Study (DRS): 1971-1975 Early Treatment DRS (ETDRS): 1979 – 1990 Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC): 1983 – Present United Kingdom Prospective Diabetes Study (UKPDS): 1977-1999

  31. Diabetes Control and Complications Trial (DCCT) • Eligibility – Type 1 Diabetes: Age 13-39 yr • No retinopathy or mild-moderate NPDR • Randomization– 1441 patients • Primary prevention: DM 1-5 yr; no DR • Secondary intervention: DM 1-15 yr; mild-mod DR • Conventional vs. intensive blood glucose control • Endpoints • Development/progression of diabetic retinopathy • Neuropathy/nephropathy outcomes

  32. DCCT Results – Type 1 DM Primary prevention Secondary prevention • Intensive control • 27% Reduction in development of DR • 78% Reduction in progression of DR • Intensive control • 54% reduction in progression of DR • 47% reduction in PDR and severe NPDR • 56% reduction in photocoagulation • 23% reduction in macular edema

  33. Epidemiology of Diabetes Interventions and Complications (EDIC): 1994 - Present • 1375 of the 1441 patients from the DCCT • Retinopathy, renal function and glycemic control monitored according to DCCT protocol • Assessed A1c levels and retinal and renal complications after the end of the DCCT

  34. Do Benefits of Intensive Glycemic Control Persist after Period of Intensive Control? • Seven years after intensive glycemic control: • 75% risk reduction in progression of DR • 69% risk reduction in PDR or severe NPDR • 58% risk reduction in DME • 52% risk reduction in need for laser

  35. Can intensive glycemic control totally prevent the development of DR? • Intensive control does NOT totally prevent the development of DR, but reduces risk of developing any DR by 27%

  36. Are some stages of DR too severe to benefit from intensive glycemic control? • No, but intensive control is most effective with earlier DR • 65% reduction in progression of DR • 47% reduction in developing severe NPDR • 48% reduction in developing PDR • 29% reduction in developing DME

  37. UKPDS Type 2 Diabetes Intensive Blood Glucose Control VS Conventional Blood Glucose Control

  38. United Kingdom Prospective Diabetes Study (UKPDS) • Eligibility – Type 2 Diabetes • Enrolled at diagnosis of diabetes • Randomization – 4209 patients • Primary prevention • Secondary intervention • Conventional vs. intensive blood glucose control • Endpoints • Development/progression of diabetic retinopathy • Neuropathy/nephropathy/cardiovascular outcomes

  39. UK Prospective Diabetes Study

  40. UKPDS Summary • Intensive blood glucose control resulted in statistically significant reduction in • 29% reduction in need for laser • 17% reduction in progression of DR • 24% reduction in need for cataract extraction • 23% reduction in vitreous hemorrhage • 16% reduction in legal blindness

  41. DCCT, EDIC, UKPDSConclusions • Implement intensive therapy as early as possible • Maintain intensive therapy for as long as possible

  42. Diabetic Retinopathy Study • Major design features • One eye of each patient assigned randomly • Scatter PRP vs. Local • Argon laser vs. Xenon Arc • Other eye • F-up without photocoagulation

  43. Diabetic Retinopathy Study • Major conclusions • Photocoagulation reduced risk of SVL by ≥50% • Modest risks • ↓ VA (1 line) • Constriction of VF (xenon > argon) • Treatment benefit outweighs risks for eyes with HR-PDR • 50% 5-year rate of SVL in such eyes without treatment reduced to 20% by treatment

  44. Early Treatment Diabetic Retinopathy Study (ETDRS) • Eligibility – Type 1 or Type 2 Diabetes • Mild NPDR through early PDR • Randomization – 3711 patients • Early vs. Deferred Scatter (Panretinal) Laser Photocoagulation • Focal laser photocoagulation for macular edema vs. no treatment • 650 mg Aspirin vs. Placebo • Endpoints • VA ≤ 5/200 for at least 4 months • Doubling of initial visual angle (e.g. 20/40 to 20/80) • Progression of retinopathy

  45. ETDRS Results • 650 mg aspirin/day • Did not alter progression of retinopathy • Did not increase risk of vitreous hemorrhage • Did not affect vision • Did not alter rate of CE

  46. ETDRS Results • Focal laser for CSME • Decreased risk of moderate visual loss • Caused occasional moderate visual gain • Decreased retinal thickening • Early Scatter Laser • Small reduction in risk of severe visual loss • Benefit of early treatment more pronounced for patients with type 2 DM or patients with type 1 DM of long duration

  47. Management for Diabetic Retinopathy • Awareness • Prevention • Screening • Early diagnosis / Fundus FA • Intensive glycemic control (DCCT/EDIC, UKPDS) • Control of concurrent systemic disorders • Hypertension (UKPDS) • Hyperlipidemia (ETDRS) • Abdominal Obesity (Eurodiab) • Anemia (ETDRS) • Laser Treatment • Vitrectomy

  48. Treatment Program for DR • Initial scatter laser photocoagulation as the DR approaches or reaches the high risk stage • Careful follow-up at 3-4 months interval following the treatment • Re-treatment of persistent or recurrent treatable lesions • Focal laser photocoagulation to reduce the risk of progression of macular edema secondary to scatter photocoagulation

  49. Today Therapeutic Modalities • Steroids – Intravitreal, implant, peribulbar • Macugen, Avastin, Lucentis, VEGF-Trap • Gene Therapy • PKC Inhibitors, GH/IGF-1 Inhibitors, Anti-AGEs • Anti-Oxidants, Aldose Reductase Inhibitors • Neuroprotectants, Vitreolysis • Combination Therapy • Novel Targets

  50. Tomorrow • Determine basic mechanisms of disease • Identify potential therapeutics targets • Develop specific novel therapies • Evaluate at subcellular, cellular & organism level • Rigorous clinical trials • Opportunity to make today’s standard of care obsolete tomorrow

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