1. Impatto della terapia ipoglicemizzante sulla retinopatia diabetica Raffaele Napoli Dipartimento di Scienze Mediche Traslazionali Università Federico II Occhio e Diabete Napoli, 17-18 aprile 2015

3. Type 2 diabetes is associated with serious complications at time of diagnosis The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001; 24 (Suppl. 1): S5-S20 Retinopathy, glaucoma or cataracts Nephropathy Neuropathy Microvascular Macrovascular Cerebrovascular disease Coronary heart disease Peripheral vascular disease

4. Hyperglycemia-Induced Tissue Damage: General Features Diabetic tissue damage Genetic determinants of individual susceptibility Repeated acute changes in cellular metabolism Cumulative long-term changes in stable macromolecules Independent accelerating factors (eg, hypertension, dyslipidemia) Hyperglycemia Brownlee M. Diabetes. 2005;54:1615-1625.

5. Microvascular Complications of Diabetes NephropathyRetinopathyNeuropathy

6. Prevalence of Diabetic Retinopathy *Severe NPDR, PDR, or clinically significant macular edema. NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; T2DM, type 2 diabetes mellitus. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Zhang X, et al. JAMA. 2010;304:649-656. NHANES 2005-2008 Adults Age ≥40 Years (N=1006) Diabetic Retinopathy Is the Leading Cause of Adult Blindness in the United States

7. Disease Duration (yrs) 1 – 5 1 - 15 Retinopathy NO very mild-to-moderate Urinary Albumin Excretion (mg/day) < 40 < 200

8. DCCT, NEJM 1993 Hyperglycemia and Retinopathy in T1D

9. Primary prevention group Secondary prevention group -76% -54% Seven field stereoscopic fundus photography Early Treatment Diabetic Retinopathy Study grading DCCT, NEJM 1993 Hyperglycemia and Retinopathy in T1D

10. Hyperglycemia and Retinopathy in T1D DCCT & EDIC, NEJM 2000 & Arch Intern Med 2009

11. Hyperglycemia and Retinopathy in T1D

12. DCCT, Diabetes Control and Complications Trial. 1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 2. DCCT. N Engl J Med. 1993;329:977-986. 3. DCCT. Diabetes. 1995;44:968-983. Relative Risk HbA1 C (%) 15 13 11 9 7 5 3 1 6789101112 HbA1 C and Relative Risk of Microvascular Complications Retinopathy Nephropathy Neuropathy Microalbuminuria 20 DCCT, NEJM 1993

13. DCCT and EDIC Findings Intensive treatment reduced the risks of retinopathy, nephropathy, and neuropathy by 35% to 90% compared with conventional treatment Absolute risks of retinopathy and nephropathy were proportional to the A1C Intensive treatment was most effective when begun early, before complications were detectable Risk reductions achieved at a median A1C 7.3% for intensive treatment (vs 9.1% for conventional) Benefits of 6.5 years of intensive treatment extended well beyond the period of most intensive implementation (“metabolic memory”) DCCT/EDIC Research Group. JAMA. 2002;15;287:2563-2569. Intensive treatment should be started as soon as is safely possible after the onset of T1DM and maintained thereafter

14. UKPDS, Lancet 1998

15. Hyperglycemia and Retinopathy in T2D

16. UKPDS, Lancet 1998 Hyperglycemia and Retinopathy in T2D

18. Reducing A1C Reduces Retinopathy Progression in T2DM *Intensive vs standard glucose control. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. Ismail-Beigi F, et al. Lancet. 2010;376:419-430. Chew EY, et al. N Engl J Med. 2010;363:233-244. UKPDSACCORD A1C reduction (%)0.91.3 Retinopathy risk reduction (%)* 291733 Retinopathy onset (P=0.003) Retinopathy progression (P=0.017) Retinopathy progression (P=0.003)

19. Hemmingsen B et al. Br Med J 2011 Hyperglycemia and Retinopathy

20. Boussageon R et al. Br Med J 2011 Hyperglycemia and Retinopathy: the sooner the better

21. RACCOMANDAZIONI Raccomandazioni generali Ottimizzare il compenso glicemico riduce il rischio e la progressione della retinopatia. (Livello della prova I, Forza della raccomandazione A)

22. Predictors of Poor Glycemic Control Younger age Longer diabetes duration Weight <85th percentile Not living in a 2-parent household Type of diabetes care provider Nonwhite race/ethnicity Female gender Lower parental education Poor early glycemic control (2 nd year after diagnosis; predictive of poor glycemic control later) Petitti DB, et al. J Pediatr. 2009;155:668-672.e1-3; Chemtob CM, et al. J Diabetes. 2011;3:153-157.

23. Primary prevention group Secondary prevention group -76% -54% Seven field stereoscopic fundus photography Early Treatment Diabetic Retinopathy Study grading DCCT, NEJM 1993 Hyperglycemia and Retinopathy in T1D

26. Glucose Variability and Health Outcomes: Direct and Indirect Pathways Irvine AA, et al. Health Psychol. 1992;11:135-138; Thompson CJ, et al. Diabetes Care. 1996;19:876-879; Reach G. Diabetes Technol Ther. 2008;10:69-80. Glucose variability Reluctance to intensify therapy High A1C Complications Morbidity Mortality Complications Morbidity Mortality Quality of life Fear of hypoglycemia Severe hypoglycemia Controversial

27. RACCOMANDAZIONI Raccomandazioni generali Ottimizzare il compenso glicemico riduce il rischio e la progressione della retinopatia. (Livello della prova I, Forza della raccomandazione A)

28. Diabetic Retinopathy Management Lesion TypeManagement Recommendation Background or nonproliferative retinopathy Optimal glucose and blood pressure control Macular edema Optimal glucose and blood pressure control Ranibizumab injection therapy Focused laser photocoagulation guided by fluorescein angiography Preproliferative retinopathy Optimal glucose and blood pressure control Panretinal scatter laser photocoagulation Proliferative retinopathy Optimal glucose and blood pressure control Panretinal scatter laser photocoagulation Vitrectomy for patients with persistent vitreous hemorrhage or significant vitreous scarring and debris Goal: detect clinically significant retinopathy before vision is threatened Annual dilated eye examination by experienced ophthalmologist, starting at diagnosis for all T2DM patients Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

29. Standards of Medical Care in Diabetes - 2015