Impatto della terapia ipoglicemizzante sulla retinopatia diabetica

Raffaele NapoliDipartimento di Scienze Mediche Traslazionali

Università Federico II

Occhio e DiabeteNapoli, 17-18 aprile 2015

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

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.

Microvascular Complications of Diabetes

Nephropathy Retinopathy Neuropathy

Vision-threaten-ing*; 4.4%

NPDR; 24.1%

None; 71.5%

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 2005-2008Adults Age ≥40 Years (N=1006)

Diabetic Retinopathy Is the Leading Cause of Adult Blindness in the United States

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

DCCT, NEJM 1993

Hyperglycemia and Retinopathy in T1D

Primary prevention group Secondary prevention group

-76%-54%

Seven field stereoscopic fundus photographyEarly Treatment Diabetic Retinopathy Study grading

DCCT, NEJM 1993

Hyperglycemia and Retinopathy in T1D

Hyperglycemia and Retinopathy in T1D

DCCT & EDIC, NEJM 2000 & Arch Intern Med 2009

DCCT & EDIC, NEJM 2000 & Arch Intern Med 2009

Hyperglycemia and Retinopathy in T1D

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.

Rela

tive

Risk

HbA1C (%)

15

13

11

9

7

5

3

16 7 8 9 10 11 12

HbA1C and Relative Risk of Microvascular Complications

RetinopathyNephropathyNeuropathyMicroalbuminuria

20

DCCT, NEJM 1993

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

UKPDS, Lancet 1998

UKPDS, Lancet 1998

Hyperglycemia and Retinopathy in T2D

UKPDS, Lancet 1998

Hyperglycemia and Retinopathy in T2D

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.

UKPDS ACCORD

A1C reduction (%) 0.9 1.3

Retinopathy risk reduction (%)* 29 17 33

Retinopathy onset

(P=0.003)

Retinopathy progression(P=0.017)

Retinopathy progression(P=0.003)

Hemmingsen B et al. Br Med J 2011

Hyperglycemia and Retinopathy

Boussageon R et al. Br Med J 2011

Hyperglycemia and Retinopathy: the sooner the better

RACCOMANDAZIONIRaccomandazioni generaliOttimizzare il compenso glicemico riduce il rischio e la progressione della retinopatia.(Livello della prova I, Forza della raccomandazione A)

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 (2nd 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.

Primary prevention group Secondary prevention group

-76%-54%

Seven field stereoscopic fundus photographyEarly Treatment Diabetic Retinopathy Study grading

DCCT, NEJM 1993

Hyperglycemia and Retinopathy in T1D

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 variabilityGlucose

variabilityReluctance to intensify

therapyReluctance to intensify

therapy

High A1CHigh A1C

ComplicationsMorbidity Mortality

ComplicationsMorbidity Mortality

Quality of lifeQuality of life

Fear of hypoglycemia

Fear of hypoglycemia

Severe hypoglycemiaSevere hypoglycemia

ControversialControversial

RACCOMANDAZIONIRaccomandazioni generaliOttimizzare il compenso glicemico riduce il rischio e la progressione della retinopatia.(Livello della prova I, Forza della raccomandazione A)

Diabetic Retinopathy Management

Lesion Type Management 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

angiographyPreproliferative retinopathy • Optimal glucose and blood pressure control

• Panretinal scatter laser photocoagulationProliferative 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.

Standards of Medical Care in Diabetes - 2015

Standards of Medical Care in Diabetes - 2015