Diabetic Microangiopathy

1. Diabetic Microangiopathy Simon Conroy (UK) EAMA January 2003

3. Diabetes an Increasing Global Burden The greater proportion of the increase is likely to occur in the developing countries, which are the communities which can least afford to treat it. Majority type II Rapid worldwide increase in obesity Ageing population 2.4% adult population (UK); 80% type II diabetics Accounts for up to 10% of annual UK healthcare budget Diabetes (type II) very common in the elderly (Meneilly & Tessier, 1995) The greater proportion of the increase is likely to occur in the developing countries, which are the communities which can least afford to treat it. Majority type II Rapid worldwide increase in obesity Ageing population 2.4% adult population (UK); 80% type II diabetics Accounts for up to 10% of annual UK healthcare budget Diabetes (type II) very common in the elderly (Meneilly & Tessier, 1995)

4. Extrapolation of ß-cell dysfunction =50% asymptomatic (Harris et al, 1993) Increased renal threshold for glucose, hence less glycosuria Impaired thirst mechanism, hence less polyuria Diagnosis often made incidentally=50% asymptomatic (Harris et al, 1993) Increased renal threshold for glucose, hence less glycosuria Impaired thirst mechanism, hence less polyuria Diagnosis often made incidentally

5. Complications at Diagnosis UKPDS Group. UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Research 1990;13:1–11.UKPDS Group. UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Research 1990;13:1–11.

6. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe- Relative risk for all-cause mortality in subjects not known as diabetic Mortality double vs ARMCs, even if undiagnosed (Harris 1990, 1993)Mortality double vs ARMCs, even if undiagnosed (Harris 1990, 1993)

7. Diabetic Microangiopathy

8. Diabetic Microangiopathy

10. Accumulation of polyol by the reduction of galactose rather than glucose owing to the higher affinity of aldose reductase for galactose Osmotic cell damage Decrease in intracellular myoinositol Decrease in Na-K-ATPase activity Shift in redox potential Glucose competitively interferes with myoinositol via a sodium-myoinositol cotransporter Sorbinil Retinopathy Trial (Pfizer) Accumulation of polyol by the reduction of galactose rather than glucose owing to the higher affinity of aldose reductase for galactose Osmotic cell damage Decrease in intracellular myoinositol Decrease in Na-K-ATPase activity Shift in redox potential Glucose competitively interferes with myoinositol via a sodium-myoinositol cotransporter Sorbinil Retinopathy Trial (Pfizer)

11. Protein Kinase C Probably caused by enhanced de novo synthesis of diacylglycerol (DAG) PKC activity increased in glomeruli, retina, aorta and heart of diabetic animals Activation of PKC begins a complex network of intracellular signalling that may alter transcription factor binding to the promoter regions of responsive genes, thereby affecting gene expression LY333531 Selective inhibitor of the PKC ß2 isoenzyme Reverses glomerular hyperfiltration Urinary albumin excretion rate fell (Ishi et al 1996) Human studies in DR underway, initial results encouraging Probably caused by enhanced de novo synthesis of diacylglycerol (DAG) PKC activity increased in glomeruli, retina, aorta and heart of diabetic animals Activation of PKC begins a complex network of intracellular signalling that may alter transcription factor binding to the promoter regions of responsive genes, thereby affecting gene expression LY333531 Selective inhibitor of the PKC ß2 isoenzyme Reverses glomerular hyperfiltration Urinary albumin excretion rate fell (Ishi et al 1996) Human studies in DR underway, initial results encouraging

12. Advanced Glycosylation End-Products Includes HbA1c AGEs in atherosclerotic plaques Serum AGE levels reflect severity of diabetic complications AGEs alter ECM Alter integrity of collagen, promote basement membrane thickening Adversely affect vascular tissue integrity Reaction to EDRF and anti-proliferative factors Bind to RAGE in endothelial cells In endothelial cells, AGE binds to RAGE resulting in Gene expression for a variety of molecules Growth factors Vascular endothelial growth factor (VEGF) Platelet-derived growth factor (PDGF) Transcription factors (NF?B, SP1 and STAT 1) Activation of proteases Matrix metalloproteinases (MMP) Calpines, capsases Synthesis of adhesion molecules Vascular endothelial cell adhesion molecule (VECAM) E-SELECTIN Platelet endothelial cell adhesion molecule (PECAM) Intercellular adhesion molecule (ICAM) Results in disruption of cellular homeostasis, recruitment of macrophages, atherogenesis, thrombogenesis and angiogenesis Aminoguanadine (thiazolidine derivatives) Reduces formation of AGEPs (animal studies) Experimental Some evidence for reducing ß-2 microgloblin, slowing diabetic cardiomyopathy, retinopathy, nephropathy, neuropathy However clinical trails dissapointing and limited by hepatotoxicity In endothelial cells, AGE binds to RAGE resulting in Gene expression for a variety of molecules Growth factors Vascular endothelial growth factor (VEGF) Platelet-derived growth factor (PDGF) Transcription factors (NF?B, SP1 and STAT 1) Activation of proteases Matrix metalloproteinases (MMP) Calpines, capsases Synthesis of adhesion molecules Vascular endothelial cell adhesion molecule (VECAM) E-SELECTIN Platelet endothelial cell adhesion molecule (PECAM) Intercellular adhesion molecule (ICAM) Results in disruption of cellular homeostasis, recruitment of macrophages, atherogenesis, thrombogenesis and angiogenesis Aminoguanadine (thiazolidine derivatives) Reduces formation of AGEPs (animal studies) Experimental Some evidence for reducing ß-2 microgloblin, slowing diabetic cardiomyopathy, retinopathy, nephropathy, neuropathy However clinical trails dissapointing and limited by hepatotoxicity

13. Other factors Oxidative stress resulting from glucose metabolism Glycosylation of proteins, changes in quaternary structure ICAM-1, leucocyte integrin (CD18) Activated in DR, via TNF-alpha Aspirin/COX 2/Etanercept Astemizole retinopathy trial Astemizole retinopathy trial

14. Diabetic Retinopathy Clinical Aspects

15. Diabetic Retinopathy Most common cause of blindness in people aged 30–69 years Most common complication to be present at time of presentation - 21% After 15 years, two-thirds of patients have background retinopathy Natural history slightly different in the elderly Maculopathy more common than proliferative retinopathy Hirvela et al 1997 24 of 113 patients (21 percent) over age 70 years had any form of retinopathy (including maculopathy) 4 (3.5 percent) had poor vision due to diabetes Cahill et al 1997 21 of 150 patients (14 percent) diabetics diagnosed after age 70 years had retinopathy 10 (7 percent) was vision ever threatened No association between retinopathy and HbA1c valuesHirvela et al 1997 24 of 113 patients (21 percent) over age 70 years had any form of retinopathy (including maculopathy) 4 (3.5 percent) had poor vision due to diabetes Cahill et al 1997 21 of 150 patients (14 percent) diabetics diagnosed after age 70 years had retinopathy 10 (7 percent) was vision ever threatened No association between retinopathy and HbA1c values

16. Diabetic retinopathy Structural abnormalities Pericyte loss Loss of endothelial cells Basement membrane thickening Endothelial cell dysfunction Hyperlipidaemia promotes maculopathy Result in: Loss of autonomic autoregulation Retinal hyperperfusion Shear stress stimulates growth factors Unregulated angiogenesis Capillary leakage Capillary dropout

17. Classification Background diabetic retinopathy BDR Pre-proliferative diabetic retinopathy PPDR Proliferative diabetic retinopathy NVD NVE Maculopathy

18. Normal Retina

19. Background Retinopathy

20. Moderate BDR

21. Maculopathy

22. Maculopathy & CWS

23. Circinates

24. Drusen

25. Circinate exudate ring

27. Severe maculopathy

28. Moderate PPDR

29. Cotton wool spots

30. Pre-proliferative DR

31. PPDR, venous beading & IRMA

32. New Vessels Elsewhere

33. New Vessels Disc

34. NVD, NVE & Laser

35. NVD, NVE & Sub-hyaloid haemorrhage

36. Pre-retinal haemorrhage

37. Fibrosis

38. Rubeosis iridis

39. Diabetic Retinopathy Therapy

40. Visual loss may well be preventable Consider also cataracts, glaucoma & ARMD Annual screening Close liaison between ophthalmology & diabetes service Visual acuity, dilated fundoscopy Retinal screening service Fluoroscene angiography Measure intra-ocular pressure

41. Life-style changes Smoking triples risk Diet – complicated! Compliance Can help in community dwellers (Reaven et al 1985) Not as helpful – even harmful - in NH residents (Coulston et al 1990) Consider supplementation (vitamins C & E, Magnesium)

42. Medical therapy Aspirin – no specific benefit (or harm) (Early Treatment Diabetic Retinopathy Trial) Statins may slow progression of PDR(Sen et al 2002) ACE inhibitors No specific benefits (Pradhan et al 2002) Octreotide Prevention of vitreous haemorrhage in PDR(Boehm et al 2001) Octreotide Prevention of vitreous haemorrhage in PDR(Boehm et al 2001)

43. DCCT: Effects of management on retinopathy Similar results for other microangiopathies Primary prevention cohort (no retinopathy at baseline) Secondary intervention cohort (mild-to-moderate nonproliferative retinopathy at baseline) Similar results seen in Stockholm Diabetes Intervention Study Similar results for other microangiopathies Primary prevention cohort (no retinopathy at baseline) Secondary intervention cohort (mild-to-moderate nonproliferative retinopathy at baseline) Similar results seen in Stockholm Diabetes Intervention Study

44. UKDPS FPG >6 mmol/l (108 mg/dl) Mean follow-up: 11 years 3-month dietary run-in period Conventional management Attain near normal body weight Fasting plasma glucose (FPG) <15 mmol/l (<270 mg/dl) Premeal glucose 4–7 mmol/l (72–126 mg/dl) Free of hyperglycaemic symptoms Intensive management Sulphonylurea (chlorpropamide or glibenclamide) or insulin Fasting plasma glucose (FPG) <6 mmol/l (108 mg/dl) Free of hyperglycaemic symptoms Premeal glucose concentration of 4–7 mmol/l (72–126 mg/dl)FPG >6 mmol/l (108 mg/dl) Mean follow-up: 11 years 3-month dietary run-in period Conventional management Attain near normal body weight Fasting plasma glucose (FPG) <15 mmol/l (<270 mg/dl) Premeal glucose 4–7 mmol/l (72–126 mg/dl) Free of hyperglycaemic symptoms Intensive management Sulphonylurea (chlorpropamide or glibenclamide) or insulin Fasting plasma glucose (FPG) <6 mmol/l (108 mg/dl) Free of hyperglycaemic symptoms Premeal glucose concentration of 4–7 mmol/l (72–126 mg/dl)

45. Effects on HbA1c Intensive management did not maintain optimal glycaemic control, a reflection of the progressive nature of Type 2 diabetes. However, in the case of the UKPDS, the term ‘intensive management can be misleading as it was no more intensive than usual clinical management in many centres at the time the study results were reported Intensive management did not maintain optimal glycaemic control, a reflection of the progressive nature of Type 2 diabetes. However, in the case of the UKPDS, the term ‘intensive management can be misleading as it was no more intensive than usual clinical management in many centres at the time the study results were reported

46. Effects of intensive glycaemic control Similar results seen in 2000 (Kumanto study) in type II DMSimilar results seen in 2000 (Kumanto study) in type II DM

47. Effects of intensiveBP control Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy and deterioration of visual acuity. UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 38. British Medical Journal 1998;317:703–713.Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy and deterioration of visual acuity. UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 38. British Medical Journal 1998;317:703–713.

48. Surgical therapy ETDRS/DRS (1970s onwards) Photocoagulation (focal or pan-retinal) Early vitrectomy for non-resolving vitreous hemorrhage (DRVS) Intra-vitreal steroid injections Intraoccular tPA may delay need for vitrectomy (Chung et 2001) Intraoccular tPA may delay need for vitrectomy (Chung et 2001)

49. Problems with treatment in the elderly Lack of symptoms Diagnosis Compliance Impaired cognitive function Dementia Diabetes related - glycaemic control helps(Tun et al, 1990) Increased susceptibility to hypoglycaemia Altered drug metabolism Polypharmacy Co-morbidity

50. Approach Functional & cognitive assessment (esp. depression) Vascular risk assessment 'Metabolic targeting' Interventions for disabilities Care for carer

51. Some answers Multidisciplinary approach and education programs for care home staff (Wilson and Pratt, 1987; Kronsbein et al, 1988; Gilden et al, 1989) Improve glycaemic control Improve compliance Improve quality of life Consisting of: Appropriate (written) educational material Drug reviews Risk factor modification National Service Framework

52. Summary points Diabetes Common and increasing Significant morbidity & mortality Diabetic retinopathy Sorbitol/PKC/AGEs Therapy aimed at basic pathophysiology unimpressive, but further trials underway BP & glycaemic control key Address co-existent cardiovascular risk factors

53. Summary points Treatment in the elderly Complicated by co-morbidity, polypharmacy & frailty Demands a multidisciplinary approach Organisation, education, outreach clinics, shared care

55. References Meneilly GS and Tessier D (1995). Diabetes in the elderly. Diabetic Medicine, 12, 949-60. Harris MI (1990). Epidemiology of diabetes mellitus among the elderly in the United States. Clinics in Geriatric Medicine, 6, 703-19. Harris MI (1993). Undiagnosed NIDDM: clinical and public health issues. Diabetes Care, 16, 642-52. Birch, KA, Heath, WF, Hermeling, RN, et al 1996. LY290181, an inhibitor of diabetes-induced vascular dysfunction, blocks protein kinase C-stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element. Diabetes, 45, 642.

56. References Hirvela, H, Laatikainen, L (1997). Diabetic retinopathy in people aged 70 years or older. Br J Ophthalmol, 81, 214. Cahill, M, Halley, A, Codd, M, et al (1997). Prevalence of diabetic retinopathy in patients with diabetes mellitus diagnosed after the age of 70 years. Br J Ophthalmol, 81, 218. Sen K, Misra A, Kumar A, Pandey RM (2002). Simvastatin retards progression of retinopathy in diabetic patients with hypercholesterolemia. Diabetes Res Clin Pract, 56(1), 1-11. Boehm BO, Lang GK, Jehle PM, Feldman B, Lang GE (2001). Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm Metab Res, 33(5), 300-6.

57. References Chung J, Kim MH, Chung SM, Chang KY (2001). The effect of tissue plasminogen activator on premacular hemorrhage. Ophthalmic Surg Lasers, 32(1), 7-12. Reaven GM et al (1985). Beneficial effects of weight loss in older patients with NIDDM. Journal of the American Geriatrics Society, 33, 93-5. Coulston M, Mandelbaum D, Reaven GM (1990). Dietary management of nursing home residents with non-insulin dependent diabetes mellitus. American Journal of Clinical Nutrition, 51, 67-71. Spengler M and Catagay M (1992). Evaluation of efficacy and tolerability of acarbose by post-marketing surveillance. Diabetes und Stoffwechsel, 1, 218-22. Tun PA, Nathan DM, Perlmuter LC (1990). Cognitive and affective disorders in elderly diabetics. Clinics in Geriatric Medicine, 6, 731-46.

58. References Wilson W and Pratt C (1987). The impact of diabetes education and peer support upon weight and glycaemic control of elderly persons with non-insulin dependent diabetes mellitus (NIDDM). American Journal of Public Health, 77, 634-5. Kronsbein P, Mulhauser I, Venhaus A, Jorgend V, Scholz V and Berger M (1988). Evaluation of a structured treatment programme on non-insulin-dependent diabetes mellitus. Lancet, ii, 1407-11. Gilden JL, Hendryx M, Casia C and Singh SP (1989). The effectiveness of diabetes education programs for older patients and theor spouses. Journal of the American Geriatrics Society, 38, 511-15. Mooradian AD, Osterweil D, Petrasek D and Morely J (1988). Diabetes mellitus in elderly nursing home residents. A survey of clinical characteristics and management. Journal of the American Geriatrics Society, 37, 838-42. Sorbinil Retinopathy Trial Research Group (1990). A randomized trial of sorbinil, an aldose reductase inhibitor in diabetic retinopathy. Arch Ophthalmol, 108, 1234.

59. References Pradhan R, Fong D, March C, Jack R, Rezapour G, Norris K, Davidson MB (2002). Angiotensin-converting enzyme inhibition for the treatment of moderate to severe diabetic retinopathy in normotensive Type 2 diabetic patients. A pilot study. J Diabetes Complications, 16(6), 377-81.