7th Annual International Diovan Symposium

1. 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006

2. From the Expert’s Files: Case Presentation Victor Dzau Duke University, Durham, USA

3. Presentation • 52-year-old African-American woman • Museum curator • History of • Type II diabetes (diet controlled) • Retinopathy and nephropathy • Referred to specialist due to BP = 160/100 mmHg despite amlodipine 10 mg, bendrofluazide 2.5 mg and atenolol 50 mg

4. Examination • Not overweight • Questioning reveals • ex-smoker for 5 years having smoked 20 cigarettes a day from age 16 years • some breathlessness on exertion • Clinic BP = 164/103 mmHg • Pulse regular • Auscultation: • Abdominal bruit • AF

5. Investigations • Creatinine = 250 μmol/L (2.82 mg/dL) • Mid-stream urine (MSU) = 2+ protein • Sugar = 9 mmol/L (162 mg/dL) • HbA1C = 7% (normal <5%) • Total cholesterol = 5 mmol/L (193 mg/dL) • Chest x-ray = normal • ECG = sinus rhythm, LVH on voltage criteria • Echo = EF 55%, LVH

6. 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006 VARIABLE 3: Hypertension andMicroalbuminuria

7. Pathophysiology of Microalbuminuria in Hypertension Michel Burnier CHUV, Lausanne, Switzerland

8. Definition of Microalbuminuria

9. Natural History of Diabetic Nephropathy Clinical type 2 diabetes Functional changes* Structural changes† Rising blood pressure Microalbuminuria Proteinuria Rising serum creatinine levels End-stagerenal disease Cardiovascular death Onset of diabetes 2 5 10 20 30 Years *Renal haemodynamics altered, glomerular hyperfiltration †Glomerular basement membrane thickening ­, mesangial expansion ­,microvascular changes +/-

10. Pathophysiological Processes Leading to Albuminuria and Glomerular Lesions Urinary protein Glucose Glycoxidation (glycation) AGEs = angiotensin AT1 receptor Increased glomerular pressure Efferent arteriolar constriction Ang II Ang II

11. Albuminuria and Progression of Nephropathies Glomerular permeability for macromolecules Excessive reabsorption of proteins in the proximal tubule Intracellular accumulation of protein degradation products Gene activations chemokines and cytokines Proliferation of fibroblasts and extracellular matrix Development of fibrosis and renal atrophy Remuzzi et al. Kidney Int 1997;51:2–15

12. Prevalence of Microalbuminuria in Patients with Hypertension* 40 30 20 10 0 Prevalence (%) Bigazzi 1992 Calvino1999 Grandi 2000 Pontremoli1997 Palatini 1996 Jensen 1997 Mean *Defined as > 140/90 mmHg except Calvino, Palatini (135/85 mmHg)Jensen (> 140/90 mmHg or on AHY) Diercks et al. Can J Cardiol 2002;18:525–35

13. Microalbuminuria is Associated with Left Ventricular Hypertrophy and Carotid Hypertrophy in Hypertensive Patients Left ventricular mass index Intima/media thickness * **** 200 150 100 50 0 1 0.8 0.6 0.4 0.2 0 * *** ** IMT (mm) LVMI (g/m2) C Ht AI– Ht AI+ C Ht AI– Ht AI+ C = control; Ht = hypertensive; Al– = no albuminuria; Al+ = with albuminuria *p<0.001 intergroup comparison; **p<0.001 compared to C;***p<0.05 compared to Ht Al–; ****p<0.01 compared to Ht Al– Pontremoli et al. Am J Hypertens 1998;11:430–8

14. Microalbuminuria as a Predictor of Vascular Disease in Non-diabetic Subjects Odds ratio for coronary heart disease Age (10 years) Male sex Systolic BP Diastolic BP Body mass index (10 kg/m2) Current or ex-smoker Treatment of hypertension Diabetes or insulin resistance Microalbuminuria 1 5 10 15 20 Odds ratio Yudkin et al. Lancet 1988;2:530–3

15. Microalbuminuria and Risk of CV Events, CHF and Death in the HOPE Trial CHF hospitalisation MI/Stroke/CV death All-cause mortality 4 3 2 1 0 Relative risk <0.22 0.22–0.57 0.58–1.62 >1.62 Alb/Crea (mg/mmol) Adjusted for age, sex, SBP/DBP, waist-hip ratio, diabetes and HbA1c Gerstein et al. JAMA 2001;286:421–6

16. Renal Insufficiency, Albuminuria and CV Survival in the HOPE Trial Systolic and diastolic BP NOT significant risk factors 2.5 2.0 1.5 1.0 0.5 0 HR for primary outcome(CV death, MI, stroke) S. creat >124 µmol/L Microalbuminuria Both Mann et al. Ann Intern Med 2001;134:629–36

17. Albuminuria and CV Diseases LIFE study, 8,029 subjects with hypertensionand LV hypertrophy, mean age 66 years 40 30 20 10 0 Normoalbuminuria Microalbuminuria (Alb/Crea >3.5 mg/mmol) Macroalbuminuria (Alb/Crea >35 mg/mmol) Prevalence (%) Diabetes Cerebrovascular Peripheral Coronary disease vascular vascular disease disease Wachtell et al. J Hypertens 2002;20:405–12

18. Composite Endpoints (CV Death, Non-fatal Stroke and MI) Stratified by Time-varying Albuminuria in the LIFE Trial >3 mg/mmoL (n=2,435, 1,708, 1,760) 1–3 mg/mmoL (n=2,219, 1,827, 1,946) 0.5–1 mg/mmoL (n=1,591, 1,587, 1,814) £0.5 mg/mmoL (n=1,961, 3,385, 2,458) 24 22 20 18 16 14 12 10 8 6 4 2 0 Endpoint rate (%) 0 6 12 18 24 30 36 42 48 54 60 66 Month Ibsen et al. Hypertension 2005;45:198–202

19. Microalbuminuria and Mortality in the General Population: the PREVEND Study n=85,421 subjects, age: 28–75 years from the Groningen area CV death Non-CV death 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Hazard ratio Hazard ratio 1 10 100 1,000 1 10 1,00 1000 Urinary albumin concentration (mg/L) Urinary albumin concentration (mg/L) Hillege et al. Circulation 2002;106:1777–82

20. Microalbuminuria and CV Complications in Hypertension: Is the Threshold Correct?The Copenhagen City Heart Study Cox-estimated age-adjusted curves of cumulative incidence of coronary heart disease for a 60-year-old person based on 1,734 hypertensive subjects with microalbuminuria and normoalbuminuria 4 3 2 1 0 UAE ³4.8 µg/min UAE ³4.8 µg/min UAE <4.8 µg/min RR of CHD 30 20 10 0 Cumulative mortality (%) <2.5 2.5–5 5–10 >10 4 3 2 1 0 RR of death 0 2 4 6 8 10 12 Years from entry <2.5 2.5–5 5–10 >10 UAE (µg/min) Klausen et al. Hypertension 2005;46:33–7

21. Microalbuminuria and Incidence of CV Events: The Framingham Study Survival free of CVD According to sex-specific median UACR 100 95 90 Percentage < Median ³ Median 0 1 2 3 4 5 6 7 8 Years Arnlov et al. Circulation 2005;112:969–75

22. Microalbuminuria What Links Microalbuminuria to CV Risk ?

23. 24-hour Blood Pressure Profile in Clinically Healthy Subjects With or Without Microalbuminuria Microalbuminuria (n=26) Normoalbuminuria (n=45) 165 140 115 90 65 40 Blood pressure (mmHg) 0 0 4 8 12 16 20 24 Clock time Clausen et al. Hypertension 1998;32:71–7

24. Expression of Endothelial Dysfunction in Humans Endothelial dysfunction Impaired endothelium-dependent vasodilation Reduces vasodilation Increased endothelin Favours vasoconstriction Increased transcapillary escape rate of albumin Increases permeability (microalbuminaria) Increased von Willebrand factor Increases prothrombotic activity Increased tPA and PAI-1 Reduces profibrinolytic activity Increased E-selectin and VCAM-1 Leucocytes adhesion and permeability Increased ICAM-1 Induces inflammation Increased fibronectin and type IV collagen fragments Alters matrix synthesis

25. Flow-associated Vasodilation of Brachial Artery in Clinically Healthy Subjects According to Microalbuminuria p<0.05 105 104 103 102 101 100 Flow-associated dilatation (%) 0 Normoalbuminuria Elevated UAE Clausen et al. Circulation 2001;103:1869–74

26. Pathobiological Processes Potentially Involved in the Development and Progression of Vascular Diseases Dyslipidaemia Hypertension Diabetes Smoking Oxidative stress Endothelial dysfunction ­ NO, ­ local mediators, ­ RAAS (Ang II) Vasoconstriction Thrombosis Inflammation Plaque rupture Vascular lesion and remodelling Adapted from Dzau. Hypertension 2001;37:1047–52

27. Chronic Kidney Disease and CV Risk

28. Vascular Effects of Angiotensin II Vasoconstriction Stimulation of Ang II type 1 receptors Release of endothelin and norepinephrine Reduction of NO bioactivity and production of peroxynitrite Inflammation Activation NADH/NADPH oxidase and production of superoxide anion Induction of MCP-1, VCAM, TNF-a, IL-6 expression Activation of monocytes and macrophages Remodelling Stimulation of SMC migration, hypertrophy and replication Induction of PDGF, bFGF, IGF-1, TGF-b expression Stimulation of matrix glycoproteins and metalloproteinase expression Thrombosis Stimulation of PAI-1 synthesis and change in tPA/PAI-1 ratio Activation of platelet with increased aggregation and adhesion

29. CV morbidity and mortality Angiotensin II Inhibition Retards the Progression of Renal Diseases Prevention Protection Benedict Study IDNT RENAAL IRMA 2 MARVAL Normoalbuminuria MicroalbuminuriaMacroalbuminuria ESRD Early stageLate stageTerminal stage Severity of renal disease

30. Reduction in Albuminuria Translates Into a Decrease in CV Events in Hypertensive Patients: LIFE Study 0.20 0.15 0.10 0.05 0 High baseline/high year 1 High baseline/low year 1 Low baseline/high year 1 Low baseline/low year 1 Fraction suffering composite endpoint 0 10 20 30 40 50 60 70 Follow-up (months) Ibsen et al. Hypertension 2005;45:198–202

31. Effect of Fosinopril on CV Event Rates in Patients with Microalbuminuria 1.00 0.98 0.96 0.94 0.92 0.90 Event-free survival HR 0.60 [0.33–1.10], p=0.098 (Log-rank) Placebo Fosinopril 0.10 0 0 10 20 30 40 Follow-up (months) Asselbergs et al. Circulation 2004;110:2809–16

32. Event-free Survival According to the Level of Microalbuminuria 1.00 0.95 0.90 0.85 0.80 Event-free survival p=0.008 UAE <50 mg/24 hours, placebo UAE >50 mg/24 hours, placebo UAE <50 mg/24 hours, fosinopril UAE >50 mg/24 hours, fosinopril 0.10 0 0 10 20 30 40 Follow-up (months) Asselbergs et al. Circulation 2004;110:2809–16

33. Conclusions • Microalbuminuria is frequent in hypertension and is associated with target organ damage and the incidence of CV complications • The pathophysiological link between microalbuminuria and CV risk is not completely understood but it may be due to endothelial dysfunction with an impaired NO balance, activation of local mediators and increased activity of the RAAS system • Blockade of the RAAS with ACE inhibitors or AT1 receptor blockers is an important therapeutic approach to reduce microalbuminuria and to prevent the development of CV and renal complications in hypertension

34. 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006

35. Point-CounterpointAre Benefits Beyond Blood Pressure Lowering Clinically Relevant?

36. Albuminuria-associated Disease:Are Benefits Beyond BP Lowering Clinically Relevant? Giancarlo Viberti, MDProfessor of Diabetes and Metabolic Medicine Cardiovascular DivisionKCL School of MedicineGuy’s HospitalKing’s College LondonLondon, UK

37. Age-specific Relation of Usual BP to Vascular Mortality In Individuals With No Previous Vascular Disease Prospective Studies Collaboration. Lancet 2002;360:1903–13

39. 2.0%(1.9% to 2.2%) 2.8%(2.5% to 3.2%) 2.3%(1.5% to 3.0%) Annual Transition Rates Through Stages of Diabetic Nephropathy No nephropathy 1.4%(1.3% to 1.5%) Microalbuminuria 3.0%(2.6% to 3.4%) DEATH Macroalbuminuria 4.6%(3.6% to 5.7%) Elevated plasma creatinine or renal replacement therapy 19.2%(14.0% to 24.4%) Adler et al. Kidney Int 2003;63:225–32

40. Relationship Between SBP and ACR in T2DM Patients with Different Degrees of AER 100 10 ACR mg/mmol 1 0.1 80 100 120 140 160 180 200 220 240 SBP mmHg Smith et al. JASN 2005;16:1069–75

41. Risk factors for microalbuminuria in type 1 diabetic patients with baseline normoalbuminuria (7 yr follow-up)

42. Excess Mortality With Hypertensionand Proteinuria In Type 2 Diabetes Status of hypertension (H) and proteinuria (P) in type 2 diabetes 1000 Standardisedmortality ratio 500 0 P-H- P-H+ P+H-P+H+ P-H- P-H+ P+H- P+H+ Men Women Wang et al. Diabetes Care 1996;19:305–12

43. Epidemiology

44. Relative Risk of Cardiovascular Disease and Mortality in Diabetes Mellitus By Quartile of Albuminuria (ACR) ACR (mg/mmol) quartiles RR (95% CI) n=3,498 Gerstein et al. JAMA 2001;286:421–6

45. Rate of eGFR Decline in Type 2 DM With Normoalbuminuria AER categories: I = ≤10 mg/24h II = 10.1 to 20 mg/24h III = 20.1 to 30 mg/24h Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94

46. Survival Curves in Type 2 DM According To Baseline AER Category AER categories: I = ≤10 mg/24h II = 10.1 to 20 mg/24h III = 20.1 to 30 mg/24h Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94

47. Albuminuria and CVD risk in hypertensive patients with LVH The LIFE Study Composite endpoint = CVD death, fatal or non-fatal stroke,fatal or non-fatal MI

48. Relative Risk of CVD and Mortality in5,545 High-risk Patients Without Diabetes by Quartile of Albuminuria (ACR) ACR (mg/mmol) quartiles RR (95% CI) Gerstein et al. JAMA 2001;286:421–26

49. Albuminuria and Incidence of CVD Events in Non-hypertensive and Non-diabetic Subjects The Framingham Heart Study Survival free of CVD According to sex-specific median UACR Median UAER: M: 3.9 μg/mg F: 7.5 μg/mg Arnlov et al. Circulation 2005;112:969–75

50. Albuminuria and Risk of CHD and Death In The General Population Third Copenhagen City Heart Study 25%-ile: 2.1 μg/min 50%-ile: 3.0 μg/min 75%-ile: 4.8 μg/min Klausen et al. Circulation 2004;110:32–35