1. Dick de Zeeuw Department of Clinical Pharmacology University Medical Center Groningen The Netherlands Early detection, prediction and potential treatment of renal and cardiovascular risk in the general population; type 2 diabetes.

2. For early detection, prediction and treatment, we should not only measure the blood pressure but also…. measure and treat the ALBUMINURIA/PROTEINURIA

3. PREVEND/it: PREVEND intervention study (ACEi and statin; n=854) Time course of type 2 diabetic renal disease; intervention options evidence from large trials IRMA 2 / LIFEdiab IDNT/RENAAL Secondary Prevention Tertiary Prevention ESRD Early Stage Late Stage End Stage Microalbuminuria Microalbuminuria Proteinuria Cardiovascular and Renal morbidity and mortality PREVEND/it Albuminuria Pre- Stage Primary Prevention IRMA 2: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (n=590) LIFEdiab: Losartan Intervention For Endpoint Reduction in Hypertension Study (n=1195) IDNT: Irbesartan Diabetic Nephropathy Trial (n=1715) RENAAL: Reduction of Endpoints in NIDDM with the AII Antagonist Losartan (n=1513) PREVEND/it: Prevention Renal and Vascular End-stage Disease (n=40.856)

4. Structure of talk Importance of albuminuria/proteinuria as a risk marker for cardiovascular and renal disease progression in  Advanced nephropathy (diabetes and non-diabetes)  Pre-nephropathy (diabetes and non-diabetes)  General “healthy” population Intervention directed at lowering albuminuria offers renal and cardiac protection beyond blood pressure control Early intervention is better and more cost effective than late intervention

5. =0.00010.84 - 0.950.89Hemoglobin (g/dL) <0.00010.61 - 0.800.70Serum albumin (per 0.5 g/dL) <0.00011.7 – 2.52.1Serum creatinine (mg/dL) <0.00014.4 - 8.76.2Urine albumin:creatinine (log, mg/g) p-Value95% Confidence Interval Hazard Ratio* RENAAL; Multivariate analysis for doubling serum creatinine or end-stage renal disease (n=1300) Keane et al; Kidney Int 2003

6. RENAAL; Baseline proteinuria as a determinant for cardiac events in type 2 diabetes De Zeeuw et al; Circulation, in press CV EndpointHeart Failure 012243648 Month 0 20 40 60 % with CV endpoint  3.0 g/g <1.5 g/g 012243648 Month 0 20 40 60 % with heart failure endpoint  3 g/g <1.5 g/g

7. RENAAL; Baseline proteinuria as a determinant for renal events in type 2 diabetes De Zeeuw et al; Kidney Int, in press Composite Endpoint ESRD 012243648 Month 0 20 40 60 80 100 % with renal endpoint  3.0 g/g <1.5 g/g 012243648 Month 0 20 40 60 80 100 % with esrd endpoint  3.0 g/g <1.5 g/g

8. Structure of talk  Importance of albuminuria/proteinuria as a risk marker for cardiovascular and renal disease progression in n Advanced nephropathy (diabetes and non-diabetes) n Pre-nephropathy (diabetes and non-diabetes) n General “healthy” population  Intervention directed at lowering albuminuria offers renal and cardiac protection beyond blood pressure control  Early intervention is better and more cost effective than late intervention

9. Hillege et al. Circulation 2000;102:203-210 Renal function determines CV mortality in patients with heart failure

10. Renal function determines CV-outcome in patients after first myocardial infarction Hillege et al. Eur Heart Journal 2003

11. LIFE; Hypertension with LVH; Baseline Albuminuria determines Cardiovascular outcome (primary combined end point) 0612182430364248546066 Month 0 2 4 6 8 10 12 14 16 18 20 22 24 Endpoint Rate (%) <= 0.5 mg/mmol (n=2282) 0.5-1.0 mg/mmol (n=1782) 1-3 mg/mmol (n=2438) > 3 mg/mmol (n=2691) Wachtell et al. Ann Intern Med. 2003;139:901-906.

12. Structure of talk  Importance of albuminuria/proteinuria as a risk marker for cardiovascular and renal disease progression in n Advanced nephropathy (diabetes and non-diabetes) n Pre-nephropathy (diabetes and non-diabetes) n General “healthy” population  Intervention directed at lowering albuminuria offers renal and cardiac protection beyond blood pressure control  Early intervention is better and more cost effective than late intervention

13. 13 PREVEND; Prevalence of albuminuria categories in the GENERAL POPULATION normal 0-10mg/l macroproteinuria >200 mg/l microalbuminuria 20-200 mg/l (7.2%) high-normal high-normal albuminuria albuminuria 10-20 mg/l 10-20 mg/l(16.6%) Hillege HL et al. J Int Med 2001;249:519-26 N=40.619

14. PREVEND; Predictive effect of baseline urinary albumin excretion on mortality; general population Hillege et al; Circulation 2002;106(14):1777-82 albumin concentration (mg/L) 0 1 2 3 4 5 2101001000 non-CV death albumin concentration (mg/L) hazard 0 1 2 3 4 5 2101001000 CV death

15. HUNT; Crude All-Cause Mortality for different MA in random non- diabetic non-hypertensive sample (follow-up 4.4yr) Romundstad S et al; Am J Kidney Dis 42 (2003)

16. Structure of talk  Importance of albuminuria/proteinuria as a risk marker for cardiovascular and renal disease progression in  Intervention directed at lowering albuminuria offers renal and cardiac protection beyond blood pressure control n Advanced nephropathy (diabetes and non-diabetes) n Pre-nephropathy (diabetes and non-diabetes) n General “healthy” population  Early intervention is better and more cost effective than late intervention

17. RENAAL; AII-antagonist (+ conv tx) is more renal protective than placebo (+ conv tx) in type 2 diabetes % with event p=0.024 Risk Reduction: 16% Placebo Losartan 012243648 0 10 20 30 40 50 Systolic Diastolic MAP 012243648 Mo 60 80 100 120 140 160 Pulse Pressure Blood Pressure (mmHg) P L Brenner et al; New Engl J Med 2001 Median Percent Change p=<0.001 35% Overall Reduction 40 012243648Mo -60 -40 -20 0 20 P L

18. RENAAL; Proteinuria Reduction ( 30%) determines the cardiovascular outcome CV EndpointHeart Failure 012243648 Month 0 10 20 30 40 % with CV endpoint >30% <0% 012243648 Month 0 10 20 30 40 % with heart failure <0% >30% De Zeeuw et al; Circulation, in press

19. RENAAL; Proteinuria Reduction Groups at Month 6 determines the renal outcome De Zeeuw et al; Kidney Int in press Renal Endpoint ESRD 012243648 Month 0 10 20 30 40 50 60 % with composite endpoint >30% <0% 012243648 Month 0 10 20 30 40 50 60 % with ESRD <0% >30%

20. RENAAL; Initial antiproteinuric response vs renal risk Albuminuria reduction (%) -90-250255072 Albuminuria reduction (%) 0.0 0.5 1.0 1.5 2.0 2.5 Hazard ratio -90-250255072 Renal Endpoint ESRD 0.0 0.5 1.0 1.5 2.0 2.5 De Zeeuw et al; Kidney Int; in press

21. Structure of talk  Importance of albuminuria/proteinuria as a risk marker for cardiovascular and renal disease progression in  Intervention directed at lowering albuminuria offers renal and cardiac protection beyond blood pressure control n Advanced nephropathy (diabetes and non-diabetes) n Pre-nephropathy (diabetes and non-diabetes) n General “healthy” population  Early intervention is better and more cost effective than late intervention

22. GFR c >103 ml/min 103-81 ml/min< 81 ml/min Hillege et al. Eur Heart Journal 2003 RAAS-intervention protects the heart in particular those with poor renal function in patients after MI

23. Days -10 -8 -6 -4 -2 0 2 4 31090360180____________________________ p=0.034 Placebo Captopril Hillege et al. Eur Heart Journal 2003 GFR (ml/min) RAAS-intervention protects the kidney of patients after myocardial infarction

24. LIFE: Hypertensive diabetic with LVH; Cardiovascular mortality comparing RAAS-i and beta-blockade LH Lindholm, et al Lancet 2002; 359:1004-1010 Systolic Diastolic Mean Arterial 061218243036424854 Study Month 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 mmHg Atenolol Losartan Cardiovascular Mortality 12 10 8 6 4 2 0 Adjusted Risk Reduction = 37%; p=0·028 Unadjusted Risk Reduction = 38%; p=0·019

25. 0 0 3 3 6 6 12 18 22 24 0 0 5 5 10 15 20 Follow-up (months) Subjects (%) Subjects (%) Control Irbesartan 150 mg Irbesartan 300 mg 70% RRR p < 0.001 70% RRR p < 0.001 IRMA 2; Hypertensive type 2 diabetes; Primary endpoint: Time to overt proteinuria Parving H-H et al. N Engl J Med 2001;345:870–8.

26. 0 0 70 130 160 0 0 3 3 6 6 9 9 12 15 18 21 24 27 Time (months) Mean SeSBP and SeDBP (mmHg) Mean SeSBP and SeDBP (mmHg) 80 90 100 110 120 140 150 Control Irbesartan 150 mg Irbesartan 300 mg Control Irbesartan 150 mg Irbesartan 300 mg Concomitant antihypertensive agents received by 56% of patients in the control group, 45% in the irbesartan 150 mg group, and 43% in the irbesartan 300 mg group Concomitant antihypertensive agents received by 56% of patients in the control group, 45% in the irbesartan 150 mg group, and 43% in the irbesartan 300 mg group IRMA 2; Hypertensive type 2 diabetes; Blood pressure response SeSBP SeDBP Parving H-H et al. N Engl J Med 2001;345:870–8.

27. IRMA-2 Change in UAER Anderson S et al. Diabetes Care 2003;26:3296-3302. -75 -65 -55 -45 -35 -25 -15 -5 5 5 15 25 Change in UAE (%) Irbesartan 150 mgIrbesartan 300 mg Placebo 3 3 6 6 9 9 12 15 18 21 24 24+1 0 0 Months 0 0

28. Structure of talk  Importance of albuminuria/proteinuria as a risk marker for cardiovascular and renal disease progression in  Intervention directed at lowering albuminuria offers renal and cardiac protection beyond blood pressure control n Advanced nephropathy (diabetes and non-diabetes) n Pre-nephropathy (diabetes and non-diabetes) n General “healthy” population  Early intervention is better and more cost effective than late intervention

29. PREVEND-IT; Effects of ACEi on Albuminuria in the “healthy” with microalbuminuria PREVEND IT DeltaAlbuminuria(%) 0 - 10 - 20 - 30 3 Months 4 Years FosinoprilPravastatin Change from Placebo - 3.12 - 3.12 - 1.85 - 1.85 - 29.5 * - 29.5 * - 31.43 * - 31.43 * * p < 0.001 Asselberg and van Gilst et al; AHA; late breaking trial session

30. Follow-up (Months) 010203040 0.90 0.95 1.00 Placebo (n = 429) PREVEND-IT; Effect of ACEi on Cardiovascular outcome in ´healthy´ individuals with microalbuminuria Fosinopril Fosinopril (n = 425) * Hazard Ratio: 0.56 (0.30 to 1.04), p = 0.07, Hazard Ratio: 0.53 (0.28 to 0.995), p < 0.05, adjusted for differences in baseline characteristics Hazard Ratio: 0.53 (0.28 to 0.995), p < 0.05, adjusted for differences in baseline characteristics RRR 44 % * Event-FreeSurvival PREVEND IT Asselberg and van Gilst et al; AHA; late breaking trial session

31. Structure of talk  Importance of albuminuria/proteinuria as a risk marker for cardiovascular and renal disease progression in  Intervention directed at lowering albuminuria offers renal and cardiac protection beyond blood pressure control  Early intervention is better and more cost effective than late intervention n Combined early and late analysis (PRIME)

32. PRIME; PRogram for Irbesartan Mortality and Morbidity Evaluation Pharmaco-economics Model Project Team  Hans-Henrik Parving  Dick de Zeeuw  Roger Rodby  Andrew Palmer  Stéphane Roze  Lieven Annemans  Mark Lamotte  Pablo Lapuerta  Roland Chen  Sylvie Gabriel  Paulo Carita  Isabelle Villadary

33. PRIME Model  Question n What is the most efficient starting point for Irbesartan treatment: at microalbuminuria level or at advanced overt nephropathy?  Method n Link IRMA-2 and IDNT studies n Project long-term outcomes for patients with microalbuminuria for progression to overt nephropathy, DSC, ESRD and death

34. PRIME Model – Disease States Dead DSC Early Overt Nephropathy Late Overt Nephropathy Progressors from IRMA-2 Start of of IDNT STARTING STATE: Cohort with baseline characteristics of patients in IRMA-2 Progressors from IDNT Late Irbesartan: START HERE Early Irbesartan and standard BP control: START HERE MAU Kidney Transplant Dialysis Palmer et al; Submitted

35. PRIME; Early vs Late intervention; effects on Cumulative Total Costs Placebo Late Irbesartan Early Irbesartan Years since baseline age of 58 Cumulative costs per patient (€) 024681012141618202224 0 5,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 45,000 Palmer et al; Submitted

36. Conclusion  Albuminuria/Proteinuria is an independent risk markers for cardiovascular and renal disease progression: each doubling of urinary albumin doubles the risk.  Optimal treatment strategy should include RAAS-intervention and target to lower the blood pressure (<130/80) and albuminuria/proteinuria (<500 mg/d): each short-term halving of albuminuria or proteinuria reduces the long-term risk by half.  These protective effects of RAAS-intervention can be achieved not only in advanced diabetes but also in early diabetes and even in the “general healthy” population  Early intervention is more cost effective than late intervention