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.

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

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)

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

= Hemoglobin (g/dL) < Serum albumin (per 0.5 g/dL) < – Serum creatinine (mg/dL) < Urine 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

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

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

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

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

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

LIFE; Hypertension with LVH; Baseline Albuminuria determines Cardiovascular outcome (primary combined end point) Month Endpoint Rate (%) <= 0.5 mg/mmol (n=2282) mg/mmol (n=1782) 1-3 mg/mmol (n=2438) > 3 mg/mmol (n=2691) Wachtell et al. Ann Intern Med. 2003;139:

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

PREVEND; Predictive effect of baseline urinary albumin excretion on mortality; general population Hillege et al; Circulation 2002;106(14): albumin concentration (mg/L) non-CV death albumin concentration (mg/L) hazard CV death

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)

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

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 Systolic Diastolic MAP Mo Pulse Pressure Blood Pressure (mmHg) P L Brenner et al; New Engl J Med 2001 Median Percent Change p=< % Overall Reduction Mo P L

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

RENAAL; Proteinuria Reduction Groups at Month 6 determines the renal outcome De Zeeuw et al; Kidney Int in press Renal Endpoint ESRD Month % with composite endpoint >30% <0% Month % with ESRD <0% >30%

RENAAL; Initial antiproteinuric response vs renal risk Albuminuria reduction (%) Albuminuria reduction (%) Hazard ratio Renal Endpoint ESRD De Zeeuw et al; Kidney Int; in press

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

GFR c >103 ml/min 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

Days ____________________________ 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

LIFE: Hypertensive diabetic with LVH; Cardiovascular mortality comparing RAAS-i and beta-blockade LH Lindholm, et al Lancet 2002; 359: Systolic Diastolic Mean Arterial Study Month mmHg Atenolol Losartan Cardiovascular Mortality Adjusted Risk Reduction = 37%; p=0·028 Unadjusted Risk Reduction = 38%; p=0·019

Follow-up (months) Subjects (%) Subjects (%) Control Irbesartan 150 mg Irbesartan 300 mg 70% RRR p < % RRR p < 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.

Time (months) Mean SeSBP and SeDBP (mmHg) Mean SeSBP and SeDBP (mmHg) 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.

IRMA-2 Change in UAER Anderson S et al. Diabetes Care 2003;26: Change in UAE (%) Irbesartan 150 mgIrbesartan 300 mg Placebo Months 0 0

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

PREVEND-IT; Effects of ACEi on Albuminuria in the “healthy” with microalbuminuria PREVEND IT DeltaAlbuminuria(%) Months 4 Years FosinoprilPravastatin Change from Placebo * * * * * p < Asselberg and van Gilst et al; AHA; late breaking trial session

Follow-up (Months) 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

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)

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

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

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

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 (€) ,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 45,000 Palmer et al; Submitted

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