The case of microalbuminuria prevention: the ROADMAP study

1. The case of microalbuminuria prevention: the ROADMAP study Reinhold Kreutz, FAHA Department for Clinical Pharmacology and Hypertension Charité – University Medicine Berlin, Germany

2. 40 Proteinuria present 35 Proteinuria absent 30 Overall Mortality 25 Cardiovascular Mortality Age-adjusted annual incidence per 1000 20 15 10 5 0 Women Men Women Men Mortality and Proteinuria: Framingham-Study 5209 men and women, 16 years follow up Kannel WB et al. Am Heart J 1984;108:1347-52

3. Proteinuria: cardiovascular events in T2D mellitus (%) Survival without CV death Incidence (%) 40 1 p<0.001 for stepwise trend 0.9 30 A 0.8 B 20 0.7 0.6 C 10 p<0.001 0.5 0 0 -1056 pts in Finland -7 yearfollow up stroke coronary events 0 10 20 30 40 50 60 70 80 90 months A: U-Prot <150 mg/L B: U-Prot 150–300 mg/L C: U-Prot >300 mg/L Miettinen H et al. Stroke. 1996;27:2033-2039.

4. recommended cut off for micro-albuminuria Albumin to creatinine ratio in spot urine and cardiovascular mortality in the normal population Second Nord-Trøndelag Health Study (HUNT II) - Norway • - 9709 individuals • - community based • 8.3 years • follow-up • - 71% participation rate Albuminuria is a continuous parameter RR: median of ACR =1 (albumin to creatinine ratio) Hallan S et al. Arch Intern Med. 2007;167:2490-2496.

5. Determination of urinary albumin excretion (UAE)in cardiorenal medicine UAE or MAU

6. UAE: samples and units of measurement Urine sample Units *Witte EC et al. J Am Soc Nephrol. 2009;20:436-443 – first morning urine suggested.

7. UAE: samples and units of measurement Urine sample Units *Witte EC et al. J Am Soc Nephrol. 2009;20:436-443 – first morning urine suggested.

8. Reduction in Albuminuria Translates to Reduction in CV Events in HypertensionLosartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study 9193 hypertensives BP: 200-160/115-95 mmHgand LVH ECG positive 24 ≤ 0.5 mg/mmol 22 0.5-1 mg/mmol randomized:losartan vs. atenolol endpoint: death, MI, stroke 20 1-3 mg/mmol 18 > 3 mg/mmol 16 14 Endpoint ratio (%) 12 10 8 6 4 2 0 • Number of at-risk patients in the strata indicates patients shifted from higher level of UACR at baseline to lower level at years 2 and 4 • Risk for composite endpoint was lower with reduced albuminuria 0 6 12 18 24 30 36 42 48 54 60 66 Month Ibsen H et al. Hypertension2005;45:198-202

9. Availability, prognostic value and cost of some markers of organ damage ESC / ESH Hypertension guidelines 2007 Mancia G et al. J Hypertens 2007 2007;25:1105-1187

10. What is the link between a renal phenotype, i.e. albuminuria and cardiovascular disease? Increasedpermeability Macromolecules/ plasma proteins

11. Steno hypothesis:Albuminuria reflects widespread vascular damage Deckert T et al. Diabetologia. 1989;32:219 –226. Increasedpermeability • oxidative stress • inflammation • metabolic syndrome Macromolecules/ plasma proteins de Zeeuw D et al. Kidney Int Suppl 2005 ;98:S25-S29, Ritz E et al. Diabetologia 2010;53:49-57

12. ACR predicted renal events in patients with type 2 diabetes in the ADVANCE study 10,640 patients followed for4.3 years 10-fold increase in baseline ACR 3.3-fold increase in risk of renal event Albuminuria predicts renal events in diabetes P for trend < 0.0001 32.0 16.0 8.0 4.0 Hazard ratio (95% CI) 2.0 1.0 0.5 0.25 3 30 300 MA Baseline UACR (mg/g) death as a result of kidney disease, requirement for dialysis or transplantation or doubling of serum creatinine to >200 mmol/L ADVANCE = Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation Albuminuria is considered a continuous event and these ranges serve only as an orientation Ninomiya T, et al. J Am Soc Nephrol. 2009;20:1813–21.

13. Causes of chronic kidney disease Abboud H & Henrich WL New Engl J Med 2010;362:56-65

14. The cardiorenal continuum Cardiorenal continuum describes the interrelated progression of CVD and renal disease Target organ damageAsymptomatic CKDmicroalbuminuria Atherosclerosis Target organ damageSymptomatic MI, HF, stroke Risk factors ESRD Death Diabetes Hypertension

15. First study to examine whether an ARB can prevent or delay the onset of Microalbuminuria in patients with T2DM 4,400 patients with T2DM and normoalbuminuria and with at least 1 cardiovascular risk factor randomized to olmesartan 40 mg /d or placebo Randomised Olmesartan and Diabetes Microalbuminuria Prevention study (ROADMAP) Haller H, et al. J Hypertens. 2006;24:403–8.

16. ROADMAP: study design Randomization to double-blind treatment 4-weekpre-randomization Olmesartan 40 mg/day (n=2200) Placebo(n=2200) MA detected MA detected Follow-up until 326 MA cases Open-labelolmesartan 40 mg/day MI, stroke, orCrCl <30 MI, stroke, orCrCl <30 Observation only Observation only End of study CrCl=creatinine clearance (ml/min) Haller H, et al. J Hypertens. 2006;24:403–8.

17. ROADMAP: preliminary results • Patients were followed for a mean of 3.2 years • Approximately 80% achieved the diabetesblood pressure goal of  130/80 mm Hg • Time to first occurrence of microalbuminuria was significantly different after one year • 178 patients in the olmesartan group vs. 210 in the placebo group (p<0.05) Haller H et al. Late-breaking clinical trial. Presented at: Renal Week 2009; Oct. 27-Nov. 1; San Diego.

18. The cardiorenal continuum Measure urinary albumin excretion and prevent diabetic kidney disease Target organ damageAsymptomatic CKDmicroalbuminuria Atherosclerosis Target organ damageSymptomatic MI, HF, stroke Risk factors ESRD Death Diabetes Hypertension

19. Thank you !