brenner-may-19课件

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide,*,Downloaded from,RENAAL,Altering the Course of Renal Disease in Hypertensive Patients with Type 2 Diabetes and Nephropathy with the A,II,Antagonist Losartan,1,Angiotensin,II,Drives Pathology in Hypertension,Hypertension,Vascular Dysfunction,Endothelial dysfunctionRemodeling/hypertrophyFibrosisAtherosclerosis,Tissue Dysfunction,Cell loss,Fibrosis,Remodeling,Ischemia,Heart,MI,HF,Kidney,ESRD,Brain,Stroke,Genetics,risk factors(diabetes,hypercholesterolemia)Environment(diet,smoking,stress),MI=myocardial infarction;HF=heart failure;ESRD=end-stage renal disease,Adapted from Weir MR,Dzau VJ,Am J Hypertens,1999;12:205S-235S;Timmermans PB et al,Pharmacol Rev,1993;45(2):205-251;and Jessup M,Brozena S,N Engl J Med,2003;348:2007-2018.,2,Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking,Endpoints Studied,ACE Inhibitor Trials,in Type 2 Diabetics,TotalReduction ofReduction ofReduction in Risk with 1 Year Follow-UpSampleProteinuriaGFR Decline of ESRD,*,Ravid et al,Ann Intern Med,1993,94YesYes,No,Lebovitz et al,Kidney Int,1994,121YesYes,No,Bakris et al,Kidney Int,1996,52YesYes,No,Ahmad et al,Diabetes Care,1996,103YesYes,No,Nielsen et al,Diabetes Care,1997,36YesYes,No,UKPDS et al,Br Med J,1998,758YesNo,No,Fogari et al,J Hum Hypertens,1999,107YesNo,No,ABCD,Diabetes Care,2000,470YesYes,No,Ruggenenti et al,(REIN),352(27)*,YesYes,Yes*,Am J Kidney Dis,2000,MICRO-HOPE*,Lancet,2000,3577YesNo,Yes*,GFR=glomerular filtration rate,*Reduction in the risk of end-stage renal disease(renal transplant or dialysis),*Only 27(8%)of the 352 patients in this study were Type 2 diabetics,*In this study there was no reduction of risk for renal dialysis for ramipril compared to placebo(p=0.70),3,Controlling the Course of Renal Disease with Losartan,Rationale for RENAAL(Losartan Renal Protection Study),:,Losartan significantly lowered BP comparable to other classes of antihypertensive drugs,Losartan demonstrated superior tolerability compared to other classes of antihypertensive drugs(placebo-like side-effect profile),Losartan was a specific antagonist of angiotensin,II,(significant driver of pathology in renal disease),Losartan had significant renoprotective effects in animal models of renal disease,Losartan was well tolerated and lowered BP in hypertensive patients with renal insufficiency,BP=blood pressure,Adapted from Goa KL,Wagstaff AG,Drugs,1996;51(5):820-845;Goldberg AI et al,J Hypertens,1995;13(suppl 1):S77-S80;Lafayette RA et al,J Clin Invest,1992;90:766-771;Remuzzi A et al,J Am Soc Nephrol,1993;4(1):40-49;Toto R et al,Hypertension,1998;31:684-691.,4,RENAAL,R,eduction of,E,ndpoints in,N,IDDM with the,A,II,A,ntagonist,L,osartan,An investigator-initiated,multicenter,double-blind,randomized,placebo-controlled study to evaluate the renal protective effects of losartan in patients with Type 2 diabetes and nephropathy,1513 Patients;250 Centers;28 Countries,Steering CommitteeChairB.M.Brenner,MD,Data and Safety Monitoring CommitteeChairC.E.Mogensen,MD,Clinical Endpoint Adjudication Committee ChairS.Haffner,MD,Coordinating Center:Merck Research LabsStudy DirectorS.Shahinfar,MD,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334;Brenner BM et al,N Engl J Med,2001;345(12):861-869.,6,RENAAL Primary Hypothesis,Long-term treatment with losartan versus placebo(alone or in combination with conventional antihypertensive therapy*)in Type 2 diabetic patients with nephropathy will increase the time to first event and decrease the incidence of doubling of sCr,ESRD,or death,*Excluding ACE inhibitors and other A,II,antagonists,sCr=serum creatinine,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,7,Losartan compared to placebo(alone or in combination with conventional antihypertensive therapy*)in patients with Type 2 diabetes and nephropathy will,Increase the time to first event and decrease the incidence of cardiovascular morbidity/mortality,Reduce proteinuria,Decrease the rate of progression of renal disease,*Excluding ACE inhibitors and other A,II,antagonists,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,RENAAL Secondary Hypothesis,8,RENAAL Inclusion/Exclusion Criteria,Inclusion criteria,Type 2 diabetes,Age 3170 years,Proteinuria:urine albumin:cr 300 mg/g or 24-hr protein 500 mg,sCr:1.33.0 mg/dl,115265 mol/L*,Exclusion criteria,Type 1 diabetes,Known non-diabetic renal disease or renal artery stenosis,Recent history of MI,CABG,PTCA,CVA,TIA,History of HF,HbA,1c,12%,CABG=coronary artery bypass graft;PTCA=percutaneous transluminal coronary angioplasty;CVA=cerebral vascular accident;TIA=transient ischemic attacks,*Lower limit 1.5 mg/dl(133,mol/L)in male patients 60 kg,Adapted from Brenner BM et al,J Renin-Angiotens-Aldoster Syst,2000;1(4):328-334.,10,Europe19%,Latin America18%,North America 46%,Asia,17%,Adapted from Brenn