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  1. Cardio Diabetes MasterClass Asianchapter January 28-30 2011, Shanghai Presentation topic The expanding role of ARB’s in CV risk management: Does it matter how we block the system? Slide lecture prepared and held by: Peter Meredith, PhD University of Glasgow Glasgow, United Kingdom

  2. The ReninAngiotensin System: ACE Inhibition Bradykinin AT1 NO, PGI2 AT2 Vasodilation, etc NO Vasodilation Tissue protection ACEI Angiotensin I ACE-independent formation of ANG II ACE Angiotensin II B2 Antiproliferation Differentiation Regeneration Anti-Inflammation Apoptosis? Vasoconstriction Proliferation Aldosterone Sympathetic NS NaCl-Retention Inflammation Apoptosis Adapted from Unger & Stoppelhaar 2007

  3. The ReninAngiotensin System: AT1 Blockade AT1 NO, PGI2 AT2 Vasodilation, etc NO Vasodilation Tissue protection Angiotensin I ACE ARB Angiotensin II B2 Antiproliferation Differentiation Regeneration Anti-Inflammation Apoptosis? Vasoconstriction Proliferation Aldosterone Sympathetic NS NaCl-Retention Inflammation Apoptosis Adapted from Unger & Stoppelhaar 2007

  4. RAAS Blockade Across the CV Continuum MI Vascular • ELITE II • Val-HeFT • CHARM • CONSENSUS I • SOLVD • PEP-CHF • I-PRESERVE Hypertension • OPTIMAAL • VALIANT • CONSENSUS II • ISIS-4 • GISSI-3 • SMILE • SAVE • AIRE • TRACE • LIFE • SCOPE • VALUE • KYOTO HEART • CAPPP • ANBP-2 • ALLHAT • CASE-J Diabetes - Renal • RENAAL • IDNT • ABCD-2V • AASK • MARVAL • ADVANCE • DETAIL • DIRECT • ROADMAP CAD Heart Failure • EUROPA • PEACE • IMAGINE • ELITE II • Val-HeFT • CHARM • CONSENSUS I • SOLVD • PEP-CHF • I-PRESERVE 2o Stroke Prevention • ACCESS • PROGRESS • PRoFESS • SCAST Pre-Diabetes • NAVIGATOR • DREAM

  5. 2007 ESH/ESC Guidelines: Choice ofAntihypertensive Drugs • The main benefits of antihypertensive therapy are due to lowering of BP per se • Five major classes of antihypertensive agents – thiazide diuretics, CCBs, ACE inhibitors, angiotensin receptor blockers (ARBs) and b-blockers – are suitable for the initiation & maintenance of antihypertensive treatment, alone or in combination. b-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetes • Because in many patients more than one drug is needed, emphasis on identification of the first class of drugs to be used is often futile. Nevertheless, there are many conditions for which there is evidence in favour of some drugs versus others either as initial treatment or as part of a combination Presented at Cardio Diabetes MasterClassShanghai

  6. Effect of Different Antihypertensives on Incident Diabetes results of a network meta-analysis of 22 clinical trials 0.57 (0.46, 0.72) p<0.0001 0.67 90.56-0.80) p<0.0001 0.75 (0.62, 0.90) p=0.002 0.77 (0.63, 0.94) p=0.009 0.90 (0.75, 1.09) p=0.30 Referent ARB ACEI CCB Placebo b Blocker Diuretic 1.25 0.5 0.7 0.9 Odds ratio of incident diabetes Elliott & Meyer 2007

  7. Regression of Left Ventricular Hypertrophy with Antihypertensive Therapy by Drug Class 0 -5 -10 -15 -20 Mean % change in LV Mass from baseline (with 95% CI’s) adjusted for change in diastolic BP & duration of treatment * p<0.05;**p<0.001 vs beta blocker change in LV Mass(%) ** * * Diuretics b-Blockers Calcium ACE-Is ARB’s Antagonists Klingbeil et al 2003

  8. Improved No change Worse Patient’s opinion Relative’s opinion Quality of Life and Antihypertensive Treatment Reported attitude % 100 80 60 40 20 0 Physician’s opinion Hosie & Wiklund 1995

  9. Persistence with Antihypertensive Therapyafter1 & 4 Years of Treatment 4 years On treatment % AT1-blocker p<0.02 compared to all other classes 70 1 year 60 50 40 30 20 10 0 AT1-blocker ACE-I CCBs Beta- blockers Diuretics Conlin et al 2001

  10. ACEIs vs ARBs: Risk of Stroke OR (95%CI) Events ARBs ACEIs ACEs v ACEIs ELITE 1997 ELITE II 2000 OPTIMAAL 2002 DETAIL 2004 VALIANT (val) 2003 ONTARGET (tel) 2008 Fixed effect model (I2=0.0%, p=0.478) Random effect model 1.41 (0.31,6.33) 1.64 (0.77,3.48) 1.06 (0.83,1.35) 1.09 (0.34,3.47) 0.85 (0.69,1.04) 0.91 (0.79,1.05) 0.93 (0.84, 1.03) 0.93 (0.90,1.03) 4/352 18/1578 140/2744 6/120 180/4909 369/8542 717/18245 3/370 11/1574 132/2733 6/130 211/4909 405/8576 768/18292 ARB + ACEs v ACEIs VALIANT (val + cap) 2003 ONTARGET (tel+ram) 2008 Fixed effect model (I2=0.0%, p=0.602) Random effect model 183/4885 373/8502 556/13387 211/4909 405/8576 616/13485 0.87 (0.71,1.06) 0.93 (0.80,1.07) 0.91 (0.81,1.02) 0.91 (0.81,1.02) Overall Estimate Fixed effect model (I2=0.0%, p=0.670) Random effect model 1273/31632 1384/31777 0.92 (0.85,0.99) 0.92 (0.85,0.99) favours 1st listed favours 2nd listed heterogeneity between groups p=0.714 0.5 1.0 2.0 Presented at Cardio Diabetes MasterClassShanghai Odds Ratio Reboldi et al 2008

  11. ACEIs vs ARBs: Risk of Myocardial Infarction OR (95%CI) Events ARBs ACEIs ACEs v ACEIs ELITE 1997 ELITE II 2000 OPTIMAAL 2002 DETAIL 2004 VALIANT (val) 2003 ONTARGET (tel) 2008 Fixed effect model (I2=0.0%, p=0.884) Random effect model 0.79 (0.17,3.54) 1.11 (0.66,1.85) 1.01 (0.87,1.18) 1.68 (0.58,4.86) 1.00 (0.90,1.11) 1.07 (0.94,1.23) 1.03 (0.95, 1.10) 1.03 (0.95,1.10) 4/352 31/1578 384/2744 9/120 796/4909 440/8542 1663/18245 4/370 28/1574 379/2733 6/130 798/4909 413/8576 1628/18292 ARB + ACEs v ACEIs VALIANT (val + cap) 2003 ONTARGET (tel+ram) 2008 Fixed effect model (I2=0.0%, p=0.148) Random effect model 756/4885 438/8502 1194/13387 798/4909 413/8576 1211/13485 0.94 (0.85,1.05) 1.07 (0.94,1.23) 0.99 (0.91,1.08) 1.00 (0.88,1.13) Overall Estimate Fixed effect model (I2=0.0%, p=0.759) Random effect model 2857/31632 2839/31777 1.01 (0.96,1.07) 1.01 (0.96,1.07) favours 1st listed favours 2nd listed heterogeneity between groups p=0.555 Odds Ratio 0.5 1.0 2.0 Presented at Cardio Diabetes MasterClassShanghai Reboldi et al 2008

  12. Antihypertensive Therapy & Type 2 Diabetes • optimal BP control with different classes of antihypertensives has shown important benefits in reducing the risks of macrovascular and microvascular disease • it has been suggested that antihypertensives that block the RAAS might over additional benefit beyond BP control by way of delaying the progression of diabetic nephropathy • whilst ACE Inhibitors have proven benefit in diminishing the progression of nephropathy in type 1 diabetes, equivalent data in type 2 diabetes is limited Presented at Cardio Diabetes MasterClassShanghai

  13. AT1 Receptor Blockers in Type 2 Diabetes • IDNT (2001) • Irbesartan offers protection in hypertensive type 2 diabetics with nephropathy • Amlodipine only provided good BP control in diabetic patients • IRMA II (2001) • Irbesartan reduced the progression to nephropathy in hypertensive type 2 diabetics with microalbumiuria • RENAAL (2001) • Losartan delays ESRD and delays the decline in renal failure in hypertensive type 2 diabetics with nephropathy • MARVAL (2001) • Vasartan was significantly more effective than amlodipine in reducing in UAER type 2 diabetics with microalbuminuria the renoprotective effects were independent of BP lowering Presented at Cardio Diabetes MasterClassShanghai

  14. Comparison of Enalapril & CandesartanCilexetil: 36 Hour ABPM after 8 Weeks Therapy hours post dose 0 4 8 12 16 20 24 28 32 36 0 4 8 12 16 20 24 28 32 36 0 0 Diastolic ABP Systolic ABP -2 -4 -4 -8 -6 -12 -8 -10 -16 Candesartan 16 mg -12 Enalapril 20 mg D SBP (mm Hg) D DBP (mm Hg) EffECT Study Group

  15. O CI N N S N CO2H N CO2H N N N N N N N N COOH N N N N N NH NH NH NH COOH EXP 3174 Valsartan Eprosartan CH3 N N OCH2CH3 CH3 N N N O CO2H N N O N CH3 Telmisartan Irbesartan Candesartan Chemical Structures of Angiotensin II Receptor Blockers OH Presented at Cardio Diabetes MasterClassShanghai

  16. Antagonism of Angiotensin II-Induced Effects by Candesartan and Losartan 125 125 Candesartan Irbesartan 100 100 0.003nM 10 nM 75 75 Control Control 0.03 nM 1 nM 50 50 25 25 0.1 M 1nM 0 0 -10 -9 -8 -7 -6 -5 -10 -9 -8 -7 -6 -5 125 125 Losartan EXP-3174 100 0.01 nM 100 Control Control 75 75 50 50 10 nM 1 nM 0.1 nM 0.1 M 25 25 0 0 -10 -9 -8 -7 -6 -5 -10 -9 -8 -7 -6 -5 Angiotensin II (nM) Morsing et al 1998

  17. Insurmountable and Surmountable Antagonism: Relation to Duration of Binding 100 candesartan 80 telmisartan olmesartan EXP 3174 60 Insurmountability (%) valsartan 40 irbesartan 20 losartan 0 0 20 40 60 80 100 120 Dissociation t1/2 Van Liefde et al 2009

  18. Number of AT1-Receptor Binding Sites for Different Angiotensin II Receptor Antagonists 3 sites - valsartan 2 sites - losartan 4 sites - candesartan Hydrogen bonds between ligand and receptor are shown as red dotted lines with hydrogen bond lengths. Carbon atoms of the ligands are coloured light blue and those of the receptors are green Bhuiyan et al 2009

  19. Candesartan 04816 mg Candesartan Meta-AnalysisBased on US New Drug Application Evaluation Reports -0 Reduction in diastolic BP (mmHg) -2 Losartan -4 Valsartan Irbesartan -6 02550100 mgLosartan 080160320 mgValsartan 075150300 mgIrbesartan Elmfeldt et al 2002

  20. A Placebo Controlled ABPM Comparison of Candesartan 8 mg and Losartan 50 mg Systolic BP Diastolic BP 4 2 0 0 -2 Change in BP (mmHg) -4 -4 * -8 * -6 * * -8 * # * # -12 * * day night day night -10 *p<0.001 vs placebo candesartancilexetil 8 mg #p<0.05 vslosartan losartan 50 mg placebo Mallion et al 1999

  21. CandesartanCilexetilvsLosartan : Mean Change From Baseline to Week 8 in Systolic ABP 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Losartan 100mg p=0.004 Candesartancilexetil 16mg Hours after dose 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 Change in SBP (mm Hg) Lacourcière & Asmar 1999

  22. Comparison of the Efficacy of Candesartan & Losartan: Meta-Analysis of Trials in the Treatment of Hypertension A systematic literature search of databases from 1980 to 1 October 2008 identified 13 studies in which candesartan and losartan (as mono-therapy or in fixed combination with HCTZ) were compared in randomised trials in hypertensive patients. Data from 4066 patients were included in the statistical analysis which was performed using RevMan software (v5), provided by the Cochrane Information Management System using a random effect model. Mean changes in SBP and DBP were compared for each drug alone and after stratification for dose and for combination with HCTZ. Meredith et al 2009

  23. Study or Subgroup Candesartan Losartan Mean Difference Mean SD Total Mean SD Total Weight 95% CI 95% CI Andersson et al 1998 Andersson et al 1998 15.7 24.5 82 12.3 22.1 83 2.1% 3.40 [ 3.40 [ - - 3.72, 10.52] 3.72, 10.52] Andersson et al 1998 Andersson et al 1998 16.9 24.3 84 12.3 22.1 83 2.1% 4.60 [ 4.60 [ - - 2.44, 11.64] 2.44, 11.64] Baguet et al 2006 Baguet et al 2006 10.8 11.3 87 8.8 8.9 89 8.7% 2.00 [ 2.00 [ - - 1.01, 5.01] 1.01, 5.01] Bakris et al 2001 Bakris et al 2001 13.3 14.8 322 9.8 14.2 332 12.6% 3.50 [1.28, 5.72] 3.50 [1.28, 5.72] Gradman et al 1999 Gradman et al 1999 11.9 14.5 162 10 14.6 170 8.2% 1.90 [ 1.90 [ - - 1.23, 5.03] 1.23, 5.03] Koenig et al 2000 Koenig et al 2000 32.2 12.8 81 23.8 12.7 79 5.8% 8.40 [4.45, 12.35] 8.40 [4.45, 12.35] Koh et al 2004 Koh et al 2004 22.1 12.1 31 22.7 12.4 32 2.8% - - 0.60 [ 0.60 [ - - 6.65, 5.45] 6.65, 5.45] Lacourciere et al 1999 Lacourciere et al 1999 12.3 10.7 109 8.4 10.5 106 9.4% 3.90 [1.07, 6.73] 3.90 [1.07, 6.73] Lacourciere et al 1999 Lacourciere et al 1999 14.5 11.8 106 10.3 11.5 100 8.0% 4.20 [1.02, 7.38] 4.20 [1.02, 7.38] Manolis et al 2000 Manolis et al 2000 15.8 12.2 462 14.4 11.7 449 17.5% 1.40 [ 1.40 [ - - 0.15, 2.95] 0.15, 2.95] Matsuda et al 2003 Matsuda et al 2003 14.2 9.7 17 15.2 10.4 15 2.1% - - 1.00 [ 1.00 [ - - 8.00, 6.00] 8.00, 6.00] Nishimura et al 2005 Nishimura et al 2005 11.4 10 12 7.9 8.1 11 1.9% 3.50 [ 3.50 [ - - 3.91, 10.91] 3.91, 10.91] Ohman et al 2000 Ohman et al 2000 19.4 16.9 151 13.7 17.4 148 5.9% 5.70 [1.81, 9.59] 5.70 [1.81, 9.59] Rayner et al 2006 Rayner et al 2006 25.8 18.3 25 17.7 15.6 27 1.3% 8.10 [ 8.10 [ - - 1.18, 17.38] 1.18, 17.38] Vidt Vidt et al 2001 et al 2001 3.30 [0.92, 5.68] 3.30 [0.92, 5.68] 13.4 15.1 307 10.1 14.9 304 11.7% 3.22 [2.16, 4.29] 3.22 [2.16, 4.29] OVERALL 2038 2028 100.0% df = 14 (P = 0.16); I ² = 27% = 19.19, ² Heterogeneity: Tau ² = 1.06; Chi Favours Candesartan Favours Losartan Test for overall effect: Z = 5.92 (P < 0.00001) -10 0 10 20 Mean Difference 95% CI Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials Meredith et al 2009

  24. Mean Difference 95% CI Candesartan, n= Losartan, n= 3.22 [2.16, 4.29] ALL TRIALS 2038 2028 Heterogeneity: Tau² = 1.06; Chi² = 19.19, df = 14 (P = 0.16); I² = 27% Test for overall effect: Z = 5.92 (P < 0.00001) 2.57 [1.71, 3.44] Monotherapy 1806 1801 Heterogeneity: Tau² = 0.00; Chi² = 9.24, df = 12 (P = 0.68); I² = 0% Test for overall effect: Z = 5.86 (P < 0.00001) 2.74 [0.83, 4.64] “Low Dose” 295 293 Heterogeneity: Tau² = 0.00; Chi² = 2.01, df = 3 (P = 0.57); I² = 0% Test for overall effect: Z = 2.81 (P < 0.005) 2.49 [1.52, 3.57] “High Dose” 1427 1425 Heterogeneity: Tau² = 0.00; Chi² = 6.86, df = 7 (P = 0.44); I² = 0% Test for overall effect: Z = 5.01 (P < 0.00001) Favours Candesartan Favours Losartan -10 0 10 Mean Difference 95% CI Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials Meredith et al 2009

  25. Candesartan & Losartan-Antihypertensive Effects: Diastolic BP in Direct Comparator Trials CandesartanLosartan WMD 95% CI Test of Overall Effect (n=) (n=) (mmHg) (mmHg) Z= p= All Trials 2038 2028 2.21 1.34, 3.07 4.99 0.0001 Monotherapy 1806 1801 1.76 1.03, 2.50 4.70 0.0001 “Low-Dose” 295 293 2.02 0.81, 3.23 3.27 0.001 “High-Dose” 1427 1425 1.63 0.59, 2.67 3.06 0.002 “HCTZ 232 227 4.34 0.82, 7.87 2.41 0.02 Combination” Meredith et al 2009

  26. Potential Benefits of Additional BP Reductions an additional 1.8 mmHg reduction in diastolic BP can be predicted to result in:- Meta-analysis of 61 cohort studies and 147 randomised trials suggests that in a 65 year old, monotherapy with a standard dose of an antihypertensive, reduces diastolic BP by approximately 5mmHg resulting in:- 0 CHD Stroke -10 -20 % reduction in events -30 -40 Prospective Studies Collaboration 2002 & Law et al 2009

  27. The Cardiovascular Continuum ARB ARB ARB ARB ARB Hypertension Hyperlipidemia Diabetes Coronary Artery Disease Plaque Rupture Atherosclerosis Myocardial Infarction Endothelial Dysfunction Dilatation/Remodeling Risk Factors Heart Failure End-Stage Heart Disease

  28. Conclusions • A volume of evidence suggests that tight blood pressure control is of pivotal importance in optimising cardiovascular outcome particularly in high risk groups • Certain classes of antihypertensive appear to offer additional benefit beyond blood pressure control • Significant pharmacological differences with respect to efficacy and duration of action are apparent within most classes of antihypertensive • For angiotensin receptor blockers these differences appear to translate into important differences in CV outcome Presented at Cardio Diabetes MasterClassShanghai