1. P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N The expanding role of ARB’s in CV risk management: Does it matter how we block the system? Peter Meredith, PhD University of Glasgow Glasgow, United Kingdom Cardio Diabetes Master Class Asian chapter January 28-30 2011, Shanghai Slide lecture prepared and held by: Presentation topic

2. The Renin Angiotensin System: ACE Inhibition AT 2 AT 1 Angiotensin I Angiotensin II B2B2B2B2 NO, PGI 2 Vasodilation, etc NOVasodilation Tissue protection VasoconstrictionProliferationAldosterone Sympathetic NS NaCl-RetentionInflammationApoptosis ACEI AntiproliferationDifferentiationRegenerationAnti-InflammationApoptosis? Adapted from Unger & Stoppelhaar 2007 ACE-independent formation of ANG II Bradykinin ACE

3. The Renin Angiotensin System: AT 1 Blockade AT 2 AT 1 Angiotensin I Angiotensin II B2B2B2B2 NO, PGI 2 Vasodilation, etc NOVasodilation Tissue protection VasoconstrictionProliferationAldosterone Sympathetic NS NaCl-RetentionInflammationApoptosis AntiproliferationDifferentiationRegenerationAnti-InflammationApoptosis? Adapted from Unger & Stoppelhaar 2007 ACE ARB

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

5.  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  - blockers – are suitable for the initiation & maintenance of antihypertensive treatment, alone or in combination.  -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 2007 ESH/ESC Guidelines: Choice of Antihypertensive Drugs January 2011 Presented at Cardio Diabetes Master Class Shanghai

6. Elliott & Meyer 2007 Effect of Different Antihypertensives on Incident Diabetes 0.9 0.50.7 ARBACEICCBPlacebo  Blocker Diuretic 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 Odds ratio of incident diabetes 1.25 results of a network meta-analysis of 22 clinical trials

7. Diuretics  -Blockers Calcium ACE-Is ARB’s Antagonists Antagonists change in LV Mass(%) 0-5-10-15-20 Regression of Left Ventricular Hypertrophy with Antihypertensive Therapy by Drug Class Klingbeil et al 2003 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

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

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

10. Reboldi et al 2008 ACEIs vs ARBs: Risk of Stroke ACEs v ACEIs ELITE1997 ELITE II2000 OPTIMAAL2002 DETAIL2004 VALIANT (val)2003 ONTARGET (tel) 2008 Fixed effect model (I 2 =0.0%, p=0.478) Fixed effect model (I 2 =0.0%, p=0.478) Random effect model Random effect model ARB + ACEs v ACEIs VALIANT (val + cap)2003 ONTARGET (tel+ram)2008 Fixed effect model (I 2 =0.0%, p=0.602) Fixed effect model (I 2 =0.0%, p=0.602) Random effect model Random effect model Overall Estimate Fixed effect model (I 2 =0.0%, p=0.670) Fixed effect model (I 2 =0.0%, p=0.670) Random effect model Random effect model 0.5 1.0 2.0 Odds Ratio favours 1 st listed favours 2 nd listed 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) 3/37011/1574132/27336/130211/4909405/8576768/18292 0.87 (0.71,1.06) 0.93 (0.80,1.07) 0.91 (0.81,1.02) 0.91 (0.81,1.02) 211/4909405/8576616/13485 0.92 (0.85,0.99) 1384/31777 Events ARBs ACEIs 4/35218/1578140/27446/120180/4909369/8542717/18245 183/4885373/8502556/13387 1273/31632 OR(95%CI) heterogeneity between groups p=0.714 January 2011 Presented at Cardio Diabetes Master Class Shanghai

11. Reboldi et al 2008 ACEIs vs ARBs: Risk of Myocardial Infarction ACEs v ACEIs ELITE1997 ELITE II2000 OPTIMAAL2002 DETAIL2004 VALIANT (val)2003 ONTARGET (tel) 2008 Fixed effect model (I 2 =0.0%, p=0.884) Fixed effect model (I 2 =0.0%, p=0.884) Random effect model Random effect model ARB + ACEs v ACEIs VALIANT (val + cap)2003 ONTARGET (tel+ram)2008 Fixed effect model (I 2 =0.0%, p=0.148) Fixed effect model (I 2 =0.0%, p=0.148) Random effect model Random effect model Overall Estimate Fixed effect model (I 2 =0.0%, p=0.759) Fixed effect model (I 2 =0.0%, p=0.759) Random effect model Random effect model 0.5 1.0 2.0 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) 4/37028/1574379/27336/130798/4909413/85761628/18292 0.94 (0.85,1.05) 1.07 (0.94,1.23) 0.99 (0.91,1.08) 1.00 (0.88,1.13) 798/4909413/85761211/13485 1.01 (0.96,1.07) 2839/31777 Events ARBs ACEIs 4/35231/1578384/27449/120796/4909440/85421663/18245 756/4885438/85021194/13387 2857/31632 OR(95%CI) heterogeneity between groups p=0.555 Odds Ratio favours 1 st listed favours 2 nd listed January 2011 Presented at Cardio Diabetes Master Class Shanghai

12. optimal BP control with different classes of antihypertensives has shown important benefits in reducing the risks of macrovascular and microvascular disease 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 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 whilst ACE Inhibitors have proven benefit in diminishing the progression of nephropathy in type 1 diabetes, equivalent data in type 2 diabetes is limited Antihypertensive Therapy & Type 2 Diabetes January 2011 Presented at Cardio Diabetes Master Class Shanghai

13. IDNT (2001) Irbesartan offers protection in hypertensive type 2 diabetics with nephropathy Irbesartan offers protection in hypertensive type 2 diabetics with nephropathy Amlodipine only provided good BP control in diabetic patients Amlodipine only provided good BP control in diabetic patients the renoprotective effects were independent of BP lowering RENAAL (2001) RENAAL (2001) Losartan delays ESRD and delays the decline in renal failure in hypertensive type 2 diabetics with nephropathy Losartan delays ESRD and delays the decline in renal failure in hypertensive type 2 diabetics with nephropathy IRMA II (2001) Irbesartan reduced the progression to nephropathy in hypertensive type 2 diabetics with microalbumiuria Irbesartan reduced the progression to nephropathy in hypertensive type 2 diabetics with microalbumiuria MARVAL (2001) MARVAL (2001) Vasartan was significantly more effective than amlodipine in reducing in UAER type 2 diabetics with microalbuminuria Vasartan was significantly more effective than amlodipine in reducing in UAER type 2 diabetics with microalbuminuria AT 1 Receptor Blockers in Type 2 Diabetes January 2011 Presented at Cardio Diabetes Master Class Shanghai

14. Comparison of Enalapril & Candesartan Cilexetil: 36 Hour ABPM after 8 Weeks Therapy EffECT Study Group Candesartan 16 mg Enalapril 20 mg hours post dose Systolic ABP Diastolic ABP -16 -12 -8 -4 0  SBP (mm Hg) -12 -10 -8 -6 -4 -2 0  DBP (mm Hg) 0481216202428323604812162024283236

15. OH N N N N Telmisartan CH 3 O COOH S N N Eprosartan COOH N O CO 2 H Valsartan EXP 3174 N N CO 2 H CI N N N NH Irbesartan O N N Candesartan N OCH 2 CH 3 N CO 2 H N N N NH N N N NH N N N NH Chemical Structures of Angiotensin II Receptor Blockers January 2011 Presented at Cardio Diabetes Master Class Shanghai

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

17. Insurmountable and Surmountable Antagonism: Relation to Duration of Binding telmisartan olmesartan candesartan EXP 3174 valsartan irbesartan losartan 0120 Dissociation t 1/2 0 100 Insurmountability (%) 80 10080 60 40 6040 20 20 Van Liefde et al 2009

18. 4 sites - candesartan 2 sites - losartan 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 Number of AT 1 -Receptor Binding Sites for Different Angiotensin II Receptor Antagonists 3 sites - valsartan Bhuiyan et al 2009

19. 025 50100 mgLosartan 080160320 mgValsartan 075150300 mgIrbesartan Reduction in diastolic BP (mmHg) Elmfeldt et al 2002 Meta-Analysis Based on US New Drug Application Evaluation Reports Candesartan 0 4 816 mg Candesartan Losartan Valsartan Irbesartan -6 -4 -2 -0

20. A Placebo Controlled ABPM Comparison of Candesartan 8 mg and Losartan 50 mg candesartan cilexetil 8 mg losartan 50 mg placebo Change in BP (mmHg) daydaynightnight Systolic BP Diastolic BP * * * * # *p<0.001 vs placebo # p<0.05 vs losartan Mallion et al 1999 * * * 4 0 -4 -8 -1220 -2 -4 -6 -8 -10 * #

21. Candesartan Cilexetil vs Losartan : Mean Change From Baseline to Week 8 in Systolic ABP 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 2468 10 12141618202224262830323436 Hours after dose Change in SBP (mm Hg) Lacourcière & Asmar 1999 Losartan 100mg Candesartan cilexetil 16mg p=0.004

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. Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials

24. Meredith et al 2009 Candesartan, n= Losartan, n= 95% CI Mean Difference Favours Candesartan 010-10 Favours Losartan Mean Difference 95% CI ALL TRIALS 20382028 3.22 [2.16, 4.29] Heterogeneity: Tau² = 1.06; Chi² = 19.19, df = 14 (P = 0.16); I² = 27% Test for overall effect: Z = 5.92 (P < 0.00001) Monotherapy18061801 2.57 [1.71, 3.44] Heterogeneity: Tau² = 0.00; Chi² = 9.24, df = 12 (P = 0.68); I² = 0% Test for overall effect: Z = 5.86 (P < 0.00001) “Low Dose” 295293 2.74 [0.83, 4.64] Heterogeneity: Tau² = 0.00; Chi² = 2.01, df = 3 (P = 0.57); I² = 0% Test for overall effect: Z = 2.81 (P < 0.005) “High Dose” 14271425 2.49 [1.52, 3.57] Heterogeneity: Tau² = 0.00; Chi² = 6.86, df = 7 (P = 0.44); I² = 0% Test for overall effect: Z = 5.01 (P < 0.00001) Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials

25. Candesartan LosartanWMD 95% CI Test of Overall Effect (n=) (n=)(mmHg)(mmHg) Z= p= All Trials203820282.21 1.34, 3.074.99 0.0001 Monotherapy 180618011.76 1.03, 2.504.70 0.0001 “Low-Dose” 295 2932.02 0.81, 3.233.270.001 “High-Dose” 142714251.63 0.59, 2.673.060.002 “HCTZ 232 2274.34 0.82, 7.872.410.02 Combination” Combination” Candesartan & Losartan-Antihypertensive Effects: Diastolic BP in Direct Comparator Trials Meredith et al 2009

26. Potential Benefits of Additional BP Reductions 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:- Prospective Studies Collaboration 2002 & Law et al 2009 0 -10 -20 -30 -40 % reduction in events CHDStroke an additional 1.8 mmHg reduction in diastolic BP can be predicted to result in:-

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

28.  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 Conclusions January 2011 Presented at Cardio Diabetes Master Class Shanghai