The concept of Diabetes & CV risk: A lifetime risk challenge Cardio Diabetes Master Class European chapter Munich, Germany May 6-8, 2011 Presentation topic RAS blockade in the real world: Clinical lessons from recent trials Slide lecture prepared and held by: Peter Meredith PhD University of Glasgow, Department of Medicine and Therapeutics, Gardiner Institute Western Infirmary Glasgow, United Kingdom

The Cardiovascular Continuum Coronary Artery Disease Angiotensin II Plaque Rupture Atherosclerosis Myocardial Infarction Endothelial Dysfunction Dilatation/Remodeling Angiotensin II has many pathophysiologic effects, mediated by stimulation of the AT1 and AT2 receptors. It is a powerful vasoconstrictor that stimulates the secretion of two other potent vasoconstrictors, vasopressin and endothelin. Angiotensin II also: Increases salt and water retention directly, and indirectly via increased aldosterone secretion. Activates the sympathetic nervous system and has a direct inotropic effect on the myocardium. Stimulates cell growth and hypertrophy, apoptosis, interstitial fibrosis, and collagen synthesis influencing vascular and cardiac remodeling. Causes platelet aggregation, promotes the production of tissue factor, induces the expression of PAI-1, and stimulates the formation of superoxide radical (1) All of these pathophysiologic effects of angiotensin II result in pivotal, and potentially deleterious, effects throughout the cardiovascular continuum (1) Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355:637–645. Risk Factors Heart Failure Hypertension Hyperlipidemia Diabetes End-Stage Heart Disease

RAS Blockade Across the CV Continuum Hypertension Vascular MI ELITE II Val-HeFT CHARM CONSENSUS I SOLVD PEP-CHF I-PRESERVE LIFE SCOPE VALUE KYOTO HEART CAPPP ANBP-2 ALLHAT CASE-J OPTIMAAL VALIANT CONSENSUS II ISIS-4 GISSI-3 SMILE SAVE AIRE TRACE 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 3

2007 ESH/ESC Guidelines: Choice of Antihypertensive 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

VALUE : Odds Ratios Over Time Primary Endpoint Time D SBP (months) (mmHg) all study 2.2 0-3 3.8 3-6 2.3 6-12 2.0 12-24 1.8 24-36 1.6 36-48 1.4 study end 1.7 Favours Valsartan Favours Amlodipine 0.5 1.0 Odds Ratio 2.0

Myocardial Infarction VALUE: Endpoints while on Monotherapy Analysis of outcomes in 7080 patients who, at the end of the initial drug adjustment period, remained on monotherapy (data was censored when monotherapy was discontinued). Between-group differences in MI and heart failure at various time points in the study. Myocardial Infarction Heart Failure 0.5 1 2 favours valsartan favours amlodipine hazard ratio Months on monotherapy 12 18 24 30 36 42 48 favours valsartan favours amlodipine 0.5 1 2 hazard ratio Julius et al 2006

LIFE: Primary Composite Endpoint 0.16 Intention-to-Treat Analysis Atenolol 0.14 BP losartan vs atenolol: -1.1 mmHg SBP/ +0.2 mmHg DBP -0.3 mmHg MAP 0.12 Losartan 0.10 Endpoint rate 0.08 0.06 0.04 Adjusted Risk Reduction 13·0%, p=0·021 Unadjusted Risk Reduction 14·6%, p=0·009 0.02 0.00 6 12 18 24 30 36 42 48 54 60 66 Month Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Dahlöf et al 2002 7

Risk Reduction: ARB versus Control major CV event CV death fatal/non-fatal stroke fatal/non-fatal MI total mortality SCOPE LIFE 0.5 1.0 1.5 Relative Risk Adapted from Dahlöf et al 2002 & Lithell et al 2003 8

MOrbidity and Mortality after Stroke – Eprosartan vs MOrbidity and Mortality after Stroke – Eprosartan vs. Nitrendipine in Secondary Prevention 500 1000 1500 days 50 100 150 200 250 300 Events (n) Eprosartan Nitrendipine Odd Ratio=0.79 (0.66, 0.96) p<0.014 Primary Endpoint: composite of total mortality + total number of cerebrovascular & cardiovascular events (including recurrent events) Schrader et al 2004 9

SCOPE: First Major Cardiovascular Events in Patients with a Previous Stroke 66% 62% 64% Non-fatal stroke All Major CV event Relative risk reduction Control Events/1000 patient years 20 40 60 80 100 Candesartan Trenkwalder et al 2005

Antagonism of Angiotensin II-Induced Effects by Candesartan and Losartan 125 Candesartan 125 Irbesartan 100 100 0.003nM 10 nM 75 Control 75 Control 0.03 nM 1 nM 50 50 25 25 1nM 0.1 M -10 -9 -8 -7 -6 -5 -10 -9 -8 -7 -6 -5 125 Losartan 125 EXP-3174 100 100 0.01 nM 75 Control Control 75 50 10 nM 50 1 nM 0.1 M 0.1 nM 25 25 -10 -9 -8 -7 -6 -5 -10 -9 -8 -7 -6 -5 Angiotensin II (nM) Morsing et al 1998 11

Insurmountable and Surmountable Antagonism: Relation to Duration of Binding 100 candesartan 80 telmisartan olmesartan EXP 3174 60 Insurmountability (%) valsartan 40 irbesartan 20 losartan 20 40 60 80 100 120 Dissociation t1/2 Van Liefde et al 2009 12

A Placebo Controlled ABPM Comparison of Candesartan 8 mg and Losartan 50 mg Systolic BP Diastolic BP 4 2 -2 -4 -6 -8 -10 Change in BP (mmHg) -4 -8 * * * * * # -12 * # * * day night day night *p<0.001 vs placebo candesartan cilexetil 8 mg #p<0.05 vs losartan losartan 50 mg placebo Mallion et al 1999 13

Candesartan Cilexetil vs Losartan : Mean Change From Baseline to Week 8 in Systolic ABP Hours after dose 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 -2 Losartan 100mg Candesartan cilexetil 16mg p=0.004 -4 -6 -8 -10 -12 -14 -16 -18 Change in SBP (mm Hg) Lacourcière & Asmar 1999 28 28 28 31 31 31 28

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

Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials Study or Subgroup OVERALL Heterogeneity: Tau ² = 1.06; Chi = 19.19, df = 14 (P = 0.16); I = 27% Test for overall effect: Z = 5.92 (P < 0.00001) Mean SD Total 2038 2028 Weight 100.0% Candesartan Losartan 95% CI Mean Difference 3.40 [ - 3.72, 10.52] 4.60 [ 2.44, 11.64] 2.00 [ 1.01, 5.01] 3.50 [1.28, 5.72] 1.90 [ 1.23, 5.03] 8.40 [4.45, 12.35] 0.60 [ 6.65, 5.45] 3.90 [1.07, 6.73] 4.20 [1.02, 7.38] 1.40 [ 0.15, 2.95] 1.00 [ 8.00, 6.00] 3.50 [ 3.91, 10.91] 5.70 [1.81, 9.59] 8.10 [ 1.18, 17.38] 3.30 [0.92, 5.68] 3.22 [2.16, 4.29] Andersson et al 1998 Baguet et al 2006 Bakris et al 2001 Gradman et al 1999 Koenig et al 2000 Koh et al 2004 Lacourciere et al 1999 Manolis et al 2000 Matsuda et al 2003 Nishimura et al 2005 Ohman et al 2000 Rayner et al 2006 Vidt et al 2001 15.7 16.9 10.8 13.3 11.9 32.2 22.1 12.3 14.5 15.8 14.2 11.4 19.4 25.8 13.4 24.5 24.3 11.3 14.8 12.8 12.1 10.7 11.8 12.2 9.7 10 18.3 15.1 82 84 87 322 162 81 31 109 106 462 17 12 151 25 307 8.8 9.8 23.8 22.7 8.4 10.3 14.4 15.2 7.9 13.7 17.7 10.1 8.9 14.6 12.7 12.4 10.5 11.5 11.7 10.4 8.1 17.4 15.6 14.9 83 89 332 170 79 32 100 449 15 11 148 27 304 2.1% 8.7% 12.6% 8.2% 5.8% 2.8% 9.4% 8.0% 17.5% 1.9% 5.9% 1.3% 11.7% 20 -10 Favours Candesartan Favours Losartan Meredith et al 2009 16

Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials 95% CI Mean Difference Favours Candesartan 10 -10 Favours Losartan ALL TRIALS 2038 2028 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) Monotherapy 1806 1801 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” 295 293 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” 1427 1425 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) Meredith et al 2009 17

Candesartan & Losartan-Antihypertensive Effects: Diastolic BP in Direct Comparator Trials Candesartan Losartan 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 18

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:- an additional 1.8 mmHg reduction in diastolic BP can be predicted to result in:- -10 -20 -30 -40 % reduction in events CHD Stroke Prospective Studies Collaboration 2002 & Law et al 2009

Hypothesis and Aim Losartan and candesartan have different pharmacological properties and blood pressure lowering abilities The aim of the Real Life study was to test the hypothesis that losartan and candesartan have different primary preventive effects on CVD risk The hypothesis was tested by setting up a large retrospective observation study in 72 Health Care Centres in Sweden REAL-LIFE 20

Selection Method 24,943 patients started on either losartan or candesartan from 1999–2007 Losartan 6,771 (48.0%) Follow-up average 2.0 years (36,339 patient years) Included 14,100 Candesartan 7,329 (52.0%) 10,843 (44%) patients were excluded: 1. CV-disease or prescription of warfarin/digitalis/nitrates 2. Malignancy 3. Another RAS-inhibitor in the first week after inclusion REAL-LIFE 21

The “Real-Life” Study: Candesartan v Losartan Losartan Candesartan p (n=6771) (n=7329) Age (years) 61.7 (12) 62.4 (12) 0.001 Women, n (%) 3723 (55.0) 4109 (56.1) 0.2030 Body mass index (kg/m2) 30.2 (5.3) 30.2 (5.4) 0.8463 Systolic BP(mmHg) 159 (20) 160 (19) 0.0124 Diastolic BP (mmHg) 89 (10) 90 (10) <0.0001 Total cholesterol (mmol/L) 5.7 (1.0) 5·7 (1.1) 0.2243 LDL cholesterol (mmol/L) 3.34 (0.81) 3·39 (0.81) 0.0647 HDL cholesterol (mmol/L) 1.38 (0.32) 1·37 (0.31) 0.4826 Triglycerides (mmol/L) 1.64 (0.81) 1·62 (0.78) 0.2965 Glucose (mmol/L) 6.3 (2.4) 6·2 (2.3) 0.0024 HbA1c (%) 5.9 (1.4) 5·8 (1.4) 0.0342 Diabetes, n (%) 1215 (17.9) 1112 (15.2) <0.0001 Serum creatinine (μmol/L) 84 (21) 84 (19) 0.6895 Potassium (mmol/L) 4.0 (0.4) 4·0 (0.4) 0.7452 Thiazides, n (%) 848 (12.5) 1087 (14.8) 0.0001 Calcium channel blockers*, n (%) 968 (14.3) 1104 (15.1) 0.2071 Beta-blockers, n (%) 1605 (23.7) 1883 (25.7) 0.0066 Oral glucose lowering , n (%) 628 (9.3) 559 (7.6) 0.0005 Statins, n (%) 727 (10.7) 688 (9.4) 0.0084 Antithrombotics, n (%) 421 (6.2) 395 (5.4) 0.0386 ARBs, n (%) 101 (1.5) 120 (1.6) 0.5301 ACEIs, n (%) 1361 (20.1) 1459 (19.9) 0.7906

Blood Pressure Reduction REAL-LIFE Blood Pressure Reduction Losartan 180 Candesartan 160 140 Systolic 120 mmHg 100 Mean arterial 80 Diastolic 60 12 24 36 48 60 72 84 96 Months Kjeldsen et al 2009

Concomitant Medication REAL-LIFE Months Thiazides losartan candesartan 90 80 70 60 50 40 30 20 10 Index 12 24 36 48 72 84 96 Calcium channel blockers Betablockers Statins Oral glucose lowering drugs Antithrombotics Kjeldsen et al 2009

Primary Outcome: Candesartan v Losartan The primary composite end-point: CVD morbidity, CVD mortality and elective coronary revascularisation 30 25 20 15 5 10 losartan candesartan Cumulative incidence (%) Adjusted* risk reduction 14.4% (p=0.0062) Unadjusted risk reduction 20.6% (p<0.0001) 24 12 36 48 72 60 84 96 time (months) Number at risk Los 6771 4548 3165 2090 1458 923 526 259 96 Can 7329 4860 3385 2242 1580 1021 592 257 76 *Adjusted for age, gender, diabetes & prescription & index year Kjeldsen et al 2009

Risk of Separate Endpoints Heart failure Arrhythmias Peripheral artery disease 12 losartan 12 losartan 12 losartan candesartan candesartan candesartan 10 10 10 8 -35.9% p=0.0004 8 8 Cumulative incidence (%) 6 Cumulative incidence (%) 6 6 Cumulative incidence (%) -38.8% p=0.0140 4 4 4 -20.0% p=0.0330 2 2 2 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) Time (months) Time (months) Chronic ischemic heart disease Myocardial infarction Stroke 12 candesartan losartan 12 losartan 12 losartan 10 candesartan 10 10 candesartan 8 8 8 Cumulative incidence (%) 6 Cumulative incidence (%) 6 Cumulative Incidence (%) 6 4 4 4 2 -14.3% p=0.1400 2 -7.0% p=0.5600 2 -5.2% p=0.6400 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) Time (months) Time (months) *Adjusted for age, gender, diabetes and prescription & index year Kjeldsen et al 2009 26

Candesartan v Losartan: Mortality in Heart Failure Patients Data from 30,254 unique patients registered from 62 hospitals and 60 outpatient clinics was extracted from the Swedish Heart Failure Registry between 2000 and 2009 A total of 5139 patients (mean [SD] age, 74 [11] years; 39% women) were treated with candesartan (n=2639) or losartan (n=2500) Survival as of 14 December, 2009, by ARB agent was analyzed by Kaplan-Meier method Predictors of survival determined by univariate and multivariate proportional hazard regression models, with and without adjustment for propensity scores and interactions Stratified analyses and quantification of residual confounding were also performed Eklind-Cervenka et al 2011

Candesartan v Losartan: Mortality in Heart Failure Patients Losartan(n=2500) Candesartan (n=2639) p‐value Mean age (years) ±SD 75.3±10.2 72.0±11.5 0.001 Women 1017(40.7%) 1006(38.1%) 0.061 NYHA: 0.001 I 164(9.0%) 234(10.9%) II 734(40.3%) 1068(50.0%) III 840(46.2%) 770(36.0%) IV 82(4.5%) 65(3.1%) EF: 0.035 >40% 892(42.3%) 992(41.6%) <40% 1215(57.7%) 1393(58.4%) Mean creatinine (mmol/L) ±SD 120±13.4 111.0±56.4 0.001 Mean MAP (mmHg) ±SD 91.5±13.4 92.6±13.9 0.003 Hypertension 1296(53.7%) 1411(55.0%) 0.365 IHD 1461(60.6%) 1286(50.7%) 0.001 Diabetes mellitus 844(34.0%) 764(29.2%) 0.001 ACE inhibitor 76(3.1%) 420(16.0%) 0.001 Beta blocker 2049(82.3%) 2295(87.1%) 0.001 Aldosterone 904(36.4%) 802(30.6%) 0.001 Eklind-Cervenka et al 2011

Candesartan v Losartan: Mortality in Heart Failure Patients 82% one year survival 90% one year 1.0 0.8 0.6 0.4 0.2 candesartan 51% five year survival 72% five year survival proportion losartan Log-rank p<0.001 1 2 3 4 5 years Number at risk Candesartan 2639 1739 957 426 125 30 Losartan 2500 1692 1097 646 359 178 Eklind-Cervenka et al 2011