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The concept of Diabetes & CV risk: A lifetime risk challenge

Cardio Diabetes Master Class European chapter Munich, Germany May 6-8, 2011. The concept of Diabetes & CV risk: A lifetime risk challenge. RAS blockade in the real world: Clinical lessons from recent trials. Presentation topic. Slide lecture prepared and held by:. Peter Meredith PhD

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The concept of Diabetes & CV risk: A lifetime risk challenge

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

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

  3. RAS Blockade Across the CV Continuum Vascular Hypertension 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

  4. 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

  5. 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 Amlodipine Favours Valsartan 0.5 1.0 Odds Ratio 2.0

  6. Heart Failure favours valsartan favours amlodipine 0.5 1 2 hazard ratio 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 Months on monotherapy 12 18 24 30 36 42 48 favours valsartan favours amlodipine 0.5 1 2 hazard ratio Julius et al 2006

  7. LIFE: Primary Composite Endpoint Intention-to-Treat Analysis 0.16 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 0 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

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

  9. Primary Endpoint: composite of total mortality + total number of cerebrovascular & cardiovascular events (including recurrent events) 300 Nitrendipine 250 Eprosartan 200 Events (n) 150 100 Odd Ratio=0.79 (0.66, 0.96) p<0.014 50 0 0 500 1000 1500 days MOrbidity and Mortality after Stroke – Eprosartan vs. Nitrendipine in Secondary Prevention Schrader et al 2004

  10. 100 80 60 40 20 0 SCOPE: First Major Cardiovascular Events in Patients with a Previous Stroke Control Candesartan Events/1000 patient years Non-fatal stroke All stroke Major CV event Relative risk reduction 66% 62% 64% Trenkwalder et al 2005

  11. 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

  12. 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

  13. 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

  14. 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 CandesartanCilexetilvsLosartan : Mean Change From Baseline to Week 8 in Systolic ABP Hours after dose 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 Change in SBP (mm Hg) Lacourcière & Asmar 1999

  15. 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

  16. 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 Test for overall effect: Z = 5.92 (P < 0.00001) Favours Candesartan Favours Losartan -10 0 10 20 Mean Difference 95% CI Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials Meredith et al 2009

  17. Mean Difference Candesartan n= Losartan n= 95% CI 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

  18. 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

  19. 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:- CHD Stroke 0 -10 -20 % reduction in events -30 -40 Prospective Studies Collaboration 2002 & Law et al 2009

  20. Hypothesis and Aim REAL-LIFE • 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

  21. Selection Method REAL-LIFE Losartan 6,771 (48.0%) 24,943 patients started on either losartan or candesartanfrom 1999–2007 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

  22. 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

  23. Blood Pressure Reduction Losartan 180 Candesartan 160 140 Systolic 120 mmHg 100 Mean arterial 80 Diastolic 60 0 96 36 72 84 0 48 12 60 24 Months Kjeldsen et al 2009 REAL-LIFE

  24. Calcium channel blockers Thiazides Betablockers 90 90 90 losartancandesartan losartancandesartan losartancandesartan 80 80 80 70 70 70 60 60 60 50 50 50 40 40 40 30 30 30 20 20 20 10 10 10 0 0 0 72 12 24 36 48 60 72 84 96 12 24 36 48 60 84 96 72 84 96 12 24 36 48 60 Index Index Index Months Months Months Statins Antithrombotics Oral glucose lowering drugs 90 90 90 80 80 80 losartancandesartan losartancandesartan losartancandesartan 70 70 70 60 60 60 50 50 50 40 40 40 30 30 30 20 20 20 10 10 10 0 0 0 24 12 24 36 48 60 72 84 96 12 48 60 72 84 96 12 24 36 48 60 72 84 96 36 Index Index Index Months Months Months Concomitant Medication REAL-LIFE Kjeldsen et al 2009

  25. 30 25 20 15 10 5 0 Primary Outcome: Candesartan v Losartan The primary composite end-point: CVD morbidity, CVD mortality and elective coronary revascularisation losartan candesartan Cumulative incidence (%) Adjusted* risk reduction 14.4% (p=0.0062) Unadjusted risk reduction 20.6% (p<0.0001) 0 12 24 36 48 60 72 84 96 time (months) *Adjusted for age, gender, diabetes & prescription & index year Kjeldsen et al 2009

  26. Risk of Separate Endpoints Heart failure Arrhythmias Peripheral artery disease losartan 12 12 12 losartan losartan losartan candesartan candesartan candesartan candesartan 10 10 10 -35.9% p=0.0004 8 8 8 Cumulative incidence (%) Cumulative incidence (%) 6 6 6 Cumulative incidence (%) -38.8% p=0.0140 4 4 4 -20.0% p=0.0330 2 2 2 0 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 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 12 12 losartan losartan candesartan candesartan 10 10 10 8 8 8 Cumulative incidence (%) Cumulative incidence (%) Cumulative Incidence (%) 6 6 6 4 4 4 -14.3% p=0.1400 -7.0% p=0.5600 -5.2% p=0.6400 2 2 2 0 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 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

  27. 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

  28. 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

  29. 1.0 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 Candesartan v Losartan: Mortality in Heart Failure Patients 90% one year survival candesartan 72% five year survival 82% one year survival survival proportion losartan 51% five year survival Log-rank p<0.001 years Number at risk Candesartan 2639 1739 957 426 125 30 Losartan 2500 1692 1097 646 359 178 Eklind-Cervenka et al 2011

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