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Balancing the HOPE, Hype and evidence

ACE Inhibitors vs Angiotensin II Antagonists in Diabetics. Balancing the HOPE, Hype and evidence. Dr Rajesh Jain, MD (Prev Medicine) Consultant Jain Hospital, Kanpur. What Are The Important Targets of Therapy?. Diabetes and CV Disease Risk.

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Balancing the HOPE, Hype and evidence

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  1. ACE Inhibitors vs Angiotensin II Antagonists in Diabetics Balancing the HOPE, Hype and evidence Dr Rajesh Jain, MD (Prev Medicine) Consultant Jain Hospital, Kanpur

  2. What Are The Important Targets of Therapy? Diabetes and CV Disease Risk • CVD accounts for more than 70% of all deaths in people with DM1 • High prevalence of CHD in people with diabetes • Despite a continuous decline in age-adjusted CHD rates in the general population: - people with DM : 45% (without DM : 25%) - evidence of prior MI in diabetic people : (25% in Caucasian men & 10 – 15% in Caucasian women vs 2% and 2.5% - 10% in those without DM) • the rate of fall is much smaller in people with type 2 DM 2 • & may be rising in women with type 2 DM Ref: 1.Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11 2. Gu K et al. JAMA 1999;281:1291-1297.

  3. What Are The Important Targets of Therapy? Diabetes and Risk of End-stage Renal Disease 25 IDDM Cumulative incidence of ESRD in IDDM and NIDDM: Joslin Diabetes Center and Mayo Clinic 20 15 Cumulative incidence (%) 10 NIDDM 5 0 0 30 35 20 5 15 25 10 Duration of diabetes (years) Ref: Krolewski, AS et al. Endocrinal Metab Clin North Am 1996;25(2):217-242

  4. For a diabetic person, the chances of suffering/ dying from heart disease and stroke much exceeds that of reaching ESRD. What is the major source of mortality and morbidity in people with diabetes ? CARDIOVASCULAR

  5. Risk of CV Events in People with Diabetes Men no DM Relative Risk of CV deaths DM Women Young Men Young Women Relative Risk of CHF Elderly Men & Women 0 2 4 6 8 10

  6. High Risk of Cardiovascular Events in Type 2 Diabetes Non-diabetic subjects - MI = No prior myocardial infarction + MI = Prior myocardial infarction Subjects with type 2 diabetes 50 45 40 35 7-year incidence of cardiovascular events (%) 30 25 20 15 10 5 0 -MI +MI -MI +MI -MI +MI -MI +MI -MI +MI -MI +MI Myocardial infarction Cardiovascular deaths Stroke Ref :Haffner SM et al. N Engl J Med 1998;339:229-234.

  7. 100 80 60 40 Neither DM nor CVD DM without CVD CVD without DM Both Dm and CVD 20 0 0 5 10 15 20 Diabetes is an Independent Predictor of All-cause Mortality - Multiple Risk Factor Intervention Trial (MRFIT) 18-year Follow-up adjusted hazard ratios DM vs neither : 1.50 (p<0.0001) CVD vs neither : 1.75 (p <0.0001) DM and CVD vs neither : 2.57 (p < 0.0001) Ref: Cohen JD, et al. AHA 2001 [abstract 105935]

  8. Survival post MI in diabetics and non-diabetics 30 % % 27 27 25 % Diabetics 20 18 % 16 Non-diabetics % 15 % 13 15 % 10 10 % 7 5 0 >65yrs <65yrs Male Female Ref: Moreno R et al. Eur, Heart J 2001; 22(15):1359-61

  9. Cardiovascular Mortality in People with Diabetes MEN WOMEN 28 d – 1 y Hospitalization – 28 d Out of Hospital 9.1 11.1 4.2 15.4 % of Deaths (Crude Rate) 9.6 2.8 22.7 9.0 28.6 22.1 11.9 10.9 Diabetes No Diabetes Diabetes No Diabetes Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75.

  10. Diabetes Vascular Risk: Microalbuminuria – a very important risk factor 10.02 10 8 6.52 6 odds ratio for MI 4 3.20 2.32 2 0 Micro-albumunimuria smoking hypertension cholesterol Ref. Eastman RC, Keem H. Lancet 1997; 350(Suppl 1) : SI29-32

  11. Diabetes, Renal Disease & Mortality - What do these people die from? CV events 60 Mortality With Nephropathy 50 40 % Mortality 30 20 10 0 MA Nephropathy CRI ESRD 3 Year Mortality Ref. Gerstein H C et al. JAMA 2001; 286 (4):421-6 Bremmer BM et al. NEJM 2001; 345(12): 861-9 Mann JF et al. Ann Intern Med 2001; 134(8): 629-36

  12. Components and Major Actions of the Kallikrein-Kinin and Renin-Angiotensin systems Angiotensinogen Kininogen renin kallikrein Bradykinin (BK) Angiotensin I ACE endopeptides BKB receptor Ang II Ang (1 – 7) Inactive peptides Vasodilation NO prostaglandins EDHF tPA ACE A (1-7) receptor Inactive Peptides AT4 receptors AT2 receptors AT3 receptors AT1 receptors VasodilationAntiproliferation Vascular integrity PAI-1 Vasodilation Antiproliferation Apoptasis Oxidation Vasocontriction Proliferation Matrix Formation Aldosterone Secretion ?

  13. Local Angiotensin System in Macrophages and Role in Atherosclerosis lumen LDL circulating monocytes ACE ACE Angiotensin II + + Y Y Y Y Y Y Y Y adhesion- molecules infiltration endothelium + oxidative stress ACE oxLDL/eLDL subintima differentiation (activation) fatty streak, plaque ACE ACE Macrophages Foam-cells + Growth factors Ang II Ang II smooth muscle cells Cytokines media mod. from Diaz et al., N Engl J Med 1997; 337 : 408-16

  14. + + + ACE Dysregulation of Extracellular Matrix Synthesis in Vulnerable Plaques Role of macrophages and Angiotensin II: Matrix synthesis Matrix degradation Collagen endothelial cells Metallo- proteinases + smooth muscle cells Elastin fibrouscap Peptides, amino acids Amino acids INF- TGF-ß Ang II, IL-6 - TNF- M-CSF MCP-1 etc. INF- Plaque T-lymphocyte Foam-cell INF- = Interferon- adapt. from Libby P, Circulation 1995: 91(11); 2844-50

  15. Ruptured Plaque in Coronary Artery Disease - Rupture of shoulder region with luminal thrombus x30 x120 ruptured cap lipid core Cross section of epicardial human coronary artery (postmortem; movat pentachrome staining) Ref: Burke et al., N Engl J Med 1997 ; 336(18);1276-82

  16. At(1-2) ACE I/D genotype Kinins kininogen AT1 ARB AT(1-2) kallikreins AT2 NEP bradykinin ACENEP - ACE inhibitors Kininase I BK(1-7)inactive stabilize BK(1-8)DES Arg BK B28 KR +9/ -9 genotype B2 B2 endothelial function tPaMVO2 Glucose uptakeLVHVascular fibrosis NO EDHF Endothelial function natriuresisangiogenesisnociception

  17. Clinical Trials • Surrogate “vascular” structure and function trials • Morbidity & mortality trials - post MI- high risk preserved LVEF vascular disease- stroke- heart failure- hypertension/ nephropathy

  18. SECURE –Effect of ramipril on atherosclerosis Overall ramipril effect : p = 0.033 Ref: Lonn E, et al. Circulation 2001;103(7):919-25

  19. Effect of ACE Inhibitors in Type 2 DM 0.025 0.02 0.015 Mm/ year 0.01 0.01 0.02 0.005 0 Placebo Enalapril Annual IMT rate Ref: Hosomi N, et al. Stroke 2001; 32(7):1539-45

  20. 6 6 5 5 4 4 3 3 2 2 1 1 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Change in LV mass volume Change in LV mass index LV endsystolic volume(mL) LV enddiastolic volume(mL) 4.15 3.98 5.31 4.16 2.9 LVMI (g/m2) P=0.042 -2.02 -0.43 -1.9 P=0.001 P=0.01 Change in LV ejection fraction -5.9 0.0 -0.5 Placebo -1.0 Cardace 2.5 mg -1.5 Cardace 10 mg -2.0 -2.5 Ref. Lonn EM, et al. Presented at American College of Cardiology,50th Annual Scientific Session; March 18-21, 2001

  21. ACE Inhibitors Benefits : - Post MI LV dysfunction Meta-analysis Of AIRE, TRACE, SAVE 40 placebo 26% reduction P < 0.0001 30 ACE inhibitor 20 cumulative mortality (%) 18% diabetics 10 0 0 1 2 5 3 4 time since randomization (years) number at risk ACE inhibitors 2995 2250 1617 892 223 Placebo 2971 2184 1521 853 138 Ref: Flather MD, et al. Lancet 2000; 355(9215):1575 - 81

  22. OPTIMAAL 17% Diabetics Losartan Captopril Losartan Captopril Losartan Captopril All-cause death RR = 1.13 (0.99-1.28) P=0.069 SCD/ RCA RR = 1.19 (0.99-1.43) P=0.072 CV death RR = 1.17 (1.01-1.34) P=0.032 Ref: Dickstein, et al. Lancet 2002;360(9335):752-60

  23. MICRO-HOPE - effect of ACE inhibition on renal and CV outcomes 3496 patients with type 2 diabetes81 patients with type 1 diabetes History of hypertension : 56%Baseline BP : 142/80mg Hg CV death Overt nephropathy MI Stroke 3 placebo 2.5 2 ramipril Risk Reduction (%) 1.5 Mean albumin – creatinine ratio 22% 24% 1 p=0.01 p=0.027 0.5 33% 37% p=0.007 0 p=0.0001 0 1 2 3 4.5 Ref: HOPE investigators: Lancet 2000;355(9200):253-9

  24. HOPE - effect of ACE inhibitors plus concomitant cardiovascular therapy on MI Characteristics No. of patients Rate of placebo added no added benefit benefit Lipid lowering drug - 6639 13.1 Lipid lowering drug + 2658 10.2 ASA - 2484 12.1 ASA + 6613 12.3 Beta blocker - 5624 12.2 Beta blocker + 3673 12.4 0.6 1.2 1 0.8 RR (95% CI) Ref : Dagenais GR, et al. Circulation 2001;104(5):522-6

  25. Ramipril and Other Outcomes : DM ramipril placebo RR (95% CI) p Microvascular nephropathy 6.5 8.4 0.76 0.60 – 0.97 0.027 laser therapy 9.4 10.5 0.88 0.72 – 1.09 0.24dialysis 0.5 0.5 1.20 0.47 – 3.05 0.70 any of above 15.1 17.6 0.84 0.71 – 0.99 0.036 TIA’s 4.4 5.9 0.74 0.55 – 0.19 0.04 Worse angina 20.1 22.4 0.87 0.76 – 1.00 0.057 Ref: HOPE investigators: Lancet 2000;355(9200):253-9

  26. HOPE / MICROHOPE - Vascular vs dialysis risk • Diabetics in HOPE were: • 40 times more likely to have a vascular event than to go on to • require dialysis • 26 times more likely to have an MI • 12 times more likely to have a stroke • 12 times more likely to die of CV causes than need dialysis Therefore the goal of treatment is vascular protection

  27. Type 2 Dm> 1 risk factors * Type 2 diabetes + ³ 1 CV risk factor (smoking, previous CV disease, hypertension, hypercholesterolemia, microalbumaria) Most Patients in Diabetes Clinics are MICRO-HOPE Patients Ref: Jones SC et al. Diabete Med 2001; 18(9): 667-70

  28. Main Outcomes in Patient with Renal Failure (serum creatinine >1.4 mg/dL [124 mmol/L]) all placebo ramipril primary outcome 80 64 55 60 46 40 36 40 32 20 0 MI 60 48 50 40 40 34 28 25 30 22 20 10 0 events (per 1000 patients –years) all cause death CV death 57 60 40 37 43 50 30 28 40 32 20 27 18 20 25 30 24 16 14 20 10 10 0 0 < 1.4 124mmol/L ³1.4 ³1.4 < 1.4 Ref: Mann JF, et al. Ann Intern Med 2001;134(8):629-36

  29. 100 100 100 100 Hypertensive patients 80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20 0 0 0 0 Serum creatinineconcentration< 1.4 mg/dL Serum creatinineconcentration³ 1.4 mg/dL Primary Outcomes in Diabetes and in Hypertension Diabetic patients Serum creatinineconcentration< 1.4 mg/dL Serum creatinineconcentration³ 1.4 mg/dL Placebo Events (MI, stroke, CV death) per 1000 person-years (n) Ramipril Normotensive patients Nondiabetic patients Serum creatinineconcentration< 1.4 mg/dL Serum creatinineconcentration³ 1.4 mg/dL Serum creatinineconcentration< 1.4 mg/dL Serum creatinineconcentration³ 1.4 mg/dL Ref: Mann JF, et al. Ann Intern Med 2001;134:629-636

  30. HOPE - Stroke in Diabetics 5 Placebo RR = 0.67 (0.50 – 0.90)(p < 0.0074) 4 Ramipril 3 % of Patients 2 1 0 0 1500 500 1000 Days of Follow-up Ref: HOPE investigators: Lancet 2000;355(9200):253-9

  31. PROGRESS - Effect of ACE inhibitors based BP reduction on stroke 16 12 28% risk reduction P < 0.0001 8 Proportion withstroke(%) placebo 4 Perindopril 4mg ± indapamide 12.5 mg 0 0 2 1 4 3 Follow-up (years) Ref. :PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041

  32. PROGRESS - Dementia (DSM – IV) and severe cognitive decline (MMSE) Events favours favours odds ratioactive placebo active placebo Dementiawith stroke 43 65 0.66(0.45 – 0.97)without stroke 150 152 0.99(0.78 – 1.24) total 193 217 0.88(0.72 – 1.08) Severe Cognitive declinewith stroke 48 86 0.55(0.39 – 0.79)without stroke 228 248 0.91(0.76 – 1.10) total 276 334 0.81(0.68 – 0.96) 0.5 2.0 1.0 Odds ratio Ref. :PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041

  33. Randomized Trials of ACE Inhibitor-based Therapy vs Placebo: - Effects on stroke Favours active control ACE favours risk ratioevents n events n inhibitors controls Primary stroke presentation ACI-I-MI collaboration 239 6391 249 6372 0.96(0.80, 1.15) BP trial listcollaboration 166 6060 240 5054 0.70(0.57, 0.85) Secondary stroke presentationPROGRESS 307 3051 420 3054 0.72(0.62, 0.83) 0.25 0.5 1.01 1.5 Risk ratio

  34. SCOPE (Study on Cognition and Prognosis in the Elderly) : - Results in stroke • Primary end point- major CV events (cardiovascular mortality + nonfatal MII + non fatal stroke) • Secondary end point - cognitive function dementia total mortality CV mortality fatal & non-fatal AMI fatal & non-fatal stroke renal function hospitalization/ quality of life/ health economies 11% candesartan vs 20% placebo : n - maintained in both groupsin patients with MMSE < 28candesartan-based treatment, smaller HMSE decline 28% RR in non-fatal stroke with candesartan(p = 0.04%)

  35. HOPE: - Heart failure n % ramipril placebo RR (95% CI) pn = 4645 n = 4652 All HF417 (9.0) 534 (11.5) 0.77 (0.68 – 0.87) < 0.001 Open ACEi for HF 240 (5.2) 327 (7.0) 0.72 (0.61 – 0.85) < 0.001 Hosp HF 141 (3.2) 161 (3.5) 0.87 (0.69 – 1.09) 0.22 HF death 24 (0.52) 27 (0.58) 0.88 (0.51 – 1.53) 0.66 CV death + all HF 624 (13.4) 807 (17.4) 0.76 (0.69 – 0.84) < 0.001 CV death + HF 383 (8.3) 491 (10.6) 0.77 (0.68 – 0.88) < 0.001 hospitalization Ref: Arnold JM et al. Circulation 2003;107:1282-88

  36. Evolution of Trials of Heart Failure with ACE Inhibitors - Diabetes : 15% - 25%, HOPE : 33% Trials Type of patient Benefits HOPE preserved LF + vascular HF prevented disease/ diabetes SOLVD-P Low EF alone HF & HF hosp.prevented SOLVD-T Low EF + CHF (II/ III) HF hosp. & mortality reduced CONSENSUS Class IV CHF Mortality reduced

  37. ELITE II - Diabetes : 24% Losartan Captopril RR p value all-cause death 280 (17.7%) 250 (15.9%) 1.13 0.16 SCD/RCA 142 (9.0%) 115 (7.3%) 1.25 0.08 Death + Hosp 752 (47.7%) 707 (44.9%) 1.07 0.18 Hosp. 659 (41.8%) 638 (40.5%) 1.04 0.44Admission Ref: Pitt B et al. Lancet 2000;355(9215):1582 - 7

  38. Val-HeFT: - 25.5% diabetics All cause mortality morbidty combined outcome of cardiac arrest with resuscitation, hospitalization for HF, or receipt of intravenous inotropic or vasodilator therapy>4h Ref: Cohn JN et al. NEJM 2001;345(23):1667-75

  39. CAPP: • Reduced CV morbidity & mortality in type 2DM • ACE inhibitors vs atenolol (n=572) Outcome RR(95% CI) RRR p previous endpoint 0.59 (0.38 – 0.91) 41% 0.018 all MI 0.34 (0.17 – 0.67) 66% 0.002 all cardiac events 0.67 (0.46 – 0.96) 33% 0.029 Total mortality 0.54 (0.31 – 0.95) 46% 0.03 Ref. Niskanen et al. Diabetes Care 2001;24(12):2091 -6

  40. CV Risk Reduction with ACE Inhibitors in Type 2 Diabetes: - ABCD, CAPPP and FACET - ACE inhibitors (n=733) vs other antihypertensive agents ( n=589) AcuteMI All-CauseMortality CVevent Stroke 0 -10 -20 - 24% -30 Relative Risk Reduction -40 -50 - 51% -60 - 62% - 63% -70 p<0.001 p<0.001 p=0.01 p=0.3 Ref: Pahor M et al. Diabetes Care 2000; 23(7):888-92

  41. LIFE: - Primary and secondary outcome adjusted* unadjusted losartan atenolol RR RR(n = 4605) (n = 4589) (%) p (%) p primary composite+ 508 588 -13 0.021 -15 0.009CV mortality 204 234 -11 0.206 -13 0.135stroke 232 309 -25 0.001 -26 0.0006MI 198 188 +7 0.491 +5 0.628total mortality 383 431 -10 0.128 -12 0.077new-onset DM# 241 319 -15 0.001 -2.5 0.001 * for degree pf :WH amd Fraomingham, risk score at randomization+ CV mortality, stroke and MI; patients with a first primary event# among patients without diabetes at randomization (losartan n=4019) atenolol, n=3979) Ref. :Dahlof B, et al. Lancet 2002: 359 (9311): 991-1003.

  42. Cardiovascular Benefits of Losartan Confirmed in Diabetic Subgroup - Primary composite end-point = CV death, MI & stroke atenolol 24 baseline BP;losartan = 174.3/97.0 mm Hg atenolol = 174.5/97.7 mm Hg losartan 20 16 DBP 95-115 mm Hg orSBP 160 – 200 mm HgECG - LVH Proportion of patients with first event (%) 12 8 4 adjusted RR = 24.5%; p = 0.031unadjusted RR = 26.7%; p = 0.017 0 study month 6 24 30 36 42 54 60 66 0 12 18 48 losartan (n) 586 549 558 548 532 520 513 501 484 459 237 127atenolol (n) 608 588 562 552 540 527 507 486 472 434 204 99 Ref. Lindholm LH, et al. Lancet 2002;359(9311):1004-10

  43. Prevention of Progression of Renal Disease In People with Diabetes Primary prevention Secondary prevention Tertiary prevention Diabeticnephropathy ESRD MA DM Glycemic controlBP controlACE inhibitor ACE inhibitorBP controlARB ARBACE inhibitorBP Control Ref. Tobe SW et al. CMAJ 2002; 167(5): 499-503

  44. ACE Inhibition Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes captopril placebo % with doubling of baseline creatinine p< 0.001 N = 343 type 1 DM baseline creatinine> 1.5 mg/dL 40 2 p< 0.001 20 0 % reduction in protuinuria % increasen in BP (mm Hg) 0 -2 -20 -4 -40 -6 -60 Ref: Lewis EJ, et al. N Engl J Med 1993, 329:1456-62

  45. Recently Completed Studies of ARBs in Patients with type 2 Diabetes and Renal Disease NO/ FEW CV BENEFITS outcome Study patients ARB primary secondary CV IDNT type 2 DM, inbestartan composite of ESRD, composite CV nephropathy vs amlodipine creatinine doubling morbidity/ mortality: or placebo mortality –23% vs NSamlodipine RENAAL hypertension composite CV nephropathy vs placebo creatinine doubling, morbidity/ mortality; mortality: -16% NS HF hosp: -32% IRMA2 type 2 DM, irbesartan 150 microalbuminuria hypertension, or 300 mg vs progression to nephropathy: micro- placebo - 39% (150 mg) albuminuria - 70% (300 mg) Ref. : Lewis EJ, et al. NEJM 2001;345(12): 851-60 Brenner BM et al. NEJM 2001; 345(12): 861-9 Parving HH, et al NEJM 2001; 345(12): 870-8

  46. IDNT Secondary End-Point: Cardiovascular Events 30 25.3% 23.0% 22.6% 20 Subjects (%) 10 0 Control Irbesartan Amlodipine n=569 n=579 n=567 No significant differences between groups Ref: Lewis EJ et al. NEJM 2001; 345(12): 851-60

  47. RENAAL : Primary Composite Endpoint & Components Composite & Losartan Placebo % riskcomponents (+CT), (+CT), reduction 95% CI n = 751n = 762 DsCr, ESRD, death 327 (43.5%) 359 (47.1%) 16 2,28 Doubling of sCr 162 (21.6%) 198 (26.0%) 25 8,39 ESRD 147 (19.6%) 194 (25.5%) 28 11,42 Death 158 (21.0%) 155 (20.3%) -2 -27,19 ESRD or death 255 (34.0%) 300 (39.4%) 20 5,32 Major CV events 247 (32.9%) 268 (35.2%) 10 p=0.26 Ref: Brenner BM et al. NEJM 345(12): 861-9

  48. Evidence base in diabetic subjects ACEIs ARBs Surrogate vascular structure   & function trials (SECURE) NIL Post MI   patients(AIRE,TRACE,SAVE)(OPTIMAAL) High risk without LVF   (HOPE/MICRO HOPE) NIL Stroke  (HOPE, PROGRESS) (SCOPE) Preventing Heart failure  (HOPE) NIL Heart failure  ? (CONSENSUS, SOLVD,HOPE) (ELITE II,Val-HeFT) Diabetes & hypertension   (CAPP,ABCD, FACET) (LIFE) Renal disease   (LEWIS II) (IDNT,RENAAL,IRMA2)

  49. The major source of morbidity and mortality in diabetics is CARDIOVASCULAR DISEASE

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