Comprehensive Cardiovascular & Metabolic Protection Liking Scientific Advances to Clinical Practice 인제의대상계백병원 당뇨병센터 고경수

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1 Comprehensive Cardiovascular & Metabolic Protection Liking Scientific Advances to Clinical Practice 인제의대상계백병원 당뇨병센터 고경수

2 Cardiovascular & metabolic risk factors The importance of BP management for HTN patients with T2DM

3 Impact of Diabetes and Other Risk Factors on Cardiovascular Mortality: MRFIT* CV Mortality (deaths/1 person-years) Risk Factors (n) + + Diabetes No Diabetes *MRFIT = Multiple Risk Factors Intervention Trial. Risk factors analyzed: smoking, hypercholesterolemia, and hypertension. Diabetes Care. 1993;16:

4 Association of SBP and CV Death in Type 2 Diabetes CV Mortality (deaths/1, person-years) No diabetes Diabetes < SBP (mm Hg) Diabetes Care. 1993;16:

5 Stroke and Ischemic Heart Disease (IHD) Mortality Rate in Each Decade of Age, Versus Usual Systolic BP at the Start of that Decade Stroke Age at risk IHD Age at risk y y y y y y Mortality* y y 4 49 y Usual SBP (mmhg) Usual SBP (mmhg) *Floating absolute risk and 95% CI Reproduced from The Lancet, 36, Lewington et al. pp

6 Cardiovascular Mortality Risk Doubles with Each 2/1 mmhg Increment in Systolic/Diastolic BP* Cardiovascular mortality risk 8 6 8X risk 4 2 1X risk 2X risk 4X risk 115/75 135/85 155/95 175/15 Systolic BP/Diastolic BP (mmhg) *Individuals aged 4 69 years Lewington et al. Lancet 22;36:193 13

7 Blood Pressure and Cardiovascular Risk: ESH ESC Guidelines BP (mmhg) Other RF, OD or disesae Normal SBP or DBP 8 84 High normal SBP or DBP Grade 1 SBP or DBP 9 99 Grade 2 SBP or DBP 1 19 Grade 3 SBP 18 or DBP 11 No other RF Average risk Average risk Low added risk Moderate added risk High added risk 1 2 RF Low added risk Low added risk Moderate added risk Moderate added risk Very high added risk 3 RF, MS, OD or diabetes Moderate added risk High added risk High added risk High added risk Very high added risk Established CV or renal disease Very high added risk Very high added risk Very high added risk Very high added risk Very high added risk MS = metabolic syndrome OD = subclinical organ damage RF = risk factors Task Force of ESH ESC. J Hypertens 27;25:115 87

8 Effect of Tight Glucose Control vs. Tight BP Control on CV Events: UKPDS Stroke Any Diabetic End Point DM Death Microvascular Complications -1 % Reduction* Tight glucose control (FPG <6 mmol/l) Tight BP control (BP <15/85 mm Hg) -5 * Reductions relate to the glucose intervention arm. P <.5 compared with tight glucose control. UK Prospective Diabetes Study Group (UKPDS 38). BMJ. 1998;317:

9 Blood Pressure Reduction of 2 mmhg Decreases the Risk of Cardiovascular Events by 7 1% Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years 2 mmhg decrease in mean SBP 7% reduction in risk of ischaemic heart disease mortality 1% reduction in risk of stroke mortality Lewington et al. Lancet 22;36:193 13

10 Goals of antihypertensive treatment Primary Goal : to achieve maximum reduction in the long-term total risk of cardiovascular disease SBP/DBP should be lowered to <14/9 mmhg for all (and to lower values if tolerated) Target BP : <13/8 mmhg in diabetics in stroke, myocardial infarction, renal dysfunction or proteinuria

11 The wealth of data for Valsartan in the blood pressure management

12 Ambulatory BP lowering effects of Valsartan after a missed dose Study Background: Approximately 3 days a month, some 15-2% of hypertensive patients do not recall taking their medication. Individuals with this frequency of missed-dose may be at an increased risk of cardiovascular events resulting in a poorer long-term prognosis (References 8 & 9 in the attached publication) Study Design: This was a prospective, randomized, open-label, blinded end-point (PROBE) parallelgroup trial in previously untreated patients with mild-to-moderate essential hypertension. 148 patients (84 men and 64 women) were randomly assigned to receive 16 weeks of treatment with valsartan 16mg/day or enalapril 2mg/day taken on waking, completed the study This study used ambulatory BP monitoring (ABPM) to compare the BP lowering effects of valsartan and enalapril over the 24-hours after missing 1 dose. ABPM was conducted for 48 consecutive hours at baseline & again after 16 weeks of therapy. Patients took a dose of their assigned treatment at the beginning of the final session of ABPM and were instructed to skip the next daily dose Hermida et al. Clinical Therapeutics 28; 3:18-12

13 Diovan 16mg provides superior BP reductions over 48-hours Mean changes from baseline in SBP and DBP during 48-hour ABPM including 24 hours after 1 missed dose following 16 weeks of therapy with valsartan 16mg/d or enalapril 1mg/d in patient with grade 1 and 2 essential hypertension Hermida et al. Clinical Therapeutics 28; 3:18-12

14 Diovan 16mg provides double-digit BP reductions Results from a 3-month study in 7 patients with mild-to-moderate essential hypertension* Mean 24-hour change in ABP at 3 months (mm Hg) DIOVAN 16 mg n= SBP p=.1 Telmisartan 8 mg n= DIOVAN 16 mg n= DBP p=.14 Telmisartan 8 mg n= p<.1 for all groups vs. baseline; *SBP: 14 to 179 mm Hg or DBP: 9 to 19 mm Hg Calvo et al. J Hypertens 24;22:

15 Diovan 8mg provides comparable BP reductions to Irbesartan 15 mg Results from a 58-week cross-over study in 4 patients* with mild-to-moderate hypertension # SBP DBP Change in BP from baseline (mm Hg) -5-1 DIOVAN 8 mg Losartan 5 mg -9.9 Irbesartan 15 mg Candesartan 8 mg -1.8 DIOVAN 8 mg -9.8 Losartan 5 mg -6.9 Irbesartan 15 mg -9.9 Candesartan 8 mg # DBP >9 and <15 mm Hg; *graph shows results from 17 evaluable patients (group 1) undergoing 4x12-week treatment periods, separated by 2 weeks washout periods;p<.1 for all groups vs. baseline Fogari et al. Curr Therapeut Res 2;61(1):

16 BP-lowering efficacy of Diovan 16 mg compared with Olmesartan 2 mg at 2 and 8 weeks Prospective, randomised, open-label, blinded end-point study of patients with mild-to-moderate hypertension: 8 weeks treatment SBP 2 weeks DBP SBP 8 weeks DBP Office BP reduction (mmhg) BP reduction (mmhg) * Diovan 16 mg (n=55) Olmesartan 2 mg (n=52) * p<.5, p<.1, p<.1 vs olmesartan Destro et al. Adv Ther 25;22:32 43

17 Diovan and Co-Diovan significantly reduce SBP by 2 mm Hg or more to get patients to goal Results from a 8-week study in 767 patients # with stage 2 systolic hypertension (VALOR study) DIOVAN 16 mg (n=261) Co-DIOVAN 16/12.5 mg (n=258) Co-DIOVAN 16/25 mg (n=255) Response rate % Mean change in SBP from baseline to 8 weeks (mm Hg) * -27.9* -28.3* # ITT population SBP 16 and 2 mm Hg); *p<.5 vs. baseline; p<.5 vs. DIOVAN 16 mg monotherapy; p<.5 vs. DIOVAN 16 mg; Response= SBP <14 mmhg or decrease in SBP 2 mmhg after 8 weeks of treatment Lacourciere et al. Clin Ther 25;27(7):113-21

18 Amlodipine/Valsartan: 43 mmhg drop in MSSBP in patients with a baseline MSSBP 18 mmhg Endpoint BP (mean, mmhg) Change from baseline at 6-week endpoint (mmhg) * MSSBP * MSDBP Baseline MSSBP/MSDB: 188/113 mmhg Randomized, double-blind, multicenter, active-controlled study 6-week treatment period * Amlodipine (5 1 mg) + Valsartan (16 mg) (n=15) Lisinopril (1 2 mg) + HCTZ (12.5 mg) (n=11) *p<.1; p<.2 vs. baseline Reproduced from Clinical Therapeutics, 29, Poldermans et al. pp

19 Amlodipine/Valsartan: BP lowering across all grades of hypertension 1 Grade 1 HTN Mean change in MSSBP from baseline (mmhg) Grade 2 HTN Grade 2 3 HTN Grade 3 Systolic BP 18 mmhg n=69 n=14 n=64 n= DBP reduction (mmhg) Data from Smith et al. J Clin Hypertens 27;9: Dose 1/16 mg Data from Poldermans et al. Clin Ther 27;29: Dose 5 1/16 mg

20 Up to 9 out of 1 patients reach BP goal <14/9 mmhg at week All patients Non-diabetic patients Diabetic patients Patients (%) 6 4 n=44 n=369 n=71 n=449 n=375 n=74 2 Amlodipine/Valsartan 5/16 mg Amlodipine/Valsartan 1/16 mg Diabetic patients with BP <13/8 mmhg at Week 16 were 45.9% and 4.7% for 5/16 mg and 1/16 mg doses, respectively Randomized, double-blind, multinational, parallelgroup, 16-week study Izzo et al. J Clin Hypertens 27 (abstract) Presented at ASH, 21 May 27, Chicago, USA Novartis data on file (Study CVAA489A241)

21 The Wealth of data for Valsartan in the organ protection

22 Mortality and Morbidity Endpoint Trials with ARB 6, VALUE 1 ONTARGET 8 CHARM 14 5,345 VALIANT 2 TRANSEND 8 SCOPE 15 5, NAVIGATOR 3 LIFE 9 SCAST* 16 Val-HeFT 4 OPTIMAAL 1 CASE-J 17 Number of patients 4, 3, 2, 29,4 JIKEI HEART 5,6 KYOTO HEART* 7 22,991 19,768 ELITE II 11 RENAAL 12 NCT9259* 13 14,815 I-Preserve 18 IDNT 19 ACTIVE* 2 SUPPORT* 21 MOSES 22 1, 1, 1,45 DIOVAN Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan 1 Julius et al. Lancet 24;363:222 31; 2 Pfeffer et al. NEJM 23;349: ; Cohn et al. NEJM 21;345: ; 5 Mochizuki et al. J Hypertens 26;24(Suppl. 4):S31; 6 Mochizuki et al. Cardiovasc Drugs Ther 24;18:35 9; 7 (NCT149227) Dahlof et al. Lancet 22;359:955 13; 1 Dickstein et al. Lancet 22;36:752 6; 11 Pitt et al. Lancet 2;355:1582 7; 12 Brenner et al. NEJM 21;345:861 9; 13 (NCT9259) Papademetriou et al. J Am Coll Cardiol 24;44:1175 8; 16 (NCT123); 17 Ogihara J Hypertens 26;24(Suppl. 4):S3; 18 Carson et al. J Card Fail 25;11:576 85; 19 Lewis et al. NEJM 21;345:851 6; 2 (NCT249795); 21 (NCT417222); 22 Schrader et al. Stroke 25;36: *Expected enrolment

23 Valsartan: Wealth of CV Outcomes Data VALUE 1 15,245 high-risk HTN patients; Double-blind, randomized study vs. amlodipine VALIANT 2 14,73 post-myocardial infarction patients; Doubleblind, randomized study vs. captopril and vs. captopril + valsartan Val-HeFT 3 5 5,1 heart failure II IV patients; Double-blind, randomized study vs. placebo JIKEI HEART 6 3,82 Japanese patients on conventional treatment for hypertension, coronary heart disease, heart failure or combination of these; Multicenter, randomized, controlled trial comparing addition of valsartan vs. non-arb to conventional treatment No difference in composite of cardiac mortality and morbidity (primary) 23% new-onset diabetes No difference vs. captopril in all-cause mortality (primary) (valsartan is as effective as standard of care) 13% morbidity and mortality (primary) left ventricular remodeling 37% atrial fibrillation occurrence heart failure signs/symptoms 28% heart failure hospitalization 39% composite CV mortality and morbidity 4% Stroke/transient ischemic attack 47% Hospitalization for heart failure 65% Hospitalization for angina 1 Julius et al. Lancet 24;363:222 31; 2 Pfeffer et al. N Engl J Med 23;349: ; 3 Maggioni et al. Am Heart J 25;149:548 57; 4 Wong et al. J Am Coll Cardiol 22;4:97 5; 5 Cohn et al. N Engl J Med 21;345:1667 7; 6 Mochizuki et al. Lancet 27;369:1431 9

24 Valsartan: Wealth of CV Protection Data MARVAL patients with T2D + microalbuminuria ± HTN: Multicenter, randomized, double-blind, active-controlled study vs. amlodipine Val-MARC 2 1,668 stage 2 HTN patients: Multicenter, open-label, randomized study vs valsartan/hydrochlorothiazide (HCTZ) Primary endpoint: % change in urinary albumin excretion rate (UAER) over 6 months 44% in UAER vs. baseline with valsartan vs. 8% with amlodipine 15.4% between-group difference favoring valsartan in patients returning to normoalbuminuria Primary endpoints: change in systolic BP and in high-sensitivity C-reactive protein (hscrp) between randomization and Week 6 Drop in systolic BP was greater with the combination 13% hscrp (marker of inflammation) vs. valsartan/hctz 1 Viberti et al. Circulation 22;16: Ridker et al. Hypertension 26;48:73 9

25 Valsartan provides Protection across the cardio-renal-metabolic continuum

26 A combined version of the CVD and renal pathophysiological continuum. Adapted from Dzau et al. Circulation 26;114: DIOVAN Provides PROTECTION Across the Cardiac Continuum Reduces AF Reduces stroke 6 Reduces LVMI Coronary thrombosis Myocardial infarction Stroke Remodeling Reduces restenosis Reduces CHF hospitalization Reduces hscrp Atherosclerosis LVH CHF Reduces CV mortality Risk factors Hypertension Dyslipidemia Diabetes Obesity Smoking Endstage heart disease 26

27 A combined version of the CVD and renal pathophysiological continuum. Adapted from Dzau et al. Circulation 26;114: DIOVAN Provides PROTECTION Across the Renal Continuum Reduces endothelial cell activation Microalbuminuria Reduces microalbuminuria Reduces proteinuria Endothelial dysfunction Proteinuria Reduces vascular resistance Reduces HOMA-IR Risk factors Hypertension Dyslipidemia Diabetes Obesity Smoking End-stage renal disease 27

28 DIOVAN Provides PROTECTION Across the Metabolic Continuum Reduces hs-crp Increases adiponectin New onset diabetes Reduces risk of NOD Inhibits platelet aggregation Reduces triglyceride Reduces fasting insulin Pre diabetes 3 studies 33 studies 5 studies in diabetes 9 studies Diabetes Reduces UAER / UPER Reduces LDL-C & TC Reduces AGE Risk factors Hypertension Dyslipidemia Obesity Endothelial dysfunction 4 studies 12 studies Diabetic complic a-tions 28

29 Supported by:- >9 studies >7 patients >4 countries >45 endpoints >7 mn patient-years exp. Reduces endothelial cell activation 2 DIOVAN Provides PROTECTION Across the Cardio-Renal-Metabolic Continuum Reduces risk of new onset diabetes 3 Reduces atrial fibrillation 4 Coronary thrombosis Reduces microalbuminuria 5 CV Continuum Myocardial infarction Stroke Renal Continuum Reduces stroke 6 Reduces triglycerides 7 Remodeling DIOVAN: #1 AHY globally Reduces proteinuria 8 Reduces CHF hospitalization 9 Reduces LV mass index 1 Atherosclerosis LVH Endothelial dysfunction Prediabetes Microalbumiuria Diabetes Continuum New Onset Diabetes Diabetes Proteinuria CHF Reduces CV mortality 1 Risk factors Hypertension Dyslipidemia Diabetes Obesity Smoking Risk factors Hypertension Dyslipidemia Diabetes Obesity Smoking Risk factors Hypertension Dyslipidemia Obesity Endothelial dysfunction A combined version of the CVD and renal pathophysiological continuum. Adapted from Dzau et al. Circulation 26;114: Diabetic Complication (Nephropathy Neuropathy Retinopathy) End stage renal disease (ESRD) End-stage heart disease 29 1.Thurmann Circulation 1998; 2.Nomura Throm Res 26; 3.Julius Lancet 24; 4.Maggioni AHJ 25; 5.Viberti Circulation 22; 6.Mochizuki Lancet 27; 7.Saiki Diab Resear 26; 8.Hollenberg J Hyper 27; 9.Weber Lancet 24; 1.Julius Hypertension 26

30 Diovan reduces LVMI and CRP in patients with HTN and LVH Mean LVMI change (%) from baseline at 6 months Results from an 6-month study in 1 Japanese patients with uncontrolled HTN # and LVH DIOVAN 8 mg od (n=5) -16.* Amlodipine 5 mg od (n=5) -1.2 Mean change of CRP levels (mg/dl) from baseline at 6 months DIOVAN 8 mg od (n=5) -.14* Amlodipine 5 mg od (n=5) # SBP/DBP >14/9 mmhg, patients completing the study; *p<.1 vs. amlodipine; LVMI=Left ventricular mass index, CRP=C-reactive protein, LVH=Left ventricular hypertrophy Yasunari et al. JACC 24;43:

31 VALUE-AF : Diovan reduces the risk of new onset AF DIOVAN significantly reduces the risk of new-onset AF by 16% and persistent AF by 32% compared with amlodipine 16% risk reduction J Hypertens 28, 26:43 411

32 Val-HeFT: Improves CV Outcomes* in CHF Results from a 23-month mean follow-up study in 5,1 patients with CHF on standard therapy (Val-HeFT study) 1 Event-free probability (%) DIOVAN (n=2,511) Placebo (n=2,499) RR=.87; 97.5% CI: Time (months) 13.2% risk reduction *Combined 1 endpoint: all-cause mortality, cardiac arrest with resuscitation, hospitalization for worsening HF, or therapy with intravenous inotropes or vasodilators; p=.9 vs. placebo; 1 endpoint of mortality was not significantly different between valsartan and placebo; DIOVAN regimen started at 4 mg bid after placebo run-in, doubled every 2 weeks to target 16 mg bid Cohn et. al. N Engl J Med 21;345:

33 JIKEI HEART: Valsartan-based therapy improved outcomes in patients with hypertension, coronary heart disease and/or heart failure CV mortality and morbidity Stroke/TIA Hospitalisation for HF Hospitalisation for angina Risk reduction (%) * p=.2 4* p=.28 47* p= * p=.1 8 TIA = transient ischemic attack *With DIOVAN-based therapy compared with non-arb therapy; primary endpoint Mochizuki et al. Lancet 27;369:1431 9

34 Diovan improves endothelial function vs Amlodipine Single-blind, crossover study of patients with hypertension (n=12): 8 weeks treatment Change in forearm blood flow (%) in response to ACh stimulation DIOVAN 13 Amlodipine Endothelial function assessed by acetylcholine (ACh) intra-arterial infusion to stimulate endothelium-dependent nitric oxide release p<.5 DIOVAN vs baseline Tzemos et al. Am J Hypertens 21;14:A66 A67

35 MARVAL: Diovan provides regression to normoalbuminuria in T2D patients vs. Amlodipine Results from a 24-week study in 291 patients with type 2 diabetes and microalbuminuria (MARVAL study) Change in UAER (%) DIOVAN 8-16 mg # (n=146) Amlodipine 5-1 mg # (n=145) -8% Patients regressing to normoalbuminuria (%) %* 15% %* DIOVAN 8-16 mg # (n=146) Amlodipine 5-1 mg # (n=145) Patients completing the study; Median UAER 2-2 μg/min; *p<.1 vs. amlodipine; # DIOVAN 8 mg and amlodipine 5 mg doses doubled at 4 weeks if BP uncontrolled (BP >135/85 mmhg); bendrofluazide 12.5 mg and doxazosin added as needed at 8 and 12 weeks, respectively, if BP still uncontrolled; UAER=Urinary albumin excretion rate Viberti G et al. Circulation. 22;16:

36 MARVAL 2 study: Study design Design of a 24-week study in patients with T2D, albuminuria, elevated BP and PP (MARVAL 2 study) Randomization Screening/ moxonidine* run-in phase DIOVAN 16 mg od DIOVAN 16 + HCTZ + 25 mg od DIOVAN 16 + HCTZ 25 mg od ± moxonidine* Amlodipine 5 mg od Amlodipine 5 mg tid Amlodipine 5 mg tid ± moxonidine* Visit Week UAER 2 µg/min; SBP>14 mmhg; PP=pulse pressure 6 mmhg *moxinidine to maximum 4 μg for treated patients; force-titration of HCTZ in both arms if no tolerability issues Viberti et al. Abstract accepted by EASD & ASN 27

37 MARVAL 2 study: Valsartan/HCTZ significantly reduce AER in type 2 DM patients Change of AER after 24 weeks treatment (%) * -35% 24% Amlodipine 5 mg tid (n=65) VAL/HCTZ 16/25 mg od (n=66) *p=.4 Viberti et al. Abstract accepted by EASD & ASN 27

38 MARVAL 2 study: Valsartan improves central arterial stiffness significantly in type 2 DM patients Mean Ao PWV (m/s) Between treatment comparison for change from baseline in mean Ao-PWV at 24 weeks showed a significantly greater reduction of -1.1 m/s for Val/HCTZ compared with amlodipine (p=.1) VAL/HCTZ Baseline After 24 weeks Amlodipine This magnitude of Ao-PWV difference translates to approximately 1 years of vascular aging Viberti et al. Abstract accepted by EASD & ASN 27

39 SMART: Diovan-based regimen reduces microalbuminuria in patients with T2D Results from a 24-week study in 15 treated and untreated Japanese patients with HTN # and T2D (SMART study) 2 Mean changes in ACR (%) % -32% p< DIOVAN-based regimen 8-16 mg od (n=73) Amlodipine-based regimen 5-1 mg od (n=77) Time (months) # treated (BP 13/8 and 18/11 mmhg) or untreated HTN (BP 14/9 and 18/13 mmhg) Patients on antihypertensive medication except ARB or CCB, DIOVAN 8 mg and amlodipine 1 mg doses doubled at 4 weeks and openlabel addition of antihypertensive medications (except ACEi) at 8 weeks if SBP/DBP>13/8; ACR=albumin-creatinine ratio; T2D=Type 2 diabetes SMART Group. Diabetes Care 27;3:

40 DROP: Diovan reduces UAER in patients witht2d, HTN and Albuminuria Results from a 3-week study in 391 patients with T2D, HTN and albuminuria (DROP study) Change in UAER from baseline (%) DIOVAN 16 mg (n=13) -25% DIOVAN 32 mg (n=13) -51%* DIOVAN 64 mg (n=131) -49%* Patients regressing to normoalbuminuria (%) % DIOVAN 16 mg (n=13) 19% DIOVAN 32 mg (n=13) 24%** DIOVAN 64 mg (n=131) UAER 2-7 μg/min; *p<.1 vs.16 mg (3 weeks vs. 4 weeks); **p<.5 vs. 16 mg; T2D=Type 2 diabetes mellitus; UAER=Urinary albumin excretion rate Hollenberg et al J Hypertens 27,25:

41 Diovan significantly increases Adiponectin in obese patients with HTN Results from a 12-week study in 72 obese patients with mild-to-moderate HTN # 2 Adiponectin (ng/ml) Leptin (ng/ml) Resistin (ng/ml) HOMA-IR Change in plasma levels from baseline to 12 weeks * * * -.2 DIOVAN 16 mg/day (n=36) Amlodipine 1 mg/day (n=36) * BMI 3kg/m 2 ; # DBP >9 mmhg and <11 mmhg; *p<.5 vs. baseline Fogari et al. Am J Hypertens 25;18:196A (abstract P-521)

42 Diovan enhances Adipocyte production of Lipoprotein Lipase and reduces Triglycerides Results from a 12-week study in 55 Japanese patients with T2D and HTN Change in parameter from baseline to week 12 (mmol/l) TG.3 p=.6.6 HDL-C -.4 p=.6 LDL-C p=.93 DIOVAN-based regimen # (n=29) Control (n=26) Change in parameter from baseline to week 12 (ng/dl) LPL p= Sitting DBP 9 mmhg and/or sitting SBP 14 mmhg; # DIOVAN 8 od added to medication taken >2 months (antihypertensives anti-hyperlipidemics and/or anti-diabetics); control group did not receive additional antihypertensive agents; T2D=Type 2 Diabetes HDL-C=High-density lipoprotein cholesterol; LDL-C=Low-density lipoprotein cholesterol LPL=Lipoprotein lipase; TG=Triglycerides

43 Diovan significantly reduces the risk of new-onset diabetes compared to Amlodipine Results from a 4.2-year mean follow-up study in 15,245 patients with HTN # and high risk of cardiac events (VALUE study) Rate of new-onset diabetes (%) % DIOVAN regimen** (n=7,649) 16.4% Amlodipine regimen** (n=7,596) 23% risk reduction of NOD* # Treated (SBP/DBP upper limit 21/115 mmhg) or untreated HTN (sitting SBP=16-21 and sitting DBP<115 mmhg), ITT population;*diovan vs. amlodipine, p<.1, NOD=new-onset diabetes; **DIOVAN 8 mg or amlodipine 5 mg/day; up-titration to valsartan/hctz 16/25 mg or amlodipine/hctz 1/25 mg; additional therapy (except ARBs) allowed at month 4 Julius et al. Lancet 24;363:

44 Diovan reduces the risk of new-onset diabetes better than Losartan Results from a retrospective cohort study # in 14,588 patients with HTN, initiating DIOVAN or losartan monotherapy between January 1998 and March 25 Risk of new-onset diabetes per 1, patient-years % risk reduction* DIOVAN (n=9,968) Losartan (n=4,62) # Using a US healthcare claims database; *Unadjusted risk, valsartan vs. losartan (95% CI: ); new-onset diabetes identified as 2 outpatient diagnoses ( 7 days apart), 1 inpatient diagnosis, or 1 prescriptions for antidiabetic medication Weycker et al. J Clin Hypertens 27; Suppl A (9):P-448

45 Direct Renin Inhibitor in the near future

46 Direct renin inhibitors uniquely suppress Ang I, Ang II and PRA Direct renin inhibitor Angiotensinogen Renin Ang I Non ACE pathways Feedback Loop Ang II AT 1 Receptor ACEIs ARBs ACE ACEI ARB Rasilez Ang I Ang II Renin PRA Azizi M et al. 26

47 Summary Diovan 16mg, the gold standard treatment for HTN with T2DM Powerful evidence of BP efficacy - Co-Diovan and Exforge are the best combination to get BP goal Protection across the cardio-renal-metabolic continuum Direct Renin Inhibitor in the near future